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Results in Journal Tumor Biology: 7,643

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Published: 9 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317732181

Abstract:
Acute myeloid leukemia is characterized by its high biological and clinical heterogeneity, which represents an important barrier for a precise disease classification and accurate therapy. While epigenetic aberrations play a pivotal role in acute myeloid leukemia pathophysiology, molecular signatures such as change in the DNA methylation patterns and genetic mutations in enzymes needed to the methylation process can also be helpful for classifying acute myeloid leukemia. Our study aims to unveil the relevance of DNMT3A and TET2 genes in global and specific methylation patterns in acute myeloid leukemia. Peripheral blood samples from 110 untreated patients with acute myeloid leukemia and 15 healthy control individuals were collected. Global 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA from peripheral blood leukocytes were measured by using the MethylFlashTM Quantification kits. DNMT3A and TET2 expression levels were evaluated by real-time quantitative polymerase chain reaction. The R882A hotspot of DNMT3A and exons 6–10 of TET2 were amplified by polymerase chain reaction and sequenced using the Sanger method. Methylation patterns of 16 gene promoters were evaluated by pyrosequencing after treating DNA with sodium bisulfite, and their transcriptional products were measured by real-time quantitative polymerase chain reaction.Here, we demonstrate altered levels of 5-methylcytosine and 5-hydroxymethylcytosine and highly variable transcript levels of DNMT3A and TET2 in peripheral blood leukocytes from acute myeloid leukemia patients. We found a mutation prevalence of 2.7% for DNMT3A and 11.8% for TET2 in the Mexican population with this disease. The average overall survival of acute myeloid leukemia patients with DNMT3A mutations was only 4 months. In addition, we showed that mutations in DNMT3A and TET2 may cause irregular DNA methylation patterns and transcriptional expression levels in 16 genes known to be involved in acute myeloid leukemia pathogenesis. Our findings suggest that alterations in DNMT3A and TET2 may be associated with acute myeloid leukemia prognosis. Furthermore, alterations in these enzymes affect normal methylation patterns in acute myeloid leukemia– specific genes, which in turn, may influence patient survival.
Published: 9 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317733984

Abstract:
Epithelial ovarian neoplasms are a heterogeneous group of tumors, including various malignancies with distinct clinicopathologic and molecular features. Mutations in BRAF and KRAS genes are the most frequent genetic aberrations found in low-grade serous ovarian carcinomas and serous and mucinous borderline tumors. Implementation of targeted therapeutic strategies requires access to highly specific and highly sensitive diagnostic tests for rapid determination of mutation status. One candidate for such test is fully integrated, real-time polymerase chain reaction–based Idylla™ system for quick and simple detection of KRAS mutations in formaldehyde fixed-paraffin embedded tumor samples. The primary aim of this study was to verify whether fully integrated real-time polymerase chain reaction–based Idylla system may be useful in determination of KRAS mutation status in patients with borderline ovarian tumors and low-grade ovarian carcinomas. The study included tissue specimens from 37 patients with histopathologically verified ovarian masses, operated on at the Department of Obstetrics and Gynecology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz (Poland) between January 2009 and June 2012. Based on histopathological examination of surgical specimens, 30 lesions were classified as low-grade ovarian carcinomas and 7 as borderline ovarian tumors. Seven patients examined with Idylla KRAS Mutation Test tested positive for KRAS mutation. No statistically significant association was found between the incidence of KRAS mutations and histopathological type of ovarian tumors. Mean survival of the study subjects was 48.51 months (range 3–60 months). Presence of KRAS mutation did not exert a significant effect on the duration of survival in our series. Our findings suggest that Idylla KRAS Mutation Test may be a useful tool for rapid detection of KRAS mutations in ovarian tumor tissue.
Seyed Morteza Bagheri, , , Mohammad Reza Ayoubpour
Published: 9 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317733144

Abstract:
Our objective was to evaluate the differences between tumoral vascular pattern of renal cell carcinoma and fat-poor angiomyolipoma by contrast-enhanced computed tomography. All included patients had a definitive pathological diagnosis of either angiomyolipoma or renal cell carcinoma, and then the contrast-enhanced computed tomography images of these patients were evaluated. The patients who had visible prominent vessels in cross-sectional imaging were selected. The tumor vascular pattern (prominent (>2 mm) intratumoral and peritumoral vessels), density, and diameter of the vessels in renal cell carcinoma and fat-poor angiomyolipoma were evaluated. All cases (n = 12) with fat-poor angiomyolipoma were found to have intratumoral vessels and all cases (n = 36) with clear cell renal cell carcinoma were found to have peritumoral vessels. There was no significant correlation detected between the diameter of tumor and the density as well as diameter of the vessels. In conclusion, the evaluation of the vascular pattern using contrast enhancement contrast-enhanced computed tomography may provide important information that is useful in helping accurate differential diagnosis of fat-poor angiomyolipoma or renal cell carcinoma preoperatively.
Janneta Tcherkassova, Sergei Tsurkan, Galina Smirnova, Julia Borisova, Ricardo Moro,
Published: 9 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317734815

Abstract:
The main objective of this study was the characterization of preclinical tumor models based on their expression of alpha-fetoprotein receptor (RECAF) for targeting cancer cells with a new non-covalent complex (AIMPILA) containing alpha-fetoprotein as the carrier and Atractyloside as an apoptosis-inducing agent. For that purpose, we measured the amount of RECAF in the homogenates of the grafted tumors T47D and SW620 and in HepG2 cell extracts. We also determined the alpha-fetoprotein binding specificity of the targeting drug AIMPILA using a solid-phase chemiluminescent assay with AIMPILA-Acrdidinium. We found that RECAF is practically absent from healthy mice tissues (100 Units/mg) where in malignant cells, the amount of alpha-fetoprotein receptors follows this order: T47D (9152 Units/mg) > HepG2 (4865 Units/mg) > SW620 (2839 Units/mg). This agrees with our findings regarding AIMPILA-induced tumor growth inhibition (T47D (T/C = 22%) > HepG2 (T/C = 51%) > SW620 (T/C = 70%), where T/C is the ratio of tumor volume in treated vs control animals). Our results demonstrate that the therapeutic response to the targeting drug AIMPILA strongly depends on the RECAF expression by human tumors and confirms the choice of the tumor models used for an AIMPILA preclinical study.
Daichiro Fujiwara, Masanobu Tsubaki, Tomoya Takeda, Yoshika Tomonari, Yu-Ichi Koumoto, Katsuhiko Sakaguchi,
Published: 9 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317734947

Abstract:
Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal–regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal–regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal–regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.
Natasha Hodgkinson, ,
Published: 9 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317734691

Abstract:
Colorectal cancer is commonly treated by tumour resection, as chemotherapy and radiation have proven to be less effective, especially if the tumour has metastasized. Resistance to therapies occurs in almost all patients with colorectal cancer, especially in those with metastatic tumours. Cancer stem cells have the ability to self-renew, and their slow rate of cycling enhances resistance to treatment and increases the likelihood of tumour recurrence. Most metastatic tumours are unable to be surgically removed, thus creating a need for treatment modalities that target cancers directly and destroy cancer stem cells. Photodynamic therapy involves a photosensitizer that when exposed to a light source of a particular wavelength becomes excited and produces a form of oxygen that kills cancer cells. Photodynamic therapy is currently being investigated as a treatment modality for colorectal cancer, and new studies are exploring enhancing photodynamic therapy efficacy with the aid of drug carriers and immune conjugates. These modifications could prove effective in targeting cancer stem cells that are thought to be resistant to photodynamic therapy. In order for photodynamic therapy to be an effective treatment in colorectal cancer, it requires treatment of both primary tumours and the metastatic secondary disease that is caused by colon cancer stem cells. This review focuses on current photodynamic therapy treatments available for colorectal cancer and highlights proposed actively targeted photosynthetic drug uptake mechanisms specifically mediated towards colon cancer stem cells, as well as identify the gaps in research which need to be investigated in order to develop a combinative targeted photodynamic therapy regime that can effectively control colorectal cancer primary and metastatic tumour growth by eliminating colon cancer stem cells.
Pavani Upendram, Shubhi Sahni, Khaliq Mohiuddin, Subhadra Poornima, Bhanumathy Gourishankar, Kiran Kumar Vattam, Pavani Boddala, E Jayashankar, Shakera Mohiuddin, Vasundhara Kamineni, et al.
Published: 9 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317698363

Abstract:
Cervical carcinoma is a frequent malignancy in developing countries despite being a preventable disease. For the first time, four screening tests were used simultaneously for identifying women with a risk of developing cervical cancer, to help clinicians and policy makers to implement the best strategy for reducing the burden of this disease. Women visiting a hospital in India were enrolled after institutional ethics clearance and informed consent. Visual inspection using acetic acid and Pap smear tests were performed on 2683 women, and 104 had abnormal cytology: atypical squamous cells of undetermined significance (n = 29), low-grade squamous intraepithelial lesion (n = 41), high-grade squamous intraepithelial lesion (n = 17), and squamous cell carcinoma (n = 17). These and 96 samples, with normal cytology, were subjected to high-risk human papilloma virus testing and fluorescent in situ hybridization evaluation. Women with abnormal cytology were followed for 5 years and evaluated with colposcopy-guided biopsy. Three accepted methods of screening and one novel fluorescent in situ hybridization assay were carried out in 200 cases. Cutoffs for fluorescent in situ hybridization were established. The screening methods had 88%–96% negative predictive value, while positive predictive value was low (20%) for visual inspection using acetic acid, 47% for fluorescent in situ hybridization, 56% for high-risk human papilloma virus, and 73% for combined high-risk human papilloma virus and fluorescent in situ hybridization. Combined high-risk human papilloma virus and fluorescent in situ hybridization had 94% sensitivity, specificity, and negative predictive value, suggesting that simultaneous screening with these two tests is appropriate for identifying women progressing to cervical cancer and not visual inspection using acetic acid, which has low positive predictive value and Pap cytology which requires to be repeated. Policy makers and clinicians can assess feasibility of incorporating this screening strategy to prevent cervical cancer.
Chae Hwa Kwon, Hye Ji Park, Yuri Choi, Yeo Jin Won, Seon Jin Lee, Do Youn Park
Published: 5 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317722070

Abstract:
The transcription factor TWIST has been reported to play an important role in tumor progression as well as resistance to anti-cancer drugs. However, the role of TWIST in gastric cancer and the molecular mechanisms by which this protein elicits drug resistance remain poorly understood. We transfected gastric cancer cell lines with lentiviral vector to generate TWIST-overexpressing stable cell lines. Our study showed that overexpression of TWIST not only increased cell migration and invasion but also induced resistance to the anti-cancer drug paclitaxel in gastric cancer. Paclitaxel increased gastric cancer cell death in dose-dependent manner; this was decreased following TWIST overexpression. Furthermore, treatment with paclitaxel decreased Akt phosphorylation and Bcl-2 expression, whereas these effects were suppressed by TWIST overexpression. Treatment of cells with Akt inhibitor or small interfering RNA targeting for Bcl-2 led to increased paclitaxel-induced cell death, indicating that TWIST elicits resistance to paclitaxel via the regulation of the Akt and Bcl-2 pathway. Our results suggest an underlying mechanism for TWIST-mediated paclitaxel resistance and indicate that TWIST represents a potential target for overcoming paclitaxel resistance in gastric cancer cells.
Published: 5 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317720643

Abstract:
The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines. Despite a low frequency of SHB gene mutations, many tumors overexpressed SHB mRNA compared with normal myeloid blood cells. AML patients with tumors expressing low SHB mRNA displayed longer survival times. A subgroup of AML exhibiting a favorable prognosis, acute promyelocytic leukemia (APL) with a PMLRARA translocation, expressed less SHB mRNA than AML tumors in general. When examining genes co-expressed with SHB in AML tumors, four other genes (PAX5, HDAC7, BCORL1, TET1) related to leukemia were identified. A network consisting of these genes plus SHB was identified that relates to certain phenotypic characteristics, such as immune cell, vascular and apoptotic features. SHB knockdown in the APL PMLRARA cell line NB4 and the monocyte/macrophage cell line MM6 adversely affected proliferation, linking SHB gene expression to tumor cell expansion and consequently to patient survival. It is concluded that tumor SHB gene expression relates to AML survival and its subgroup APL. Moreover, this gene is included in a network of genes that plays a role for an AML phenotype exhibiting certain immune cell, vascular and apoptotic characteristics.
Si Hyoung Kim, Jun Goo Kang, , Sung-Hee Ihm, , Hyung Joon Yoo, Seong Jin Lee
Published: 5 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317722068

Abstract:
The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index. Gemigliptin led to cell death in conjunction with overexpression of the phosphorylated protein levels of Akt, extracellular signal–regulated kinase 1/2, and adenosine monophosphate–activated protein kinase. In gemigliptin-treated cells, wortmannin augmented cell death, whereas AZD6244 and compound C did not affect cell survival. Wortmannin decreased phosphorylated adenosine monophosphate–activated protein kinase protein levels, and AZD6244 increased phosphorylated Akt protein levels. Meanwhile, cotreatment of both gemigliptin and AUY922, compared with treatment of AUY922 alone, potentiated cell death. All the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of gemigliptin with AUY922. In treatment of both gemigliptin and AUY922, compared with AUY922 alone, the protein levels of total and phosphorylated Akt, phosphorylated extracellular signal–regulated kinase 1/2, and phosphorylated adenosine monophosphate–activated protein kinase increased without alteration in those of total extracellular signal–regulated kinase 1/2 and total adenosine monophosphate–activated protein kinase. The percentage of apoptotic cells increased. The protein levels of Bax and cleaved poly (ADP-ribose) polymerase increased, whereas Bcl2 protein levels were unchanged, resulting in increment of Bax/Bcl2 ratio. Transfection of Bax small interfering RNA did not cause any variation in cell viability, the percentage of viable cells and cytotoxic activity. Our results demonstrate that gemigliptin exerts a cytotoxic activity with concomitant alterations in expression of Akt, extracellular signal–regulated kinase 1/2, and adenosine monophosphate–activated protein kinase in thyroid carcinoma cells. Furthermore, gemigliptin synergizes with AUY922 in induction of cytotoxicity via regulation of Akt, extracellular signal–regulated kinase 1/2, and adenosine monophosphate–activated protein kinase as well as involvement of Bcl2 family proteins in thyroid carcinoma cells.
Published: 4 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317716501

Abstract:
Multidrug resistance in tumor cells is still a big challenge in cancer treatment. Therefore, identification ofsafe and effective multidrug resistance–reversing compounds with minimal side effects is an important approach in cancer treatment. Here, we investigated the role and potential mechanisms of peroxisome proliferator–activated receptor γ in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effect of doxorubicin on cell viability following treatment with balaglitazone, a peroxisome proliferator–activated receptor γ agonist, was evaluated using trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Rhodamine123 assay was used to determine the activity of two common drug efflux membrane transporters P-glycoprotein and multidrug resistance protein-1. P-glycoprotein, multidrug resistance protein-1, and phosphatase and tensin homolog deleted on chromosome 10 messenger RNA/protein expression levels were measured by quantitative reverse transcription polymerase chain reaction and western blot analyses. Annexin V/fluorescein isothiocyanate assay was also employed to investigate apoptosis. We showed that balaglitazone considerably enhanced the cytotoxicity of doxorubicin. Balaglitazone also significantly downregulated P-glycoprotein expression and activity in K562/DOX cells and reduced multidrug resistance through elevation of intracellular doxorubicin in cells. Furthermore, upon balaglitazone treatment, phosphatase and tensin homolog deleted on chromosome 10 expression could be restored in K562/DOX cells in a peroxisome proliferator–activated receptor γ–dependent manner. We concluded that peroxisome proliferator–activated receptor γ agonist, balaglitazone, could reverse multidrug resistance by inducing phosphatase and tensin homolog deleted on chromosome 10 and peroxisome proliferator–activated receptor/ phosphatase and tensin homolog deleted on chromosome 10 signaling pathway. These findings suggest that targeting peroxisome proliferator–activated receptor γ might serve as an effective approach for circumventing multidrug resistance in chemotherapy of cancerous patients.
Rui Hou, Yanjun Xu, Qijie Lu, Yang Zhang, Bing Hu
Published: 4 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317719275

Abstract:
Angiogenesis plays an important role in tumor growth, invasiveness, and metastasis. It is well established that prostate cancer is exposed to fluctuating oxygen tensions and both acute and chronic hypoxia exist, and these conditions can upregulate angiogenesis-associated proteins such as hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A. Low-frequency low-intensity ultrasound with microbubbles can induce obvious microvessel damage in tumors, cause cell necrosis or apoptosis. However, there is no information about whether the blocking blood effect of low-frequency low-intensity ultrasound with microbubbles has an influence on hypoxia environment of prostate cancer. Therefore, we investigated the impact of different low-frequency low-intensity ultrasound with microbubbles radiation times on prostate tumors, observed the change in the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A protein levels, as well as cell proliferation, apoptosis, and tumor volume. The results indicated that as the radiation was repeated four times on each treatment day, the effects of interruption were durable, the cell proliferation was inhibited, and apoptosis was promoted, and the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were lower in the treatment group than in the control group. When the radiation was carried out once per treatment day, the hypoxia response was stimulated, the hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A expression levels were higher compared with the control group, and cell proliferation was promoted. In addition, the tumor volume increased obviously in the hypoxia-stimulated group, whereas tumors grew slowly in the hypoxia-suppressed group. The results of this work demonstrated that under the same conditions, different radiation times of low-frequency low-intensity ultrasound with microbubbles affect the hypoxia response differently, and the effect at least partly stimulates or inhibits tumor growth.
Dongjie Yao, Hujun Cui, Shufen Zhou, Ling Guo
Published: 4 October 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317712443

Abstract:
Lung cancer is one of the most severe threats with the highest mortality rate to humans in the world. Recently, morin has been reported to have anti-tumor properties observed in several types of cancers. However, its mechanism is still unclear. We assessed the influences of morin on cell viability, colony formation, and migration ability of A549 and employed microRNA array to identify the microRNAs affected by morin. We found that morin-treated A549 cells showed statistically decreased cell viability, colony formation, and migration rate when comparing with the dimethyl sulfoxide–treated cells. Microarray results showed that with the treatment of morin, the expression level of miR-135b significantly reduced compared the control group, suggesting that morin may exert its anti-cancer property by suppressing the expression of miR-135b. In addition, we found a potential binding site of miR-135b within 3′ untranslated region of CCNG2-encoding cyclin homolog cyclin-G2. We evidenced that miR-135b directly targets CCNG2, which could be a potential biomarker of lung cancer prognosis. Morin exerts its anti-tumor function via downregulating the expression of miR-135b that directly targets and represses CCNG2.
, , Bin Peng, Chang-Ning Wang, Qing Wang, Zhuan Bian
Published: 1 January 2006
Tumor Biology, Volume 27, pp 175-180; https://doi.org/10.1159/000093054

Abstract:
Odontogenic keratocysts (OKC) are aggressive lesions in the jaws, which can occur as isolated cases or in association with nevoid basal cell carcinoma syndrome (NBCCS). Mutations on PTCH gene have been identified in patients with NBCCS. It was hypothesized that PTCH mutations may be causative in isolated OKC. This study aims to investigate germline mutations of PTCH in families with OKC and NBCCS. Three Chinese families with OKC and NBCCS were enrolled in the study. The diagnosis was based on examination and medical history. Mutation analysis was performed by amplifying all exons of PTCH and sequencing the products. One family with isolated OKC (family 1) and the other two families with NBCCS were diagnosed. Three novel germline mutations in PTCH were identified, including a missense mutation (p.S1089 > P) in family 1, a nonsense mutation (p.Q160X) in family 2 and a de novo mutation (c.768_777delGACAAACTTC) in family 3. It is proposed that isolated OKC can be inherited in an autosomal dominant mode. The results suggest that germline mutations on PTCH can cause isolated OKC, and that the PTCH gene responsible for NBCCS plays an important role in the formation of OKCs even when they are not syndrome-related.
, Thannaporn Kittisiam, Sujitra Tanvanich
Published: 26 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317725834

Abstract:
The study was to evaluate the prevalence of mismatch repair gene defect among Thai patients with endometrial cancer and its association with clinico-pathological features and survivals. The formalin fixed paraffin-embedded blocks of EMC tissue from hysterectomy specimens of patients having surgery in our institution between 1 Jan 1995 and 31 December 2016 were assessed for the immunohistochemical expression of 4 mismatch repair proteins (MLH1, PMS, MSH2, MSH 6). Mismatch repair gene defect was determined by a negative expression of at least 1 protein. Among 385 EMC patients included in the study, mean age was 57.3 ± 10.8 years with 62.3% aged ⩽ 60 years. The most frequent mismatch repair gene defect was MSH6 (38.7%), followed by PMS2 (34.3%), MLH1 (33.2%), and MSH2 (16.4%). Overall, 55.1% showed negative expression of at least one protein. We found significantly higher mismatch repair gene defect in patients aged ⩽ 60 years, with early stage disease, and negative lymph node status than the other comparative groups: 59.2% vs 48.3% for age (p = 0.037), 58.2% vs 45.2% (p = 0.027) for stage, and 58.1% vs 44.6% (p = 0.048) for nodal status. The 5-year progression-free survival, overall survival, and endometrial cancer-specific survival of patients with mismatch repair gene defect was higher than those without gene defect. The differences were statistically significant for only progression-free survival and endometrial cancer-specific survival: 87.7% (95% confidence interval = 83.0%–92.4%) vs 81.5% (95% confidence interval = 75.4%–87.6%) (p = 0.049) for progression-free survival and 91.0% (95% confidence interval = 86.9%–95.1%) vs 85.5% (95% confidence interval = 80.0%–91.0%) (p = 0.044) for endometrial cancer-specific survival, respectively. In conclusion, more than half of Thai endometrial cancer patients had mismatch repair gene defect. The patients with mismatch repair gene defect had significantly younger age (⩽ 60 years) and better prognosis in terms of early stage, negative nodal status, and longer survivals.
Ching-Fang Wu, Ching-Tai Lee, Yao-Hung Kuo, Tzu-Haw Chen, Chi-Yang Chang, I-Wei Chang, Wen-Lun Wang
Published: 25 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317725922

Abstract:
Patients with esophageal squamous cell carcinoma have poor survival and high recurrence rate, thus an effective prognostic biomarker is needed. Endothelin-converting enzyme-1 is responsible for biosynthesis of endothelin-1, which promotes growth and invasion of human cancers. The role of endothelin-converting enzyme-1 in esophageal squamous cell carcinoma is still unknown. Therefore, this study investigated the significance of endothelin-converting enzyme-1 expression in esophageal squamous cell carcinoma clinically. We enrolled patients with esophageal squamous cell carcinoma who provided pretreated tumor tissues. Tumor endothelin-converting enzyme-1 expression was evaluated by immunohistochemistry and was defined as either low or high expression. Then we evaluated whether tumor endothelin-converting enzyme-1 expression had any association with clinicopathological findings or predicted survival of patients with esophageal squamous cell carcinoma. Overall, 54 of 99 patients with esophageal squamous cell carcinoma had high tumor endothelin-converting enzyme-1 expression, which was significantly associated with lymph node metastasis ( p = 0.04). In addition, tumor endothelin-converting enzyme-1 expression independently predicted survival of patients with esophageal squamous cell carcinoma, and the 5-year survival was poorer in patients with high tumor endothelin-converting enzyme-1 expression ( p = 0.016). Among patients with locally advanced and potentially resectable esophageal squamous cell carcinoma (stage II and III), 5-year survival was poorer with high tumor endothelin-converting enzyme-1 expression ( p = 0.003). High tumor endothelin-converting enzyme-1 expression also significantly predicted poorer survival of patients in this population. In patients with esophageal squamous cell carcinoma, high tumor endothelin-converting enzyme-1 expression might indicate high tumor invasive property. Therefore, tumor endothelin-converting enzyme-1 expression could be a good biomarker to identify patients with worse survival and higher risks of recurrence, who might benefit from the treatment by endothelin-converting enzyme-1 inhibitor.
, Ludmila Krejcova, , Zbynek Heger, Jan Hrabeta, Tomas Eckschlager, Marie Stiborova, Vojtech Adam, Monika Kratochvilova, , et al.
Published: 25 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317711656

Abstract:
Neuroblastoma represents a malignancy of the sympathetic nervous system characteristic by biological heterogeneity. Thus, chemotherapy exhibits only low effectivity in curing high-risk forms. Previous studies revealed the cytotoxic potential of valproate on neuroblastoma cells. Nevertheless, these studies omitted effects of hypoxia, despite its undeniable tumorigenic role. In this study, we addressed the question whether valproate promotes binding of platinum-based anti-cancer drugs (cisplatin, carboplatin and oxaliplatin) to DNA and role of hypoxia, cellular antioxidant capacity and cisplatin resistance in this process. Following parameters differed significantly when cells were exposed to treatment with platinum-based drugs: elevation of platinum content bound to DNA, elevation of total thiol content, GSH/GSSG ratio, glutathione reductase and peroxidase, superoxide dismutase and elevation of antioxidant capacity. Hypoxia caused a decrease in cytosine/adenine peak, and no changes in platinum–DNA binding properties were observed. After valproate co-treatment, oxidative stress–related parameters and cytosine/adenine peak were only elevated. The amount of platinum bound to DNA was not changed significantly. Valproate is not able to enhance platinum binding to DNA in neuroblastoma cells, neither in case of intrinsic resistance (UKF-NB-4) nor in case of acquired resistance (UKF-NB-4CDDP). Therefore, another mechanism different from increase in platinum binding to DNA should be considered as a synergistic effect of valproate by cisplatin treatment.
, Galina M Kazanskaya, Diana V Kostromskaya, , , Alexandr M Volkov, Vyacheslav V Kobozev, Alexei S Gaitan, ,
Published: 25 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317724282

Abstract:
Neuron-glial antigen 2 (NG2, also known as CSPG4) and hyaluronic acid receptor CD44 are chondroitin sulphate proteoglycans actively involved in brain development and its malignant transformation. Here, we aimed to compare prognostic significances of NG2, CD44 and Ki-67 expression in glioblastoma multiforme patients. Totally, 45 tissue samples and 83 paraffin-embedded tissues for 75 patients were analysed. The prognostic values of the genes were analysed using Kaplan–Meier survival curves. Grade III gliomas showed 2-fold difference in NG2 expression between anaplastic astrocytoma and oligoastrocytoma (10.1 ± 3.5 and 25.5 ± 14.5, respectively). For grade IV gliomas, upregulated NG2 expression (21.0 ± 6.8) was associated with poor glioblastoma multiforme prognosis (overall survival < 12 months) compared with glioblastoma multiforme patients with good prognosis (4.4 ± 3.2; overall survival > 12 months). Multivariate survival analysis using Cox proportional hazards model confirmed that high NG2 expression was associated with low survival of the patients (hazard ratio: 3.43; 95% confidence interval: 1.18–9.93; p = 0.02), whereas age (hazard ratio: 1.02; 95% confidence interval: 0.96–1.09; p = 0.42), tumour resection (hazard ratio: 1.03; 95% confidence interval: 0.98–1.08; p = 0.25) and sex (hazard ratio: 0.62; 95% confidence interval: 0.21–1.86; p = 0.40) did not show significant association with prognosis. Although the positive correlation was shown for NG2 and CD44 expression in the glioblastomas (Pearson coefficient = 0.954), Kaplan–Meier and multivariate survival analyses did not revealed a significant association of the increased CD44 expression (hazard ratio: 2.18; 95% confidence interval: 0.50–9.43; p = 0.30) or high Ki-67 proliferation index (hazard ratio: 1.10; 95% confidence interval: 1.02–1.20; p = 0.02) with the disease prognosis. The results suggest that upregulation of NG2/CSPG4 rather than changes in CD44 or Ki-67 expression is associated with low overall survival in glioblastoma multiforme patients, supporting NG2/CSPG4 as a potential prognostic marker in glioblastoma.
Published: 22 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317706212

Abstract:
Epithelial–mesenchymal transition is a crucial event for metastasis and could be mediated by several pathways such as phosphoinositide 3-kinase/Akt, mitogen-activated protein kinases, as well as many epigenetic regulators. Special AT-rich sequence-binding protein 2 is an epigenetic regulator involved in epithelial–mesenchymal transition and osteoblastic differentiation. It has been reported that the crosstalk between several pathways is responsible for the regulation of epithelial–mesenchymal transition in cancer cells. However, crosstalks between p38 and Akt pathways involved in epithelial–mesenchymal transition are still unknown. We recently reported that there is a crosstalk between p38 and Akt pathways in non-small-cell lung carcinoma cells, and this crosstalk is associated with E-cadherin and special AT-rich sequence-binding protein 2 expressions. Therefore, we aimed to determine whether this crosstalk has a mediator role in the regulation of epithelial–mesenchymal transition in non-small-cell lung carcinoma. Our results showed that inhibition of p38 leads to the disruption of this crosstalk via decreased expression of phosphatase and tensin homolog (PTEN) and subsequently increased activation of Akt in non-small-cell lung carcinoma cells. Then, we found that p38 inhibition upregulated special AT-rich sequence-binding protein 2 expression and reversed epithelial–mesenchymal transition in non-small-cell lung carcinoma cells. Furthermore, special AT-rich sequence-binding protein 2 knockdown abolished the effect of p38 inhibition on epithelial–mesenchymal transition in non-small-cell lung carcinoma cells. In conclusion, our results strongly indicate that the crosstalk between p38 and Akt pathways can determine special AT-rich sequence-binding protein 2 expression and epithelial character of non-small-cell lung carcinoma cells, and special AT-rich sequence-binding protein 2 is a critical epigenetic regulator for epithelial–mesenchymal transition mediated by p38 pathway in non-small-cell lung carcinoma. Our findings will contribute to illuminate the molecular mechanisms of the epithelial–mesenchymal transition process that has a critical significance for lung cancer metastasis.
Published: 22 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317721620

Abstract:
The BRAFV600E-specific inhibitor vemurafenib blocks mitogen-activated protein kinase pathway and induces cell cycle arrest at G0/G1 phase leading to apoptosis of melanomas. To gain an understanding of the dynamics of cell cycle regulation during vemurafenib therapy, we analyzed several vemurafenib-resistant human melanoma sublines derived from BRAFV600E harboring vemurafenib-sensitive parental lines. Vemurafenib provoked G0/G1 phase arrest in parental but not in vemurafenib-resistant sublines. We hypothesized that refractoriness of vemurafenib-resistant sublines to vemurafenib-mediated cell cycle inhibition can be partially rescued by the chromatin modifier suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid promoted G2/M arrest at expense of S phase irrespective of vemurafenib sensitivity. In parental lines, combination of suberoylanilide hydroxamic acid and vemurafenib induced both G0/G1 arrest and apoptosis, whereas in vemurafenib-resistant sublines combination induced G0/G1 as well as G2/M arrest resulting in dramatic cytostasis. Vemurafenib-resistant sublines exhibited extracellular signal–regulated protein kinases 1 and 2 but not AKT and hyperphosphorylation. Gene expression profiling revealed mitogen-activated protein kinase hyperactivation and deregulations of cyclins and cyclin-dependent kinases in vemurafenib-resistant sublines, all of which were reversed by suberoylanilide hydroxamic acid; changes that may explain the cytostatic effects of suberoylanilide hydroxamic acid. These results suggest that unresponsiveness of vemurafenib-resistant sublines to the biological effects of vemurafenib may be amenable by suberoylanilide hydroxamic acid. These in vitro results, while require further investigation, may provide rational biological basis for combination therapy in the management of vemurafenib-resistant melanoma.
Zane Deliu, Timothy Tamas, Juel Chowdhury, Madeeha Aqil, Maaly Bassiony, James A Radosevich
Published: 22 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317723778

Abstract:
Previously, we have shown that A549, a human lung adenocarcinoma, can be adapted to nitric oxide (NO). NO is a nitrogen-based free radical that is synthesized by a family of enzymes known as nitric oxide synthases. NO has been shown to be overexpressed in patient populations of different cancers. In addition, it has been observed that patients who express high levels of nitric oxide synthases tend to have poorer clinical outcomes than those with low levels of expression. The original cell line A549 (parent) and the adapted A549-HNO (high nitric oxide) cell line serve as a useful model system to investigate the role of NO in tumor progression and prognosis. We have previously shown that the A549-HNO-adapted cells grow aggressively when compared to A549-parent cells. Furthermore, we have shown that the A549-HNO-adapted cells exhibit a higher percentage of cell viability when exposed to ultraviolet and X-ray radiation than the A549-parent cells. Cancer patients who develop resistance to one treatment often become resistant to other previously unencountered forms of treatment. This phenomenon is known as cross-tolerance. To determine whether NO is a potential cross-tolerance causing agent, we have expanded our research by conducting parallel studies to a variety of other agents and conditions beyond radiation and ultraviolet exposure. We exposed both cell lines to varying levels of chemotherapeutic drugs (taxol and doxorubicin), temperature, pH, calcium chloride, cadmium chloride, copper chloride, sodium chloride, ferrous chloride, and sodium-R-lipoic acid. Our results show that the A549-HNO cells exhibit greater viability than the A549-parent cells when exposed to each of the various conditions. Therefore, NO is one potential driving force that can make tumor cells exhibit cross-tolerance.
, Paulina Orellana, Cynthia Villarroel, Luis Contreras, , Maki Kobayashi, , Marjorie De la Fuente, Juan Carlos Triviño, Udo Kronberg, et al.
Published: 22 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317724517

Abstract:
Colorectal cancer is a multistep process affecting several signaling pathways including EGFR (epidermal growth factor receptor), a therapeutic target for metastatic disease. Our aim was to characterize the mutational and expression profiles of the EGFR pathway in colorectal tumors and to integrate these results according to five previously defined groups. We screened seven genes for mutations ( KRAS-BRAF-PIK3CA-PIK3R1-AKT1-MAP2K1-PTEN) and six proteins (EGFR-p110α-p85α-PTEN-phosphoAKT-phosphoMEK1) by immunohistochemistry, PTEN deletion, and MSI. At least one mutated gene was observed in 68% of tumors ( KRAS 45%, PIK3CA 21%, BRAF 14%, and PTEN 7%). PTEN deletion was observed in 10.7% of tumors and 19.6% were MSI-High. In all, 54% of tumors showed a high EGFR expression, 48% p110α, 4.4% phosphoAKT, and 22% phosphoMEK1; and 43% showed low PTEN expression and 22% p85α. In total, five groups of tumors were defined based on MSI, BRAF, and KRAS mutations. Three groups gather mainly early-stage tumors, whereas a fourth group is mostly conformed by advanced tumors. We described here that 71.4% of tumors from one group have a mutated PI3K/PTEN pathway, in comparison to other groups having 32%, 27%, and 25%. In addition, the five groups are differentiated by molecular features such as EGFR, p85α, p110α, and PTEN, showing variable expression among tumor groups. In conclusion, alterations on the EGFR pathway were found in a high percentage of colorectal cancer patients. Using the integration of diverse molecular markers, we ratified previous classification in an ethnic group having relevant genetic differences and living in a different environmental background, adding complementary molecular targets related to therapy.
Durval Santos Marques, Jessica Grativol, Rodrigo Alves Da Silva Peres, , Etel Rodrigues Pereira Gimba
Published: 22 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317725442

Abstract:
Osteopontin-c splicing isoform activates ovarian cancer progression features. Imbalanced expression of splicing factors from serine/arginine -rich and heterogeneous ribonucleoproteins families has been correlated with the generation of oncogenic splicing isoforms. Our goal was to investigate whether there is any association between the transcriptional patterns of these splicing factors in ovarian cells and osteopontin-c expression levels. We also aimed to investigate the occurrence of these splicing factors binding sites inside osteopontin exon 4 and adjacent introns. To test associations between osteopontin-c and splicing factors expression patterns, we used an in vitro model in which OVCAR-3 cells overexpressing osteopontin-c (OVCAR-3/OPNc++) presented higher transcriptional levels of osteopontin-c than two other ovarian carcinoma cells (TOV-112D, SKOV-3) and ovarian non-tumoral cell lines (IOSE 364 and IOSE 385). The transcriptional levels of osteopontin-c, serine/arginine-rich, and hnRNP factors were evaluated using real-time polymerase chain reaction. Human Splice Finder software was used to search for putative splicing factor binding sites in osteopontin genomic regions. OVCAR-3/OPNc++ cells presented higher transcriptional levels of hnRNP than serine/arginine-rich when compared to TOV-112D, SKOV-3, and IOSE cells. TOV-112D and SKOV-3 cells also overexpressed hnRNP in relation to serine/arginine-rich transcripts. Putative binding sites for these splicing factors have been predicted on osteopontin exon 4 and their upstream and downstream intronic regions. Our data showed that higher osteopontin-c expression levels are associated with a predominance of hnRNP in relation to serine/arginine-rich transcripts and that osteopontin exon 4 and adjacent intronic sequences contain predicted binding sites for some of these tested splicing factors. In conclusion, differential expression of these splicing factors in ovarian cancer cells could be one of the putative mechanisms leading to aberrant splicing of the osteopontin primary transcript. Future work, aiming to control ovarian cancer progression by downregulating osteopontin-c levels, could include strategies that also regulate heterogeneous ribonucleoproteins and serine/arginine-rich expression levels in order to modulate osteopontin splicing.
Dan Chen, Ding Liu, Zhiwei Chen
Published: 21 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317705762

Abstract:
Osteosarcoma is the most common primary bone cancer in young adults and adolescents. Drug resistance is the main cause leading to therapeutical failure. The mechanisms of drug resistance of osteosarcoma have not been fully understood. Notably, recent researches associate microRNA with drug resistance in osteosarcoma cells, raising the awareness that targeting microRNAs may help in chemotherapy success. In this review, we summarize the mechanisms linking microRNAs to drug resistance and ongoing researches on microRNAs in drug response to osteosarcoma. In addition, the therapeutic potential of microRNAs in chemotherapy will also be discussed.
Farheen Alam, Fatima Mezhal, Hussain EL Hasasna, Vidhya A Nair, Sr Aravind, Maha Saber Ayad, ,
Published: 21 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317714634

Abstract:
This study aimed to analyze the expression of microRNAs in relation to p53 status in breast cancer cells and to delineate the role of Moesin in this axis. We used three isogenic breast carcinoma cell lines MCF7 (with wild-type p53), 1001 (MCF7 with mutated p53), and MCF7-E6 (MCF7 in which p53 function was disrupted). MicroRNA expression was analyzed using microarray analysis and confirmed by real-time polymerase chain reaction. The 1001 clone with mutant p53 showed 22 upregulated and 25 downregulated microRNAs. The predicted targets of these 47 microRNAs were >700 human genes belonging to interesting functional groups such as stem cell development and maintenance. The most significantly downregulated microRNAs in the p53-mutant cell line were from the miR-200 family. We focused on miR-200c which targets many transcripts involved in epithelial-to-mesenchymal transition including Moesin. We found that Moesin was expressed in 1001 but not in its p53 wild-type parental MCF7 consistent with the observed mesenchymal features in the 1001, such as vimentin positivity, E-cadherin negativity, and ZEB1 positivity in addition to the morphological changes. After Moesin silencing, the p53-mutant cells 1001 reverted from mesenchymal-to-epithelial phenotype and showed subtle reduction in migration and invasion and loss of ZEB1 and SNAIL expression. Interestingly, Moesin silencing restored the 1001 sensitivity to Doxorubicin. These results indicate that loss of miR-200c, as a consequence of p53 mutation, can upregulate Moesin oncogene and thus promote carcinogenesis. Moesin may play a role in metastasis and drug resistance of breast cancer.
Ce Shi, Ling Qin, Hongyu Gao, Lina Gu, Chang Yang, Hebing Liu, Tianbo Liu
Published: 7 September 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317714631

Abstract:
NUCKS (nuclear, casein kinase, and cyclin-dependent kinase substrate) is implicated in the tumorigenesis of several human malignancies, but its role in ovarian cancer remains unknown. We aim to investigate NUCKS expression and its clinical significance in ovarian cancer. The messenger RNA expression of NUCKS was determined in normal and malignant ovarian tissues using quantitative polymerase chain reaction assay. Immunohistochemistry was applied to detect the status of NUCKS protein expression in 121 ovarian cancer tissues. NUCKS protein high expression was detected in 52 (43.0%) of 121 patients. NUCKS messenger RNA expression was gradually upregulated in non-metastatic ovarian cancers ( n = 20), metastatic ovarian cancers ( n = 20), and its matched metastatic lesions ( n = 20) in comparison with that in normal ovarian tissues ( n = 10; p < 0.05). Elevated expression of NUCKS in ovarian cancer was associated significantly with the Federation of Gynecology and Obstetrics stage ( p = 0.037), histological grade ( p = 0.003), residual disease ( p = 0.013), lymph node metastasis ( p = 0.002), response to chemotherapy ( p < 0.001), and recurrence ( p = 0.013). In the multivariate Cox analysis, NUCKS expression was an independent prognostic marker for overall survival and disease-free survival in ovarian cancer with p values of <0.001 for both. Especially, NUCKS overexpression had prognostic potential for overall survival and disease-free survival ( p < 0.001 for both) in advanced ovarian cancers and only for disease-free survival in early ovarian cancers ( p = 0.017). Our data suggest that NUCKS overexpression may contribute to progression and poor prognosis in ovarian cancer especially in advanced ovarian cancer.
Roxana Ulăreanu, , Florentina Cojocaru, , Violeta Ristoiu, Luciana Stanica, Dan F Mihăilescu,
Published: 31 August 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317720940

Abstract:
Transient receptor potential melastatin 8 (TRPM8), a membrane ion channel, is activated by thermal and chemical stimuli. In pancreatic ductal adenocarcinoma, TRPM8 is required for cell migration, proliferation, and senescence and is associated with tumor size and pancreatic ductal adenocarcinoma stages. Although the underlying mechanisms of these processes have yet to be described, this cation-permeable channel has been proposed as an oncological target. In this study, the glycosylation status of the TRPM8 channel was shown to affect cell proliferation, cell migration, and calcium uptake. TRPM8 expressed in the membrane of the Panc-1 pancreatic tumoral cell line is non-glycosylated, whereas human embryonic kidney cells transfected with human TRPM8 overexpress a glycosylated protein. Moreover, our data suggest that Ca2+ uptake is modulated by the glycosylation status of the protein, thus affecting cell proliferation.
Fereshteh Ahmadinejad, , Mohammad-Amin Honardoost, Mostafa Gholami Arjenaki, Mohammad Moazeni-Bistgani, Soleyman Kheiri,
Published: 31 August 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317698362

Abstract:
Breast cancer is considered as the most prevalent malignancy in women worldwide. Despite emergence of several prognosticators for better management of patients, there are still limitations for their clinical application due to the complexity of breast tumors, and therefore, new biomarkers for better prognosis of clinical outcomes would be of the great essence. MicroRNAs are highly conserved small non-coding regulatory RNAs involved in post-transcriptional regulating of gene expression during different cellular mechanisms. Accumulating studies suggest that miR-218 plays a multifunctional role in various cancer types and different stages. Here, to address prognostic significance of miR-218 in breast cancer, we investigate the expression profile of miR-218 and B-cell-specific Moloney murine leukemia virus integration site 1 ( BMI1) gene, as one of the putative targets of miR-218, in 33 paired breast tumors and their adjacent normal tissues with respect to the clinicopathological features of patients using quantitative real-time polymerase chain reaction. The correlation of both miR-218 and BMI1 gene expression with overall survival of breast cancer patients was also examined recruiting OncoLNC data portal. Finally, to better understand biological function of miR-218 in breast cancer, we performed in silico Gene Ontology and signaling pathway enrichment analysis on miR-218 targetome. According to our data, significant elevation of the expression of miR-218 and downregulation of BMI1 were observed in clinical breast cancer specimens compared with normal tissues ( p < 0.0001). The lower expression of miR-218 was associated with lymph node metastases, higher grades, and poorer prognosis (logrank p = 0.00988), whereas no significant difference in overall survival was observed between patients with higher and lower expression of BMI1 (logrank p = 0.254). These findings suggest that miR-218 expression profiling might be clinically applicable as a prognostic biomarker in breast cancer. In addition, our in silico enrichment analyses revealed that the association of miR-218 expression with breast cancer prognosis might be through its involvement in endocytosis and gap junction biological pathways.
Xueda Hu, Jingyi Chen, Xiaoshun Shi, Fenglan Feng, King Wai Lau, Yaoqi Chen, Yusong Chen, Long Jiang, Fei Cui, Yalei Zhang, et al.
Published: 29 August 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317700001

Abstract:
RNA editing is a widespread post-transcriptional mechanism that confers specific and reproducible nucleotide changes in selected RNA transcripts and plays a critical role in many human cancers. However, little is known about how RNA editing operates in non-small-cell lung cancers. Here, we measured the sequence and expression level of genes of antizyme inhibitor 1 and adenosine deaminase acting on RNA family in 30 non-small-cell lung cancer patient samples and 13 cell lines and revealed RNA editing S367G in antizyme inhibitor 1 is a high-frequent molecular events. We determined overexpression of antizyme inhibitor 1 with RNA editing, implying the oncogenic function of this alteration. We also detected the association of adenosine deaminase acting on RNA overexpression with RNA editing occurred in antizyme inhibitor 1. Furthermore, the RNA editing could cause a cytoplasmic-to-nuclear translocation of antizyme inhibitor 1 protein and conferred the malignant phenotype of non-small-cell lung cancer cells. The in vivo experiment confirmed that this RNA editing confers higher capacity of tumor migration as well. In conclusion, antizyme inhibitor 1 RNA editing and its involvement in tumorigenesis of non-small-cell lung cancer pave a new way for potential clinical management of non-small-cell lung cancer.
Michael Sidiropoulos, Georgios Pampalakis, Georgia Sotiropoulou, Dionyssios Katsaros,
Published: 1 January 2005
Tumor Biology, Volume 26, pp 324-336; https://doi.org/10.1159/000089290

Abstract:
The human kallikrein 10 (KLK10)/normal epithelial cell-specific-1 (NES1) gene is highly expressed in normal mammary, ovary and prostate cells, but its expression is dramatically decreased in cancer cell lines. Recently, it has been shown that CpG island hypermethylation of the KLK10 gene is responsible for the tumor-specific loss of KLK10 gene expression in certain breast cancer cell lines. We examined the role of CpG island hypermethylation in the tumor-specific loss of KLK10 expression in breast, ovarian and prostate cancers. We treated cells with the demethylating agent 5-aza-2'-deoxycytidine (dC) and monitored changes in KLK10 mRNA by RT-PCR and secreted hK10 protein expression by ELISA. The following cell lines were used: MDA-MB-231, MDA-MB-468, MCF-7, ZR-75-1, T-47D and BT-474 (breast); BG-1, MDAH-2774, HTB-75, HTB-161, PA-1 and ES-2 (ovary), and LNCaP and PC-3 (prostate). Upregulation of KLK10 mRNA levels, which was accompanied by an increase in secreted hK10 protein concentration, was observed for a subset of breast, ovarian, and prostate tumor cell lines after 5-aza-2'-dC. Genomic sequencing of sodium-bisulfite-treated DNA demonstrated that CpG sites within the KLK10 gene exon 3 were highly methylated. Hypermethylation of exon 3 CpG regions was also detected in primary ovarian cancers. These data suggest that CpG island hypermethylation plays an important role in the downregulation of kallikrein 10 mRNA and protein expression, but it cannot explain the pattern of expression of this gene in all cell lines or tissue tested.
, K. Nustad, T. Stigbrand
Published: 1 January 2003
Tumor Biology, Volume 24, pp 165-171; https://doi.org/10.1159/000074423

Abstract:
Since 1996, the nine ISOBM Workshops have so far characterized more than 300 monoclonal antibodies to a variety of tumor markers that include CA125, AFP, PSA, MUC1, Cytokeratins, Sialyl Lea, hCG, CEA, ALP, and more recently SCC, and S100. Besides the basic characterization of antibodies and their epitope configurations, several workshops have also addressed specific problems associated with multiple antigen variants. These workshops have been able to make significant advances well beyond those possible through any normal collaboration study. The data and impact of these workshops with their summary reports are reviewed.
Sawsan M Elsonbaty, , Fatma Sm Moawed
Published: 16 August 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317708703

Abstract:
β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host’s biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated β-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated β-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated β-glucan–treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal–regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated β-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated β-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of β-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic parenchyma. The severity of hepatic architecture changes was significantly decreased with both β-glucan therapeutic and preventive treatments. In conclusion, irradiated β-glucan modulated signal growth factors, vascular endothelial growth factor A, extracellular signal–regulated kinase 1, and phosphatidylinositol-3-kinase, which contributed to experimental hepatocarcinogenesis.
Jiehui Di, Keyu Gao, Debao Qu, Yaoyao Wu, Jing Yang,
Published: 10 July 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317701653

Abstract:
Human renal cell carcinoma which is a highly vascular tumor is the leading cause of death from urologic cancers. Angiogenesis has a pivotal role in oncogenesis and in the viability and expansion of renal cell carcinoma. Rap2B, as a small guanosine triphosphate–binding protein of the Ras family, was first discovered in the early 1990s during the screening of a platelet complementary DNA library. Previous studies have shown that Rap2B aberrantly expressed in human carcinogenesis and promoted the development of tumors via multiple signaling pathways. However, the function of Rap2B in tumor angiogenesis that is necessary for tumor growth and metastasis remains unknown. In this study, we examined the role of Rap2B in angiogenesis in renal cell carcinoma by Western blot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, human umbilical vascular endothelial cells growth assay, and endothelial cell tube formation assay. We found that Rap2B promoted angiogenesis in vitro and in vivo. Moreover, our data illustrated that phosphoinositide 3-kinase/AKT signaling pathway is involved in Rap2B-mediated upregulation of vascular endothelial growth factor and renal cell carcinoma angiogenesis. Taken together, these results revealed that Rap2B promotes renal cell carcinoma angiogenesis via phosphoinositide 3-kinase/AKT/vascular endothelial growth factor signaling pathway, which suggests that Rap2B is a novel therapeutic target for renal cell carcinoma anti-angiogenesis therapy.
Xiaoran Li, , Yaqing Li, Xiaoli Li, Yali Zhong, , Dandan Yu, Viktor Berge, Mariusz Adam Goscinski, Gunnar Kvalheim, et al.
Published: 8 August 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317713671

Abstract:
Our earlier study revealed that long-term ethidium bromide application causes mitochondrial DNA depletion in human prostate cancer DU145 cell line (DU145MtDP), and this DU145MtDP subline appears to have expanded CD44Bright cell population than its parental wild type DU145 cells (DU145WT). Increasing evidence suggests that CD44Bright cells are highly cancer stem cell like, but it is not clear about their dynamic transition between CD44Dim and CD44Bright phenotypes in prostate cancer cells, and how it is affected by mitochondrial DNA depletion. To address these questions, four cell subpopulations were isolated from both DU145WT and DU145MtDP cell lines based on their CD44 expression level and mitochondrial membrane potential. The cell motility and colony formation capability of the fluorescence activated cell sorting–sorted cell subpopulations were further examined. It was discovered in the DU145WT cells that CD44Dim cells could transit into both CD44Dim and CD44Bright phenotypes and that CD44Bright cells were prone to sustain their CD44Bright phenotype as renewal. However, such transition principle was altered in the DU145MtDP cells, in which CD44Bright cells showed similar capability to sustain a CD44Bright phenotype, while the transition of CD44Dim cells to CD44Bright were suppressed. It is concluded that mitochondrial DNA depletion in the human prostate cancer DU145 cells influences their renewal and CD44 subphenotype transition. Such alterations may be the driving force for the enrichment of CD44Bright DU145 cells after the mitochondrial DNA depletion, although the molecular mechanisms remain unclear.
Ji-Feng Li, Yu-Ze Song
Published: 8 August 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317709989

Abstract:
Circular RNAs are a novel type of non-coding RNAs generated from back splicing, which has been verified to mediate multiple tumorigenesis. However, the role of circular RNA in osteosarcoma is still unclear. In this study, we preliminarily screened the circular RNAs expression profiles in osteosarcoma and investigated the potential regulation mechanism. The circular RNAs expression profiles in osteosarcoma were screened using circular RNA microarray analysis, and results showed that there were 1152 circular RNAs upregulated and 915 circular RNAs downregulated in tumor tissue compared to adjacent tissue. Hsa_circ_0001564, located at 5q35.3 and its associated gene symbol is CANX, was one of the significantly overexpressed circular RNAs in osteosarcoma tissue, as well as in osteosarcoma cell lines. In functional experiments, hsa_circ_001564 knockdown significantly suppressed the proliferation activity, induced cell-cycle arrest in G0/G1 phase, and promoted apoptosis in HOS and MG-63 cells. Subsequently, we explored the probable mechanism of hsa_circ_001564, and fortunately, bioinformatics analysis revealed that miR-29c-3p contained the complementary binding region with hsa_circ_0001564, which was confirmed by dual-luciferase reporter assay. Moreover, rescue experiments illustrated that miR-29c-3p could reverse the oncogenesis effect of hsa_circ_001564. Our study discovers that hsa_circ_0001564 acts as miR-29c-3p sponge to mediate the tumorigenicity, which could act as a potential biomarker for the osteosarcoma and provide a novel insight for competing endogenous RNA mechanism in osteosarcoma.
Jing Yu, Qi Han,
Published: 10 July 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317709129

Abstract:
Long non-coding RNAs play important roles in the regulation of cellular processes including cell proliferation, differentiation, and metastasis. The dysregulation of long non-coding RNAs, such as the SPRY4-IT1 (SPRY4 intronic transcript 1), has been associated with various types of malignancies. However, the functional roles and regulatory mechanism of SPRY4-IT1 in ovarian cancer remain to be elucidated. Here, we quantified the expression level of SPRY4-IT1 in ovarian cancer patients and found its downregulation in ovarian cancer tissues compared to the adjacent normal tissues. Patients with lower SPRY4-IT1 expression were associated with a relatively poor prognosis. In consistency, the expression of SPRY4-IT1 was found to be reduced in four human ovarian cancer cell lines compared to normal ovarian epithelial cells. Next, two ovarian cancer cell lines SKOV3 and HO8910 were employed in vitro assays to investigate biological functions of SPRY4-IT1 in ovarian cancer. The cell proliferation was reduced following SPRY4-IT1 overexpression in SKOV3/HO8910 cells based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. The SPRY4-IT1 overexpression also dramatically arrested cell cycle and promoted cell apoptosis. Both wound-healing and transwell-based assays demonstrated that cell migration and invasion were inhibited following SPRY4-IT1 overexpression. Meanwhile, overexpression of SPRY4-IT1 increased E-cadherin and decreased N-cadherin and vimentin protein levels, indicating that SPRY4-IT1 may regulate ovarian cancer cell metastasis through the inhibition of epithelial–mesenchymal transition. Taken together, our findings suggest that SPRY4-IT1 regulates various cellular processes of ovarian cancer cells and its downregulation may contribute to ovarian cancer progression and metastasis partly via affecting the epithelial–mesenchymal transition.
Wenpeng Wang, Jusheng An, Yan Song, Minjie Wang, Manni Huang,
Published: 10 July 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317707373

Abstract:
While human papillomavirus vaccine was recently approved by China Food and Drug Administration, mapping of high-risk human papillomavirus distribution and attribution in cervical precancerous lesions in China becomes critical in development of a high-risk human papillomavirus-based cervical cancer screening and prevention strategy. In total, 1016 patients with cervical precancerous lesions diagnosed in the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences were analyzed retrospectively, including 111 patients with low-grade squamous intraepithelial lesions and 905 patients with high-grade squamous intraepithelial lesions. HPV16, 58, 52, 33, and 31 were the most common high-risk human papillomavirus genotypes in order of decreasing frequency among high-risk human papillomavirus-positive high-grade squamous intraepithelial lesions; this differed from the high-risk human papillomavirus distribution in low-grade squamous intraepithelial lesions (HPV16, 52, 39, 56, and 58). The distribution of high-risk human papillomavirus genotypes in single-type infections for high-grade squamous intraepithelial lesions (HPV16, 58, 33, and 52) was similar to that in multiple-type infections (HPV16, 58, 52, and 33). By contrast, a more diverse distribution spectrum of high-risk human papillomavirus genotypes for low-grade squamous intraepithelial lesions was observed between single-type (HPV16, 52, 39, and 56) and multiple-type infection (HPV52, 68, 58, 59, 39 and 56). A previously published method was adopted to calculate the fractional proportion of individual high-risk human papillomavirus genotypes in multiple infections. For this proportional attribution, HPV16 (48.9%), 58 (10.0%), 33 (5.5%), and 52 (5.5%) were the most frequent among all high-grade squamous intraepithelial lesions, whereas HPV16 (13.2%), 52 (11.6%), 39 (9.5%), and 56 (7.6%) were the most frequent among all low-grade squamous intraepithelial lesions. Differences in high-risk human papillomavirus distribution and proportional attribution in different cervical pathology statuses (high-grade squamous intraepithelial lesions and low-grade squamous intraepithelial lesions) demonstrated the critical role of persistent infection of certain high-risk human papillomavirus such as HPV16, 58, 33, and 52 in carcinogenesis of cervical cancer. Distinctively high prevalence of HPV58, 33 and 52 in Chinese cervical intraepithelial neoplasia population, especially in high-grade squamous intraepithelial lesions, should be taken into consideration in cervical cancer screening strategy and vaccine development.
Xiao-Lin Li, Dong-Qing Zhang, David Wang, David S. Knight, Lija Yin, Jianxiong Bao, , Jonathan Glass, ,
Published: 1 January 2008
Tumor Biology, Volume 29, pp 359-370; https://doi.org/10.1159/000178981

Abstract:
Ovarian cancer is the fifth most common cause of cancer death in women. Due to a lack of appropriate animal models, studies involving tumorigenicity, tumor progression and immune response at the molecular level are limited. We isolated many clones derived from thesurvivors of a transformed mouse ovarian epithelial cell line IG-10 in immune- competent mice and found that the clones displayed diverse phenotypes. Most clones were deficient in components of the MHC-I antigen presentation pathway. Soft-agarose colony assays showed different growth rates among clones. However, this did not completely correlate with each clone’s in vivo tumorigenicity regarding growth, tumor mass and ascites formation, suggesting the possibility that the clones may display contrasting intrinsic gene expression. We therefore performed two types of arrays to evaluate gene expression at transcriptional and translational levels. The results showed differences in expression of COL4α5, NOS-2, and SOCS-1 genes at the transcriptional level, MIP-2 gene at the protein level and CCL5, CXCL-10, IL-1α genes at both transcriptional and protein levels between low and high tumorigenic clones. Thus, our animal cell model together with the identified genes may provide a useful tool to study ovarian cancer immune response, tumorigenicity and tumor-host cell interactions in the tumor microenvironment.
Published: 28 July 2017
Tumor Biology, Volume 39; https://doi.org/10.1177/1010428317713675

Abstract:
Virus-directed enzyme prodrug therapy is one of the major strategy of increasing cytotoxicity of bioreductive agents. This research intended to examine new selected benzimidazole derivatives as a substrate for nitroreductase, the enzyme involved in nitroreduction which is responsible to the production of cytotoxic metabolites. In this way, the selectivity and strength of cytotoxicity can be raised. The effect of benzimidazoles on virus transfected cells and non-virus transfected cells A549 cell line was established by Annexin V + propidium iodide test, western blot, and polymerase chain reaction analysis of specific pro- and anti-apoptotic proteins in the corresponding gene expression and additionally nitroreductase gene expression. Our results proved the pro-apoptotic properties of all tested compounds in normoxia and hypoxia, especially according to virused A549 cells where the time of exposition was reduced from 48 to 4 h. In this shorten period of time, the strongest activity was shown by N-oxide compounds with nitro-groups. The apoptosis was confirmed by generation of BAX gene and protein and reduction of BCL2 gene and protein.
, Robert M. Sharkey, Rina Kashi, Keith Sides, Rhona Stein, David M. Goldenberg
Published: 1 January 1997
Tumor Biology, Volume 18, pp 367-377; https://doi.org/10.1159/000218051

Abstract:
Single and fractionated doses of radioimmunotherapy (RAIT) and standard chemotherapy (0.6 mg 5-FU/day and 0.36 leuco-vorin/day on days 1–5) result in decreases in vascular permeability (VP) in the GW-39 human colonic xenograft. The effect of a single dose of RAIT (MN-14 anticarcinoembryonic antigen, Mu-9 anticolon-specific antigen, PAM-4 anti-MUC-1, RS-7 and RS-11 antiepithelial glycoprotein labeled with 131I) has also been evaluated in 10 other tumors. Fourteen days after a fixed 1,500-cGy dose of RAIT, 3 colonic tumors (LS174T, HT-29 and MOSER) all exhibited decreases in VP (58, 75 and 70%, respectively). Two colonic (LoVo and GS-7) and 1 breast tumor (MDA-468) did not exhibit any change in VP, and 1 lung (CALU-3), 1 cervical (ME-180), 1 pancreatic (CaPan-1) and 1 breast cancer line (ZR-75) exhibited increases in tumor VP (214, 289, 170 and 139%, respectively). The differences in VP response to RAIT do not appear to be related to the type of tumor, the size of tumor or the antigen being targeted by RAIT. The differences in tumor VP response to RAIT are discussed in terms of the ability to achieve significant tumor accretion of a second dose of radioantibody on a multiple-dosing regimen. We have begun to investigate the mechanism(s) which regulate the varying responses of tumor VP to RAIT by assessing the role that nitric oxide plays. Administration of arginine, a substrate for nitric oxide synthase, results in increases in both baseline and RAIT-modified VP in GW-39 and ME-180 tumors.
A. Bottini, A. Berruti, M. Tampellini, B. Morrica, A. Brunelli, E. Gnocchi, M.P. Brizzi, S. Aguggini, E. Fara, P. Alquati, et al.
Published: 1 January 1997
Tumor Biology, Volume 18, pp 301-310; https://doi.org/10.1159/000218043

Abstract:
Serum levels of CA 15–3, mucinous-like cancer antigen, carcinoembryonic antigen, tissue polypeptide antigen and tissue polypeptide-specific antigen (TPS) have been determined in 99 patients with T2–4 N0–1 M₀ breast cancer (BC) before and after primary (neoadjuvant) chemotherapy and after surgery. As a whole, no difference in marker levels was apparent according to tumor and patient characteristics, with the only exception of TPS values, which showed an inverse relationship with the histologic grade. Serum marker levels did not substantially change with respect to baseline either after chemotherapy, despite the high response rate obtained, or after surgery. These data indicate a limited contribution of the primary tumor to the serum marker levels and are consistent for the scarce usefulness of marker evaluation in BC patients with an early stage of disease. Interestingly, pretreatment elevated CA 15–3 levels were correlated with a higher recurrence rate, further supporting the prognostic significance of this tumor marker.
Prahlad Parajuli, Sukh Mahendra Singh
Published: 1 January 1997
Tumor Biology, Volume 18, pp 104-112; https://doi.org/10.1159/000218021

Abstract:
The effect of the ascitic growth of Dalton’s lymphoma (DL), a T cell lymphoma, on the immune responses of the host mice to exogenous antigens, with respect to the humoral response, delayed-type hypersensitivity (DTH) response and the antigen-presenting ability of macrophages was investigated. The humoral immune response to sheep red blood cells (SRBC) as well as the antigen-presenting ability of macrophages (with keyhole limpet hemocyanin as the standard antigen) in the DL-bearing mice were consistently higher than in the normal mice, although the magnitude showed a decline during later tumor stages. However, the DTH response to SRBC was suppressed in the DL-bearing mice compared with the response in the normal mice. The possible mechanisms are discussed. In vivo administration of FK565, a synthetic biological response modifier, enhanced the humoral immune response as well as the antigen-presenting ability of the macrophages in the normal and early DL-bearing mice, whereas these immune responses n the later tumor-bearing animals were found to be nonresponsive to FK565 treatment. In contrast, the DTH response in the normal as well as in the DL-bearing mice was suppressed on FK565 administration. This is the first study of its kind regarding the effect of the ascitic growth of any T cell lymphoma on various aspects of the immune response to exogenous antigens and the correlation thereof with an immuno-modulator.
Ayman Shabana, Mathias Onsrud
Published: 1 January 1994
Tumor Biology, Volume 15, pp 361-367; https://doi.org/10.1159/000217913

Abstract:
The serum levels of tissue polypeptide-specific (TPS) antigen were measured using the M3 monoclonal antibody in an enzyme immunoassay in 33 patients with ovarian cancer, in 26 women with benign pelvic masses and in 26 women with a laparoscopically proven normal pelvis. The results were compared with the serum levels of the CA 125 antigen. At a cutoff level of 135 U/l for TPS and 20 U/l for CA 125 (95th percentile of the healthy controls), the sensitivity of the tests for detecting a malignant tumor was 77% for TPS and 87% for CA 125. The specificities were 85% for TPS and 92% for CA 125. Adding TPS to CA 125 did not increase the diagnostic values compared to using the CA 125 test alone. For both markers, the rate of positivity was higher in advanced stage than in early-stage ovarian cancer. No correlation between marker levels and survival was found. Serial determinations performed with 4 patients during therapy and follow-up showed that both TPS and CA 125 are good predictors of tumor response and recurrence.
Yasuo Hanazawa, Kenichi Sato, Namiko Kuroiwa, Masako Ogawa, Atsuko Kuriyama, Mineko Asanagi, Noriko Kato, Yoichi Moriyama, Keisuke Horitsu, Shinji Fujimura
Published: 1 January 1994
Tumor Biology, Volume 15, pp 7-16; https://doi.org/10.1159/000217868

Abstract:
There was a 2- to 7-fold increase in nicotinamide methyltransferase activity in the livers of mice and rats bearing seven different kinds of tumors compared with the respective control normal livers, while activity in the tumors themselves was hardly detectable. The activity in the liver started to increase markedly 3-7 days after i.p. transplantation of Ehrlich ascites tumors into the mice, maintaining a plateau up to death. Metabolic conversion of 14C-nicotinamide to 14C-N1methylnicotinamide was 3-fold higher in the slices of the ascites tumor host liver than in the normal liver, but the conversion to other radioactive metabolites was not significantly different. Nicotinamide methyltransferase was finally purified 20,000-fold with a yield of 4% from the cytosolic fraction of the ascites tumor host liver by means of five purification steps. At every purification step, only one enzyme fraction was detected. The enzyme finally isolated exhibited a single protein band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with a molecular weight of 26,000. As for the compounds investigated, including the substrates for methyltransferases other than nicotinamide methyltransferase, only quinoline could be the substrate for enzyme activity. It is suggested that the increase in enzyme activity in the tumor host liver probably derived from the endogenous enzyme preexisting in the liver before tumor transplantation.
Massimo Gion, Gino Cappelli, Riccardo Mione, Giulio Vignati, Antonio Fortunato, Silvana Saracchini, Roberto Biasioli, Marcella Gulisano
Published: 1 January 1993
Tumor Biology, Volume 14, pp 325-333; https://doi.org/10.1159/000217847

Abstract:
The biological and analytical components of variability of tumor markers should be distinguished from the variations due to tumor progression. The aim of the present study was to evaluate tumor marker variability in the follow-up of patients resected for breast cancer. So far, we have carried out 2,085 CEA and 2,550 CA 15-3 determinations in 435 patients. The total variability of both CEA and CA 15-3 was widely scattered among different subjects (CEA coefficient of variation 0-105%; CA 15-3 coefficient of variation 0-89.2%). The biological variability of CA 15-3, which was calculated in a limited number of cases, was scattered between 0 and 23% and was higher than the intra-assay variability. From these findings we conclude that when evaluating serial marker assays the intra-individual variability should be assayed initially to obtain a reference value of individual variability in relapse-free conditions.
M. Ferdeghini, , C. Prontera, G. Malagnino, A. Fanucchi, C. Annicchiarico, V. Facchini, R. Bianchi
Published: 1 January 1993
Tumor Biology, Volume 14, pp 303-309; https://doi.org/10.1159/000217843

Abstract:
Preoperative serum soluble interleukin-2 receptor (sIL·2R) and CA 125 levels were measured in 183 patients with ovarian masses undergoing laparotomy. Serum sIL·2R levels were higher in the 54 patients with epithelial ovarian cancer than in the 129 patients with benign ovarian diseases (p
U. Elsässer-Beile, S. Von Kleist
Published: 1 January 1993
Tumor Biology, Volume 14, pp 69-94; https://doi.org/10.1159/000217827

Abstract:
Cytokines are key mediators of immunity and inflammation. These proteins or glycoproteins act as communication signals between different populations of leukocytes but neither their effects nor their production are restricted to immune cells. In the last few years many new cytokines and their effects have been discovered and it was agreed that when the amino acid sequence of a new cytokine was established it would be assigned the name interleukin (IL), with an added number. The detection of cytokines in disease states promises to provide useful information for diagnostic purposes. The therapeutic utility of cytokines has been explored in many clinical and preclinical studies and in a wide variety of infectious diseases, autoimmune diseases and neoplasias. Since the production of cytokines is modulated by several biological agents such as hormones, prostaglandins and drugs, these may also serve as therapeutic targets for immunomodulation.
M.K. Schwartz
Published: 1 January 1987
Tumor Biology, Volume 8, pp 134-138; https://doi.org/10.1159/000217510

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