Frontiers in Oncology

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ISSN / EISSN : 2234-943X / 2234-943X
Published by: Frontiers Media SA (10.3389)
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Fuquan Deng, Xiaoyuan Li, Fengjiao Yang, Hongwei Sun, Jianmin Yuan, Qiang He, Weifeng Xu, Yongfeng Yang, Dong Liang, Xin Liu, et al.
Published: 26 January 2022
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.818329

Abstract:
Background: 68 Ga-prostate-specific membrane antigen (PSMA) PET/MRI has become an effective imaging method for prostate cancer. The purpose of this study was to use deep learning methods to perform low-dose image restoration on PSMA PET/MRI and to evaluate the effect of synthesis on the images and the medical diagnosis of patients at risk of prostate cancer. Methods: We reviewed the 68 Ga-PSMA PET/MRI data of 41 patients. The low-dose PET (LDPET) images of these patients were restored to full-dose PET (FDPET) images through a deep learning method based on MRI priors. The synthesized images were evaluated according to quantitative scores from nuclear medicine doctors and multiple imaging indicators, such as peak-signal noise ratio (PSNR), structural similarity (SSIM), normalization mean square error (NMSE), and relative contrast-to-noise ratio (RCNR). Results: The clinical quantitative scores of the FDPET images synthesized from 25%- and 50%-dose images based on MRI priors were 3.84±0.36 and 4.03±0.17, respectively, which were higher than the scores of the target images. Correspondingly, the PSNR, SSIM, NMSE, and RCNR values of the FDPET images synthesized from 50%-dose PET images based on MRI priors were 39.88±3.83, 0.896±0.092, 0.012±0.007, and 0.996±0.080, respectively. Conclusion: According to a combination of quantitative scores from nuclear medicine doctors and evaluations with multiple image indicators, the synthesis of FDPET images based on MRI priors using and 50%-dose PET images did not affect the clinical diagnosis of prostate cancer. Prostate cancer patients can undergo 68 Ga-PSMA prostate PET/MRI scans with radiation doses reduced by up to 50% through the use of deep learning methods to synthesize FDPET images.
Yi-Hsuan Huang, Sung-How Sue, Zih-Syuan Wu, Shih-Ming Huang, Shih-Yu Lee,
Published: 26 January 2022
Frontiers in Oncology, Volume 12; https://doi.org/10.3389/fonc.2022.811716

Abstract:
Background: Breast cancer in women is one of the leading causes of cancer mortality worldwide, and curative therapy is the main focus of clinical treatment. Anesthetic-analgesic techniques might alter stress responses and immunity and thereby influence outcomes in cancer patients. This study investigated the effect of tramadol on breast cancer progression and metastasis. Methods: The effects of tramadol on two different subtypes of human breast adenocarcinoma cell lines, MDA-MB-231 and MCF-7, were studied with regard to cell growth, migration, colony formation and invasion and normoxic or hypoxic microenvironment for the expression of hypoxia-inducible factor-1α, reactive oxygen species, epithelial-mesenchymal transition related and cyclin-related proteins. The co-administration of tramadol and doxorubicin was studied to determine whether the effective doxorubicin dose might be reduced in combination with tramadol. Results: The results showed that tramadol inhibited cell growth at concentrations more than 0.5 and more than 1.0 mg/mL in MDA-MB-231 and MCF-7 cells, respectively. Additionally, cell migration, colony formation and invasion were inhibited in a dose-dependent manner by tramadol in both cell lines. The combination of tramadol and doxorubicin induced synergistic effects in MDA-MD-231 cells and, with specific dosage combinations in MCF-7 cells. Conclusions: Tramadol may regulate epithelial-mesenchymal transition and possess cytotoxic effects in breast cancer cells. Tramadol inhibits the progression of breast cancer cells and might be a candidate for combination therapy, especially for triple-negative breast cancer, and is a promising treatment strategy for breast cancer.
Yannan Zheng, Wenhui Zhang, Lin Xu, Hua Zhou, Man Yuan,
Published: 26 January 2022
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.795548

Abstract:
Liver cancer is the third most common cause of cancer-related death following lung and stomach cancers. As a highly lethal disease, liver cancer is diagnosed frequently in less developed countries. Natural compounds extracted from herbs, animals and natural materials have been adopted by traditional Chinese medicine (TCM) practices and reported to be effective in the development of new medications for the treatment of diseases. It is important to focus on the mechanisms of action of natural compounds against hepatocellular carcinoma (HCC), particularly in terms of cell cycle regulation, apoptosis induction, autophagy mediation and cell migration and invasion. In this review, we characterize novel representative natural compounds according to their pharmacologic effects based on recently published studies. The aim of this review is to summarize and explore novel therapeutic drug targets of natural compounds, which could accelerate the discovery of new anticancer drugs.
Jihua Tian, Xing Zeng, Jie Wan, Jiahua Gan, Chunjin Ke, Wei Guan, , Chunguang Yang
Published: 26 January 2022
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.819098

Abstract:
Purpose: To compare the cause-specific survival (CSS) and overall survival (OS) of patients with localized T3a renal cell carcinoma (RCC) after partial nephrectomy (PN) or radical nephrectomy (RN).Methods: We obtained the demographic and clinicopathological data of 7,127 patients with localized T3a RCC and who underwent PN or RN from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were divided into fat invasion cohort and venous invasion cohort for subsequent analysis. Kaplan–Meier analysis (KMA) and univariate and multivariate Cox proportional hazards regression analyses were used to evaluate the effects of PN or RN on OS and CSS. Meanwhile, 65 cases with clinical T1 (cT1) RCC upstaged to pathological T3a (pT3a) who were treated in Tongji Hospital (TJH) from 2011 to 2020 and underwent PN or RN were identified.Results: In the study cohort, 2,085 (29.3%) patients died during the 1–172 months’ follow-up, of whom 1,155 (16.2%) died of RCC. In the two cohorts of fat invasion and venous invasion, KMA indicated that the PN group had favorable survival (p < 0.001). However, after propensity score matching (PSM), univariate and multivariate Cox regression analyses showed that the PN and RN groups had comparable CSS in the fat invasion cohort (p = 0.075) and the venous invasion cohort (p = 0.190). During 1–104 months of follow-up, 9 cases in the Tongji cohort had disease recurrence. There was no significant difference in recurrence-free survival between the RN group and the PN group (p = 0.170).Conclusions: Our analysis showed that after balancing these factors, patients with localized pT3a RCC receiving PN or RN can achieve comparable oncologic outcomes. PN is safe for selected T3a patients.
Jimin Park, Seung Ki Kim, Steffanus Pranoto Hallis, Bo-Hyun Choi,
Published: 26 January 2022
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.808300

Abstract:
Cancer stem cells (CSCs) exhibit intrinsic therapy/stress resistance, which often cause cancer recurrence after therapy. In this study, we investigated the potential relationship between the cluster of differentiation (CD)-133, a CSC marker of colon cancer, and nuclear factor erythroid 2-like 2 (NFE2L2; NRF2), a master transcription factor for the regulation of multiple antioxidant genes. In the first model of CSC, a sphere culture of the colorectal cell line HCT116, showed increased levels of CD133 and NRF2. Silencing of CD133 reduced the levels of CSC markers, such as Kruppel-like factor 4 (KLF4) and ATP-binding cassette subfamily G member 2 (ABCG2), and further suppressed the expression levels of NRF2 and its target genes. As a potential molecular link, CD133-mediated activation of phosphoinositide 3-kinase/serine-threonine kinase (PI3K/AKT) signaling appears to increase the NRF2 protein levels via phosphorylation and the consequent inhibition of glycogen synthase kinase (GSK)-3β. Additionally, NRF2-silenced HCT116 cells showed attenuated sphere formation capacity and reduced CSC markers expression, indicating the critical role of the NRF2 pathway in the development of CSC-like properties. As a second model of CSC, the CD133high cell population was isolated from HCT116 cells. CSC-like properties, including sphere formation, motility, migration, colony formation, and anticancer resistance, were enhanced in the CD133high population compared to CD133low HCT116 cells. Levels of NRF2, which were elevated in CD133high HCT116, were suppressed by CD133-silencing. In line with these, the analysis of The Cancer Genome Atlas (TCGA) database showed that high levels of CD133 expression are correlated with increased NRF2 signaling, and alterations in CD133 gene or expression are associated with unfavorable clinical outcome in colorectal carcinoma patients. These results indicate that the CD133/NRF2 axis contributes to the development of CSC-like properties in colon cancer cells, and that PI3K/AKT signaling activation is involved in CD133-mediated NRF2 activation.
Yaxun Jia, Min Wang, Xiaolin Sang, , , Kui Jiang,
Published: 26 January 2022
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.812264

Abstract:
While PARP inhibitor (PARPi) therapies have shown promising results in the treatment of high-grade serous ovarian cancer (HGSOC) harboring homologous recombination deficiencies, primary resistance to PARPi frequently occurs and even initial responders may eventually become resistant. Therefore, the development of novel effective combinatorial strategies to treat HGSOC is urgently needed. Here, we report that H2O2-induced oxidative stress sensitized HGSOC cells to PARPi BMN 673. Furthermore, Phenethyl isothiocyanate (PEITC) as a ROS-inducing agent significantly enhanced the cytotoxic effects of BMN 673. Mechanistically, combined use of PEITC and BMN 673 resulted in ROS overproduction and accumulation, enhanced DNA damage, G2/M arrest and apoptosis, all of which were significantly reversed by the ROS scavenger N-Acetyl-L-cysteine. We also showed that while PEITC did not further enhance the ability of BMN 673 on PARP1 trapping in HGSOC cells, the therapeutic effects of the PEITC/BMN 673 combination were at least in part dependent on the presence of PARP1. Importantly, the PEITC/BMN 673 combination potently abrogated the growth of HGSOC tumor spheroids and patient-derived organoid models of HGSOC and cervical cancer. Our findings provide a basis for further investigation of the utility of PARPi combination regimen in HGSOC and cervical cancer through ROS-mediated mechanisms.
Xiaoxiang Rong, Jinyu Lv, Yantan Liu, Zhaojun Wang, Dongqiang Zeng, Yuedan Li, ShaoWei Li, Jianhua Wu, Zheyu Shen, Min Shi, et al.
Published: 26 January 2022
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.802257

Abstract:
Background: Promising development in immune checkpoint blockade (ICB) therapy has shown remarkable results in the treatment of gastric cancer (GC). However, the objective response rate in GC remains unsatisfactory. Noninvasive imaging to predict responses to ICB therapy via tumor microenvironment (TME) assessment is needed. Accordingly, this study aimed to evaluate the role of 68Ga-FAPI-04 PET/CT in the assessment of the immunosuppressive TME in GC and to cross-correlate imaging findings with responses to ICB therapy.Methods: The correlation between fibroblast-activation-protein (FAP) expression and immunosuppressive cell infiltration was analyzed using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) database, and GC tissue microarrays. To characterize the TME, TMEscores were calculated based on RNA-seq data from four GC patients. A total of 21 patients with GC underwent 68Ga-FAPI-04 PET/CT before ICB treatment, and two of them were imaged after ICB therapy.Results: FAP expression was found to be closely correlated with poor prognosis and infiltration of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), exhausted T cells, and regulatory T cells (Tregs) in GC. We also found a strong relationship (R2 = 0.9678, p = 0.0162) between 68Ga-FAPI-04 uptake and TMEscore. Further analyses indicated that high 68Ga-FAPI-04 uptake was correlated with reduced therapeutic benefits from ICB therapy.Conclusions: 68Ga-FAPI-04 PET/CT may be used to noninvasively image the cancer-associated fibroblasts immunosuppressive TME in vivo and also potentially serve as a predictive biomarker of survival and antitumor immune response among patients who received ICB therapies.
Published: 26 January 2022
Frontiers in Oncology, Volume 12; https://doi.org/10.3389/fonc.2022.729250

Abstract:
In the stereotactic body radiotherapy (SBRT) and immunotherapy era, we are moving toward an “immunological radiation plan”, i.e., radiation scheduling with abscopal effect as a vital endpoint as well. The literature review of part A enumerates the advantages of the intermediate dose of SBRT 6–10 Gy per fraction, appropriate use of dose painting, proper timing with immunotherapy, and the potential of immunoadjuvants to maximize cell kill in the irradiated lesions, found to have improved the abscopal effects. Part B summarizes part A, primarily the findings of animal trials, forming the basis of the tenets of the proposed model given in part C to realize the true abscopal potential of the SBRT tumor cell kill of the index lesions. Part C proposes a theoretical model highlighting tumor vasculature integrity as the central theme for converting “abscopal effect by chance” to “abscopal effect by design” using a harmonized combinatorial approach. The proposed model principally deals with the use of SBRT in strategizing increased cell kill in irradiated index tumors along with immunomodulators as a basis for improving the consistency of the abscopal effect. Included is the possible role of integrating immunotherapy just after SBRT, “cyclical” antiangiogenics, and immunoadjuvants/immune metabolites as abscopal effect enhancers of SBRT tumor cell kill. The proposed model suggests convergence research in adopting existing numerous SBRT abscopal enhancing strategies around the central point of sustained vascular integrity to develop decisive clinical trial protocols in the future.
Tianping Li, Linna Sun, Qinghe Li, Xunrong Luo, Mingfang Luo, Haizhu Xie,
Published: 26 January 2022
Frontiers in Oncology, Volume 11; https://doi.org/10.3389/fonc.2021.825429

Abstract:
Purpose: To develop and validate a radiomics nomogram for the prediction of clinically significant prostate cancer (CsPCa) in Prostate Imaging-Reporting and Data System (PI-RADS) category 3 lesions.Methods: We retrospectively enrolled 306 patients within PI-RADS 3 lesion from January 2015 to July 2020 in institution 1; the enrolled patients were randomly divided into the training group (n = 199) and test group (n = 107). Radiomics features were extracted from T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC) imaging, and dynamic contrast-enhanced (DCE) imaging. Synthetic minority oversampling technique (SMOTE) was used to address the class imbalance. The ANOVA and least absolute shrinkage and selection operator (LASSO) regression model were used for feature selection and radiomics signature building. Then, a radiomics score (Rad-score) was acquired. Combined with serum prostate-specific antigen density (PSAD) level, a multivariate logistic regression analysis was used to construct a radiomics nomogram. Receiver operating characteristic (ROC) curve analysis was used to evaluate radiomics signature and nomogram. The radiomics nomogram calibration and clinical usefulness were estimated through calibration curve and decision curve analysis (DCA). External validation was assessed, and the independent validation cohort contained 65 patients within PI-RADS 3 lesion from January 2020 to July 2021 in institution 2.Results: A total of 75 (24.5%) and 16 (24.6%) patients had CsPCa in institution 1 and 2, respectively. The radiomics signature with SMOTE augmentation method had a higher area under the ROC curve (AUC) [0.840 (95% CI, 0.776–0.904)] than that without SMOTE method [0.730 (95% CI, 0.624–0.836), p = 0.08] in the test group and significantly increased in the external validation group [0.834 (95% CI, 0.709–0.959) vs. 0.718 (95% CI, 0.562–0.874), p = 0.017]. The radiomics nomogram showed good discrimination and calibration, with an AUC of 0.939 (95% CI, 0.913–0.965), 0.884 (95% CI, 0.831–0.937), and 0.907 (95% CI, 0.814–1) in the training, test, and external validation groups, respectively. The DCA demonstrated the clinical usefulness of radiomics nomogram.Conclusion: The radiomics nomogram that incorporates the MRI-based radiomics signature and PSAD can be conveniently used to individually predict CsPCa in patients within PI-RADS 3 lesion.
Hongying Lan, Yu Gao, Zhengyang Zhao, Ziqing Mei,
Published: 26 January 2022
Frontiers in Oncology, Volume 12; https://doi.org/10.3389/fonc.2022.834681

Abstract:
Ferroptosis is a novel characterized form of cell death featured with iron-dependent lipid peroxidation, which is distinct from any known programmed cell death in the biological processes and morphological characteristics. Recent evidence points out that ferroptosis is correlated with numerous metabolic pathways, including iron homeostasis, lipid metabolism, and redox homeostasis, associating with the occurrence and treatment of hematological malignancies, such as multiple myeloma, leukemia, and lymphoma. Nowadays, utilizing ferroptosis as the target to prevent and treat hematological malignancies has become an active and challenging topic of research, and the regulatory network and physiological function of ferroptosis also need to be further elucidated. This review will summarize the recent progress in the molecular regulation of ferroptosis and the physiological roles and therapeutic potential of ferroptosis as the target in hematological malignancies.
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