Cancer Biology and Medicine

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ISSN : 2095-3941
Published by: Cancer Biology and Medicine (10.20892)
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Et Al. Yu Deng, Hongyan Jin
Cancer Biology and Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0344

Abstract:
Menopausal hormone therapy (MHT) has been widely used for the clinical treatment of symptoms associated with menopausein women. However, the exact nature of the relationship between MHT and the increased risk of breast cancer has not been fullyelucidated. The results of the Women’s Health Initiative’s randomized controlled clinical studies showed that estrogen monotherapywas associated with a lower incidence of breast cancer as compared to estrogen-progesterone combined therapy, with an elevated riskof breast cancer. The evidence currently available from randomized trials and observational studies is based on data from differentpopulations, drug formulations, and routes of administration. Even though the risks of MHT and breast cancer have received agreat deal of attention, information regarding the unpredictable toxicological risks of estrogen and progestogen metabolism needsto be further analyzed. Furthermore, the diversity and complexity of the metabolic pathways of estrogen and different progestogensas well as the association of the different estrogen and progestogen metabolites with the increased risk of breast cancer need to beadequately studied. Therefore, this review aimed to describe the biological effects of estrogen, progesterone, and their metaboliteson the proliferation of breast cancer cells, based on relevant basic research and clinical trials, to improve our understanding of thebiological functions of estrogen and progestogen as well as the safety of MHT.
Et Al. Jia Lu, Ting Li, Zhichao Liao, Hui Yu, Yongtian Zhao, Haixiao Wu, Zhiwu Ren, Jun Zhao, Ruwei Xing, Sheng Teng, et al.
Cancer Biology and Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0270

Abstract:
Objective: Sarcomas are a group of rare malignancies with various subtypes. Patients with metastatic sarcoma who have failedtraditional treatments can possibly achieve better prognoses from using novel therapies, including anti-programmed death-1(PD-1)-based therapies. Methods: We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15, 2016 to December 30, 2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditionaltreatments. Furthermore, 8 patients underwent panel DNA and whole transcript sequencing. Results: Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group. The medianfollow-up time was 5.77 months. The median progression-free survival was 7.59 months, the overall response rate was 16.7% and thedisease control rate was 55.6%. Based on whole exome and transcript sequencing data, there was no association between TMB, TNB,MSI, HLA-LOH, and PD-L1 expressions and sarcoma types with clinical responses. Immunotherapy efficacy and bioinformaticsanalyses indicated higher intratumoral heterogeneity (ITH) in progressive disease (PD) patients and lower ITH in partial response(PR) and stable disease patients. A higher percentage of immune cell infiltration, especially monocytes, was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients. Enrichment analysis revealed that anincreased TGF-β signaling pathway was reversely correlated with anti-PD-1 efficacy, while a decreased inflammatory responsesignaling pathway was positively correlated with anti-PD-1 efficacy. Conclusions: Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated. ITH,monocyte ratio, stroma subtypes, and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.
Et Al. Yangyang Kong, Chang Xu, Xiaohui Sun, Hao Sun, Xiaotong Zhao, Ningning He, Kaihua Ji, Qin Wang, Liqing Du, Jinhan Wang, et al.
Cancer Biology and Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0178

Abstract:
Objective: We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase (PARP) inhibitor, olaparib, andthe Bloom syndrome protein (BLM) helicase inhibitor, ML216, in non-small cell lung cancer (NSCLC) cells. Methods: Radiosensitization of NSCLC cells was assessed by colony formation and tumor growth assays. Mechanistically, the effectsof ML216, olaparib, and radiation on cell and tumor proliferation, DNA damage, cell cycle, apoptosis, homologous recombination(HR) repair, and non-homologous end joining (NHEJ) repair activity were determined. Results: Both olaparib and ML216 enhanced the radiosensitivities of olaparib-sensitive H460 and H1299 cells, which was seen asdecreased surviving fractions and Rad51 foci, increased total DNA damage, and γH2AX and 53BP1 foci (P < 0.05). The expressions ofHR repair proteins were remarkably decreased in olaparib-treated H460 and H1299 cells after irradiation (P < 0.05), while olaparibcombined with ML216 exerted a synergistic radiosensitization effect on olaparib-resistant A549 cells. In addition to increases ofdouble strand break (DSB) damage and decreases of Rad51 foci, olaparib combined with ML216 also increased pDNA-PKcs (S2056)foci, abrogated G2 cell cycle arrest, and induced apoptosis in A549 lung cancer after irradiation in vitro and in vivo (P < 0.05).Moreover, Western blot showed that olaparib combined with ML216 and irradiation inhibited HR repair, promoted NHEJ repair,and inactivated cell cycle checkpoint signals both in vitro and in vivo (P < 0.05). Conclusions: Taken together, these results showed the efficacy of PARP and BLM helicase inhibitors for radiosensitizing NSCLCcells, and supported the model that BLM inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization, as well asproviding the basis for the potential clinical development of this combination for tumors intrinsically resistant to PARP inhibitorsand radiotherapy.
Et Al. Yan Qin, Haizhu Chen, Peng Liu, Changgong Zhang, Jianliang Yang, Lin Gui, Xiaohui He, Liqiang Zhou, Shengyu Zhou, Shiyu Jiang, et al.
Cancer Biology and Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0193

Abstract:
Objective: Limited data about the prognostic significance of BCL2 mutations and BCL2 copy number variations in diffuse largeB-cell lymphoma (DLBCL) are available. This study aimed to comprehensively describe BCL2 genetic alterations in DLBCL patients,and examine correlation of BCL2, TP53 and other genetic alterations with outcomes in patients treated with R-CHOP. Methods: Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with de novo DLBCL. MYC,BCL2, and BCL6 protein expressions were detected by immunohistochemistry. Results: The presence of BCL2 alterations significantly correlated with poor progression-free survival (PFS) (5-year PFS: 13.7%vs. 40.8%; P = 0.003) and overall survival (OS) (5-year OS: 34.0% vs. 70.9%; P = 0.036). Importantly, patients who harbored BCL2gain/amplifications (BCL2GA/AMP) also had a remarkably inferior 5-year PFS (11.1% vs. 38.3%; P < 0.001) and OS (22.1% vs. 69.6%;P = 0.009). In contrast, neither BCL2 mutations nor BCL2 translocations were significantly prognostic for survival. Multivariableanalyses showed that the presence of BCL2 alterations, especially BCL2GA/AMP, TP53 mutations, and International Prognostic Index(IPI) were significantly associated with inferior PFS and OS. Novel prognostic models for OS were constructed based on 3 riskfactors, including BCL2 alterations (Model 1) or BCL2GA/AMP (Model 2), TP53 mutations, and IPI, to stratify patients into 4 riskgroups with different survival outcomes. Conclusions: This study showed that DLBCL patients treated with R-CHOP, BCL2 alterations, especially BCL2GA/AMP and TP53mutations were significantly associated with inferior outcomes, which were independent of the IPI. The novel prognostic modelswe proposed predicted outcomes for DLBCL patients treated with R-CHOP, but further validation of the prognostic models is stillwarranted.
Et Al. Nahid Arghiani, Khalid Shah
Cancer Biology and Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0294

Abstract:
MicroRNAs (miRNAs) are a class of endogenously expressed non-coding regulators of the genome with an ability to mediate avariety of biological and pathological processes. There is growing evidence demonstrating frequent dysregulation of microRNAs incancer cells, which is associated with tumor initiation, development, migration, invasion, resisting cell death, and drug resistance.Studies have shown that modulation of these small RNAs is a novel and promising therapeutic tool in the treatment of a varietyof diseases, especially cancer, due to their broad influence on multiple cellular processes. However, suboptimal delivery of theappropriate miRNA to the cancer sites, quick degradation by nucleases in the blood circulation, and off target effects have limitedtheir research and clinical applications. Therefore, there is a pressing need to improve the therapeutic efficacy of miRNA modulators,while at the same time reducing their toxicities. Several delivery vehicles for miRNA modulators have been shown to be effectivein vitro and in vivo. In this review, we will discuss the role and importance of miRNAs in cancer and provide perspectives on currentlyavailable carriers for miRNA modulation. We will also summarize the challenges and prospects for the clinical translation of miRNAbasedtherapeutic strategies.
Et Al. Shanshan He, Bowen Ding, Gang Li, Yubei Huang, Chunyong Han, Jingyan Sun, Qingfeng Huang, Jing Liu, Zhuming Yin, Shu Wang, et al.
Cancer Biology and Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0368

Abstract:
Objective: The number of immediate breast reconstruction (IBR) procedures has been increasing in China. This study aimed toinvestigate the oncological safety of IBR, and to compare the survival and surgical outcomes between implant-based and autologousreconstruction. Methods: Data from patients diagnosed with invasive breast cancer who underwent immediate total breast reconstruction between2001 and 2016 were retrospectively reviewed. Long-term breast cancer-specific survival (BCSS), disease-free survival (DFS), andlocoregional recurrence-free survival (LRFS) were evaluated. Patient satisfaction with the breast was compared between the implantbasedand autologous groups. BCSS, DFS, and LRFS were compared between groups after propensity score matching (PSM). Results: A total of 784 IBR procedures were identified, of which 584 were performed on patients with invasive breast cancer (implantbased,n = 288; autologous, n = 296). With a median follow-up of 71.3 months, the 10-year estimates of BCSS, DFS, and LRFS were88.9% [95% confidence interval (CI) (85.1%–93.0%)], 79.6% [95% CI (74.7%–84.8%)], and 94.0% [95% CI (90.3%–97.8%)],respectively. A total of 124 patients completed the Breast-Q questionnaire, and no statistically significant differences were notedbetween groups (P = 0.823). After PSM with 27 variables, no statistically significant differences in BCSS, DFS, and LRFS were foundbetween the implant-based (n = 177) and autologous (n = 177) groups. Further stratification according to staging, histological grade,lymph node status, and lymph-venous invasion status revealed no significant survival differences between groups. Conclusions: Both immediate implant-based and autologous reconstruction were reasonable choices with similar long-termoncological outcomes and patient-reported satisfaction among patients with invasive breast cancer in China.
Et Al. Zhiliang Wang, Wen Cheng, Zheng Zhao, Zheng Wang, Chuanbao Zhang, Guanzhang Li, Anhua Wu, Tao Jiang
Cancer Biology & Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0173

Abstract:
Objective: Lower grade gliomas (LGGs), classified as World Health Organization (WHO) grade II and grade III gliomas, comprisea heterogeneous group with a median survival time ranging from 4–13 years. Accurate prediction of the survival times of LGGsremains a major challenge in clinical practice.Methods: We reviewed the expression data of 865 LGG patients from 5 transcriptomics cohorts. The comparative profile of immunegenes was analyzed for signature identification and validation. In-house RNAseq and microarray data from the Chinese GliomaGenome Atlas (CGGA) dataset were used as training and internal validation cohorts, respectively. The samples from The CancerGenome Atlas (TCGA) and GSE16011 cohorts were used as external validation cohorts, and the real-time PCR of frozen LGG tissuesamples (n = 36) were used for clinical validation.Results: A total of 2,214 immune genes were subjected to pairwise comparison to generate 2,449,791 immune-related gene pairs(IGPs). A total of 402 IGPs were identified with prognostic values for LGGs. The HOXA9-related and CRH-related scores facilitatedidentification of patients with different prognoses. An immune signature based on 10 IGPs was constructed to stratify patients intolow and high risk groups, exhibiting different clinical outcomes. A nomogram, combining immune signature, 1p/19q status, andtumor grade, was able to predict the overall survival (OS) with c-indices of 0.85, 0.80, 0.80, 0.79, and 0.75 in the training, internalvalidation, external validation, and tissue sample cohorts, respectively.Conclusions: This study was the first to report a comparative profiling of immune genes in large LGG cohorts. A promisingindividualized immune signature was developed to estimate the survival time for LGG patients.
Et Al. Sha Li, Jinyi Liu, Xiangjin Zheng, Liwen Ren, Yihui Yang, Wan Li, Weiqi Fu, Jinhua Wang, Guanhua Du
Cancer Biology & Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2020.0651

Abstract:
Colorectal cancer (CRC) is the third most common and the second most fatal cancer. In recent years, more attention has been directedtoward the role of gut microbiota in the initiation and development of CRC. Some bacterial species, such as Fusobacterium nucleatum,Escherichia coli, Bacteroides fragilis, Enterococcus faecalis, and Salmonella sp. have been associated with CRC, based upon sequencingstudies in CRC patients and functional studies in cell culture and animal models. These bacteria can cause host DNA damage bygenotoxic substances, including colibactin secreted by pks + Escherichia coli, B. fragilis toxin (BFT) produced by Bacteroides fragilis,and typhoid toxin (TT) from Salmonella. These bacteria can also indirectly promote CRC by influencing host-signaling pathways,such as E-cadherin/β-catenin, TLR4/MYD88/NF-κB, and SMO/RAS/p38 MAPK. Moreover, some of these bacteria can contributeto CRC progression by helping tumor cells to evade the immune response by suppressing immune cell function, creating a proinflammatoryenvironment, or influencing the autophagy process. Treatments with the classical antibacterial drugs, metronidazole orerythromycin, the antibacterial active ingredients, [email protected] Ag (electrostatically assembled from inorganic silver nanoparticles and theprotein capsid of bacteriophage M13), berberine, and zerumbone, were found to inhibit tumorigenic bacteria to different degrees. Inthis review, we described progress in elucidating the tumorigenic mechanisms of several CRC-associated bacteria, as well as progressin developing effective antibacterial therapies. Specific bacteria have been shown to be active in the oncogenesis and progression ofCRC, and some antibacterial compounds have shown therapeutic potential in bacteria-induced CRC. These bacteria may be usefulas biomarkers or therapeutic targets for CRC.
Et Al. Panpan Ma, Xinxin Jin, Zhiwei Fan, Zhou Wang, Suhui Yue, Changyue Wu, Shiyin Chen, Yuanyuan Wu, Miaomiao Chen, Donghua Gu, et al.
Cancer Biology & Medicine, Volume 18; https://doi.org/10.20892/j.issn.2095-3941.2021.0137

Abstract:
Objective: PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpointblockade. The factors that drive inducible PD-L1 expression have been extensively studied, but mechanisms that result in constitutivePD-L1 expression in cancer cells are largely unknown.Methods: DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout. Protein function was inhibited by chemical inhibitors.Protein levels were examined by Western blot, mRNA levels were examined by real-time RT-PCR, and surface protein expression wasdetermined by cellular immunofluorescence and flow cytometry. Immune evasion was examined by in vitro T cell-mediated killing.Results: We determined the core regions (chr9: 5, 496, 378–5, 499, 663) of a previously identified PD-L1L2-super-enhancer (SE).Through systematic analysis, we found that the E26 transformation-specific (ETS) variant transcription factor (ETV4) bound to thiscore DNA region but not to DNA surrounding PD-L1L2SE. Genetic knockout of ETV4 dramatically reduced the expressions of bothPD-L1 and PD-L2. ETV4 transcription was dependent on ERK activation, and BRAF/TAK1-induced ERK activation was dependenton extracellular signaling from αvβ3 integrin, which profoundly affected ETV4 transcription and PD-L1/L2 expression. Geneticsilencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible toT cell-mediated killing.Conclusions: We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETV4to PD-L1L2-SE to induce PD-L1-mediated immune evasion. These results provided new insights into PD-L1L2-SE activation andpathways associated with immune checkpoint regulation in cancer.
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