Frontiers in Oncology

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ISSN / EISSN : 2234-943X / 2234-943X
Published by: Frontiers Media SA (10.3389)
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, Meibao Feng, Minhong Wang, Liang Zhang, Meirong Li, Chencui Huang
Published: 14 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.689136

Abstract:
Purpose This study established and verified a radiomics model for the preoperative prediction of the Ki67 index of gastrointestinal stromal tumors (GISTs). Materials and Methods A total of 344 patients with GISTs from three hospitals were divided into a training set and an external validation set. The tumor region of interest was delineated based on enhanced computed-tomography (CT) images to extract radiomic features. The Boruta algorithm was used for dimensionality reduction of the features, and the random forest algorithm was used to construct the model for radiomics prediction of the Ki67 index. The receiver operating characteristic (ROC) curve was used to evaluate the model’s performance and generalization ability. Results After dimensionality reduction, a feature subset having 21 radiomics features was generated. The generated radiomics model had an the area under curve (AUC) value of 0.835 (95% confidence interval(CI): 0.761–0.908) in the training set and 0.784 (95% CI: 0.691–0.874) in the external validation cohort. Conclusion The radiomics model of this study had the potential to predict the Ki67 index of GISTs preoperatively.
Yumeng Zhu, Xiaochao Wang, Yanqing Xu, Lu Chen, Peipei Ding, Jianfeng Chen,
Published: 14 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.736725

Abstract:
Background C5AR2 (GPR77, C5L2) is the second receptor for C5a that is a potent protein generated by complement activation. C5AR2 can mediate its own signaling events and exert significant immunomodulatory effects through those events. However, research of C5AR2 in cancer is limited, and its function remains unclear in breast cancer. Methods The expression of C5AR2 and its correlations with prognosis, immune infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI) in more than thirty types of cancers were described through GTEx, TCGA, PrognoScan, TIMER2.0, CCLE, HPA, and TISIDB database. C5AR2 showed strong relationships to those immune marker sets in breast cancer. Otherwise, CCK8 assay and Transwell assay were conducted to illustrate the role of C5AR2 in migration, invasion, and proliferation of breast cancer cells. Results Generally, C5AR2 expression differed across most cancerous and noncancerous tissues, and high C5AR2 expression significantly related to poor prognosis in BRCA, GBM, KICH, LAML, LGG, LIHC, PAAD, and STAD. Moreover, C5AR2 expression levels were dramatically correlated with recognized immune infiltration, especially the polarization of macrophages in breast cancer. Gene set enrichment analysis confirmed that C5AR2 participates in regulating multiple signaling pathways involved in tumorigenesis as well as tumor immunity. C5AR2 overexpression facilitated the functions such as migration, invasion, and proliferation in breast cancer cells, which is consistent with bioinformatics analysis. Conclusions C5AR2 is involved in immune infiltration and malignant characteristics of breast cancer, which may be a prospective biomarker for breast cancer.
, Riccarda Granata, Raúl M. Luque
Published: 14 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.755735

Abstract:
Editorial on the Research TopicPathophysiological Interrelationship Between Obesity, Metabolic Diseases, and Cancer Obesity and metabolic syndrome are chronic endocrine-metabolic diseases that represent emerging global epidemics and capital health problems for the global population (1–3). Unfortunately, the presence of obesity and metabolic syndrome increases the risk of developing more severe endocrine pathologies [e.g. insulin resistance or type-2 diabetes (T2D)], cardiovascular complications, and some cancer types (4–8). Indeed, emerging evidence indicates that cancer development, progression, and aggressiveness are strongly influenced by the presence of metabolic alterations such as obesity and metabolic syndrome, wherein 20% of cancer incidence seems to be attributable to obesity (9). However, the precise association of the different indicators of metabolic dysregulation (body weight, obesity, metabolic syndrome, hyperglycemia, etc.), as well as the molecular, cellular, and endocrine-metabolic mechanisms underlying the pathophysiological association between metabolic abnormalities and cancer, remain to be fully elucidated. This Research Topic compiles eight original research, clinical trial, review, and systematic review articles that advance our knowledge of and shed light on the complex pathophysiological association between obesity, metabolic diseases, and cancer. Firstly, the review by Scully et al. provides a detailed summary of the epidemiological evidence linking the different components of obesity and metabolic syndrome and their associated comorbidities (BMI, insulin resistance, hyperinsulinemia, dyslipidemia, and T2D) and different cancer types, including colon, breast, prostate, and liver. These epidemiological data are in line with those reviewed by the International Agency for Research on Cancer (IARC) and the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) that indicated an association of excessive body fat with increased risk of certain cancer types (10, 11). The review by Scully et al. recapitulates evidence from preclinical and cross-sectional clinical studies, suggesting a substantial interaction between adipose tissue and cancer, which could contribute to the obesity-associated promotion of tumor growth. This relationship is especially evident in some cancer types such as breast cancer and esophageal adenocarcinoma, which are particularly affected by the obesogenic status. Examples of this close association are presented in the mini review of Bhardwaj and Brown, which explores the role of adipose tissue in obesity as a driver of breast cancer growth and development, and the review by Elliot and Reynolds, that recapitulates the epidemiological evidence supporting the association between visceral obesity and metabolic syndrome with esophageal adenocarcinoma. Moreover, the original research article by Ardesch et al. demonstrates the importance of dissecting out the different components of the metabolic dysregulations and the diverse indicators of obesity (BMI, adiposity, etc.) to appropriately analyze their association with cancer incidence as they demonstrate that, in the case of lung cancer, there is a non-linear association between BMI and the risk of lung cancer while waist circumference, waist-to-hip ratio, and other body shape indexes are positively and linearly associated with the risk of this cancer type. Therefore, the risk of cancer development in patients with obesity and/or other metabolic alterations should be specially monitored by more proactive screening programs or by implementing prevention/reversal strategies aimed to reduce the cases of different cancer types associated with metabolic dysregulations. As demonstrated by the clinical trial article by Sung et al., subjects who were willing to undergo colorectal cancer screening tended to accept a subsequent breast and prostate cancer screening, indicating the effectiveness and compliance of a one-stop service for cancer screening among asymptomatic subjects, which could be specially relevant in patients with metabolic complications. In this line, the reviews by Bhardwaj and Brown and Elliot and Reynolds also recapitulate current evidence indicating the impact of obesity-related strategies, such as pharmacological interventions, physical activity, and weight lost in cancer incidence and/or development. However, these results should be interpreted considering the metabolic status of the patients, in that the systematic review by Lin et al., indicated that, in patients with T2D, weight change achieved by hypoglycemic agents or strategies over short and medium periods are not associated with incidence of most neoplasms, although it was effective in decreasing the incidence of prostate, bladder, and uterine neoplasms. Finally, the review articles by Scully et al., Bhardwaj and Brown, and Elliot and Reynolds also examine the mechanisms underlying the pathophysiological relationship between obesity, metabolic diseases, and cancer. Among the proposed drivers of this association, they reviewed the implication of key hormonal systems (insulin/IGF-I, estrogens, or sex steroids), as well as certain adipokines, circulating lipids, and other adipose tissues-derived mediators, such as immune cells (macrophages) and cytokines/interleukins. The accumulated evidence assigning a key role to novel mechanisms related to tumor and adipose tissues microenvironment or to the putative role of the microbiome in this pathophysiological interrelationship is also emphasized. Altogether, it seems evident the existence of common drivers that could be mediating the pathological crosstalk between obesity/adiposity/metabolic syndrome and different cancer types, as clearly illustrated by the review of Ku and Cheng, focused on the impact of the master regulator Activating Transcription Factor 3 (ATF3) in metabolism and cancer. ATF3 is a stress-induced transcription factor that exerts...
Weili Li, Wenling Zhang, Lixin Sun, Li Wang, Zhumei Cui, Hongwei Zhao, DanBo Wang, Yi Zhang, Jianxin Guo, Ying Yang, et al.
Published: 13 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.730753

Abstract:
Objective To compare the 5-year overall survival (OS) and disease-free survival (DFS) of patients with cervical cancer who received neoadjuvant chemotherapy followed by surgery (NACT) with those who received abdominal radical hysterectomy alone (ARH). Methods We retrospectively compared the oncological outcomes of 1410 patients with stage IB3 cervical cancer who received NACT (n=583) or ARH (n=827). The patients in the NACT group were divided into an NACT-sensitive group and an NACT-insensitive group according to their response to chemotherapy. Results The 5-year oncological outcomes were significantly better in the NACT group than in the ARH group (OS: 96.2% vs. 91.2%, respectively, p=0.002; DFS: 92.2% vs. 87.5%, respectively, p=0.016). Cox multivariate analysis suggested that NACT was independently associated with a better 5-year OS (HR=0.496; 95% CI, 0.281-0.875; p=0.015), but it was not an independent factor for 5-year DFS (HR=0.760; 95% CI, 0.505-1.145; p=0.189). After matching, the 5-year oncological outcomes of the NACT group were better than those of the ARH group. Cox multivariate analysis suggested that NACT was still an independent protective factor for 5-year OS (HR=0.503; 95% CI, 0.275-0.918; p=0.025). The proportion of patients in the NACT group who received postoperative radiotherapy was significantly lower than that in the ARH group (p<0.001). Compared to the ARH group, the NACT-sensitive group had similar results as the NACT group. The NACT-insensitive group and the ARH group had similar 5-year oncological outcomes and proportions of patients receiving postoperative radiotherapy. Conclusion Among patients with stage IB3 cervical cancer, NACT improved 5-year OS and was associated with a reduction in the proportion of patients receiving postoperative radiotherapy. These findings suggest that patients with stage IB3 cervical cancer, especially those who are sensitive to chemotherapy, might consider NACT followed by surgery.
Seung Woo Hong, Se Hoon Kim, Seung Hoon Lim, Eun Jig Lee, Sun Ho Kim, Cheol Ryong Ku,
Published: 13 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.739290

Abstract:
Background The new World Health Organization (WHO) classification system proposed a cell lineage-based classification scheme for pituitary adenomas in which transcription factors (TFs) play a major role as key classifiers. We aimed to evaluate clinical relevance of the new classification system in a clinical setting. Methods TF staining was retrospectively performed for 153 clinically and histologically well characterized pituitary adenomas. Then, 484 pituitary adenomas were prospectively stained for TFs and then for relevant pituitary hormones. TF and hormone stain-based diagnoses were compared, and differences in clinical manifestations were evaluated. Results The accuracies of antibodies for three TFs were successfully validated and had an overall matching rate was 89.6%. We identified 50 (10.4%) cases with discrepancies between TF and pituitary hormone stains. Gonadotroph adenomas lacking follicle-stimulating hormone and luteinizing hormone stains account for most discrepancies. Null cell adenomas may be more prevalent than reported and may be clinically more aggressive than gonadotroph adenomas. Conclusion The new WHO classification is mostly well matched with the traditional classification. However, until the new classification is further validated and interpreted in the context of long-term clinical outcomes, routine histological examination should include full slate of immunostains for pituitary hormones as well as TFs.
Yongzhi Zheng, Yan Huang, Shaohua Le, Hao Zheng, Xueling Hua, Zaisheng Chen, Xiaoqin Feng, Chunfu Li, Mincui Zheng, Honggui Xu, et al.
Published: 13 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.712747

Abstract:
Background A high ecotropic viral integration site 1 (EVI1) expression (EVI1 high) is an independent prognostic factor in adult acute myeloid leukemia (AML). However, little is known of the prognostic value of EVI1 high in pediatric AML. This study aimed to examine the biological and prognostic significance of EVI1 high in uniformly treated pediatric patients with AML from a large cohort of seven centers in China. Methods A diagnostic assay was developed to determine the relative EVI1 expression using a single real-time quantitative polymerase chain reaction in 421 newly diagnosed pediatric AML patients younger than 14 years from seven centers in southern China. All patients were treated with a uniform protocol, but only 383 patients were evaluated for their treatment response. The survival data were included in the subsequent analysis (n = 35 for EVI1 high, n = 348 for EVI1 low). Results EVI1 high was found in 9.0% of all 421 pediatric patients with de novo AML. EVI1 high was predominantly found in acute megakaryoblastic leukemia (FAB M7), MLL rearrangements, and unfavorable cytogenetic aberrance, whereas it was mutually exclusive with t (8; 21), inv (16)/t (16; 16), CEBPA, NPM1, or C-KIT mutations. In the univariate Cox regression analysis, EVI1 high had a significantly adverse 5-year event-free survival (EFS) and overall survival (OS) [hazard ratio (HR) = 1.821 and 2.401, p = 0.036 and 0.005, respectively]. In the multivariate Cox regression analysis, EVI1 high was an independent prognostic factor for the OS (HR = 2.447, p = 0.015) but not EFS (HR = 1.556, p = 0.174). Furthermore, EVI1 high was an independent adverse predictor of the OS and EFS of patients with MLL rearrangements (univariate analysis: HR = 9.921 and 7.253, both p < 0.001; multivariate analysis: HR = 7.186 and 7.315, p = 0.005 and 0.001, respectively). Hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) provided EVI1 high patients with a tendential survival benefit when compared with chemotherapy as a consolidation (5-year EFS: 68.4% vs. 50.8%, p = 0.26; 5-year OS: 65.9% vs. 54.8%, p = 0.45). Conclusion It could be concluded that EVI1 high can be detected in approximately 10% of pediatric AML cases. It is predominantly present in unfavorable cytogenetic subtypes and predicts adverse outcomes. Whether pediatric patients with EVI1 high AML can benefit from HSCT in CR1 needs to be researched further.
Hongjian Zhao, Junjun Huang, Ming Chen, Baoru Li, Xinran Chen,
Published: 13 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.695525

Abstract:
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, with most mortalities being caused by metastases. However, the underlying molecular mechanism of CRC metastases remains largely unknown. Emerging evidence has shown the role of the tripartite motif family, especially tripartite motif protein 6 (TRIM6), in carcinogenesis. In this study, we used CRC cell lines with TRIM6 knockdown and overexpression to investigate the function of TRIM6 in CRC metastasis. We found that TRIM6 promotes CRC cell migration and invasion both in vitro and in vivo. TRIM6 knockdown slows down the migration and invasion processes, whereas TRIM6 overexpression accelerates CRC cell migration and invasion. TRIM6 is potentially the upstream regulatory factor for signal transducer and activator of transcription 3 (STAT3) via the suppressor of cytokine signaling 2 (SOCS2). A total of 70 samples from patients with CRC further confirmed that TRIM6 expression level is positively correlated with STAT3 phosphorylation and negatively correlated with SOCS2 expression. Therefore, TRIM6 could be a potential therapeutic target for CRC metastasis.
Panpan Jiang, Ziyang Mao, Qinyang Wang, Xiaohui Jia, Luying Geng, Hong Xu, Lili Jiang, Chengcheng Yang, Min Jiao,
Published: 13 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.698199

Abstract:
Background Nivolumab + ipilimumab + two cycles chemotherapy (N-I + chemo, intensive immunotherapy but chemo-light) and pembrolizumab + chemotherapy (Pem + chemo) were both recommended as first-line treatment for metastatic non-small cell lung carcinoma (NSCLC) patients. We conducted this indirect comparison to compare the efficacy of and safety between these two treatments for providing reference for decision making. Methods Relevant databases were searched for eligible trials. A well-accepted adjusted indirect treatment comparison (ITC) approach was selected to pool efficacy results and safety outcomes. Subgroup analyses were stratified according to PD-L1 expression and clinical characteristics. Results Four eligible randomized trials (CheckMate9LA, KEYNOTE-021G, KEYNOTE 189, KEYNOTE 407) involving 2017 patients were available to analyze. The ITC results suggested that N-I + chemo is comparable to Pem + chemo in OS (HR 1.03, 95% CI 0.82-1.30) and ORR (RR 0.81, 95% CI 0.62-1.06), but tended to yield inferior PFS (HR 1.28, 95% CI 1.04-1.59) than did Pem + chemo. As for safety profiles, N-I + chemo showed no significant difference relative to Pem + chemo in any grade adverse events: (RR 1.03, 95% CI 0.99-1.10), but demonstrated reduced toxicity in chemo-related adverse events, such as anemia (RR 0.63, 95% CI 0.49-0.81), neutropenia (RR0.51, 95% CI 0.33-0.79), and thrombocytopenia (RR 0.38, 95% CI 0.21-0.69). Conclusions N-I + chemo is a promising treatment option for providing comparable OS related to Pem + chemo. However, for never smoker female patients, Pem + chemo is preferable to choose for demonstrating favorable OS benefit than N-I + chemo.
Yu-Hsuan Kuo, Ti-Chun Chan, Hong-Yue Lai, Tzu-Ju Chen, Li-Ching Wu, ,
Published: 13 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.749142

Abstract:
Background The mitochondrial pyruvate dehydrogenase complex (PDC) link glycolysis to the tricarboxylic acid cycle by decarboxylating pyruvate to acetyl coenzyme A irreversibly. Cancer cells are characterized by a shift in cellular metabolism from mitochondrial respiration to glycolysis. PDC activity inhibition mediated by phosphorylation via pyruvate dehydrogenase kinase (PDK) has been linked to cancer. However, the clinical significance of PDKs in urothelial cancer prognosis is not clear. We investigated the role and prognostic value of PDK3 expression in patients with upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC). Patients and Methods We retrospectively analyzed clinical data and pathological features. Formalin-fixed urothelial carcinoma (UC) tissues were collected and embedded in paraffin. The correlation of PDK3 expression with clinical characteristics, pathological findings and patient outcomes, including metastasis-free survival (MFS) and disease-specific survival (DSS) were analyzed by Pearson’s chi-square test, Kaplan–Meier analysis, and the multivariate Cox proportional hazards model. Results Data from 295 patients with UBUC and 340 patients with UTUC were evaluated. High PDK3 expression significantly correlated with several pathologic variables such as high T stage, lymph node metastases, high tumor grade, vascular invasion, and high mitotic rate (all P < 0.001). High PDK3 expression was associated with poor disease-specific survival (DSS) (P < 0.0001) and metastatic free survival (MFS) (P < 0.0001) in a Kaplan–Meier analysis. Additionally, multivariate analysis demonstrated increased PDK3 expression is a significant predictive risk factor for DSS [hazard ratio (HR) in UBUC, 2.79, P = 0.009; in UTUC, 2.561, P = 0.03] and MFS (HR in UBUC, 1.907, P = 0.024; in UTUC, 1.793, P = 0.044). The gene co-expression analysis showed abundant PDK3 co-upregulated genes were involved in the processes of DNA replication and repair through the Gene Ontology classification system. Conclusion High PDK3 expression has been linked to negative pathologic characteristics and poor oncological outcomes, suggesting that it could be used as a predictive biomarker for UC. PDK3 mRNA levels and its co-upregulated genes were strongly associated with DNA replication and repair. These results suggest that PDK3 may play a key role in tumor proliferation and development.
Published: 13 September 2021
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.671014

Abstract:
Endogenous metabolites are a class of molecules playing diverse and significant roles in many metabolic pathways for disease. Honokiol (HNK), an active poly-phenolic compound, has shown potent anticancer activities. However, the detailed crucial mechanism regulated by HNK in colorectal cancer remains unclear. In the present study, we investigated the therapeutic effects and the underlying molecular mechanisms of HNK on colorectal cancer in a mouse model (ApcMin/+) by analyzing the urine metabolic profile based on metabolomics, which is a powerful tool for characterizing metabolic disturbances. We found that potential urine biomarkers were involved in the metabolism of compounds such as purines, tyrosines, tryptophans, etc. Moreover, we showed that a total of 27 metabolites were the most contribution biomarkers for intestinal tumors, and we found that the citrate cycle (TCA cycle) was regulated by HNK. In addition, it was suggested that the efficacy of HNK was achieved by affecting the multi-pathway system via influencing relevant metabolic pathways and regulating metabolic function. Our work also showed that high-throughput metabolomics can characterize the regulation of metabolic disorders as a therapeutic strategy to prevent colorectal cancer.
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