Cancer Letters

Organoid technology in cancer precision medicine Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Xinyi Xia, Fei Li, Juan He, Rebiguli Aji, Dong Gao Abstract Organoid technology has been remarkably improved over the last decade. Various organoids have been derived from different types of tissues and recapitulate their organ-specific gene expression signatures, particular tissue spatial structures and functions of their original tissue. The patient-derived organoids (PDOs) have been used to elucidate crucial scientific questions, including the relationships between genetic/epigenetic alterations and drug responses, cell plasticity during disease progressions, and mechanisms of drug resistances. With the great expectations, PDOs will be widely used to facilitate the personalized medical decisions, which have the potential to profoundly improve patient outcomes. In this review, we will discuss the developmental details, current achievements, applications and challenges of organoid technology in precision cancer medicine.

Vps4A mediates the localization and exosome release of β-catenin to inhibit epithelial-mesenchymal transition in hepatocellular carcinoma Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Qingfang Han, Lihong Lv, Jinxing Wei, Xin Lei, Haoming Lin, Guolin Li, Jun Cao, Jiyan Xie, Weibang Yang, Shaobin Wu, Jia You, Jing Lu, Peiqing Liu, Jun Min Abstract We previously reported that Vps4A acted as a tumor suppressor by influencing the microRNA profiles of exosomes and their parental cells in hepatocellular carcinoma (HCC). However, the underlying mechanism and if Vps4A contributes to sorting proteins into exosomes are not well known. Here, we performed mass spectrometry analysis of the immunoprecipitated Vps4A complex and confirmed that Vps4A was associated with β-catenin and CHMP4B. Through this interaction, Vps4A promoted the plasma membrane (PM) localization and exosome release of β-catenin. Silencing Vps4A or CHMP4B decreased the PM localization and exosome sorting of β-catenin. Vps4A overexpression decreased β-catenin signaling pathway and inhibited epithelial-mesenchymal transition (EMT) and motility of HCC cells. And, silencing Vps4A or CHMP4B promoted EMT in HCC. Furthermore, the expression of Vps4A was significantly related to that of several EMT markers in HCC tissues and the level of exosomal β-catenin in patients with metastatic HCC was significantly lower compared to that of control patients. In conclusion, through the interaction with CHMP4B and β-catenin, Vps4A regulates the PM localization and exosome sorting of β-catenin, consequently decreases β-catenin signaling, and thereby inhibits EMT and metastasis in HCC.

Combined Bcl-2/Src inhibition synergize to deplete stem-like breast cancer cells Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Qi Sun, Yufen Wang, Jay S. Desgrosellier Abstract Breast cancer cells with stem cell properties play an important role in tumor progression and thus are key targets for therapy. Here, we show that combined Bcl-2/Src inhibition synergize to deplete stem-like cells. While Src inhibition increases pro-apoptotic PUMA, we find that a significant amount interacts with Bcl-2 and Bcl-xL, promoting resistance to cell death. Consistent with this, the clinically-approved Bcl-2 selective drug venetoclax was sufficient to overcome resistance by preventing PUMA/Bcl-2 binding, enhancing apoptosis. This effect was specific to stem-like breast cancer cells as there was no effect on luminal or basal-like cell types. In contrast, the Mcl-1 inhibitor S63845 potently targeted basal-like, but not stem-like cells, highlighting dependency on distinct sentinel Bcl-2 family members. Our findings reveal Bcl-2/Src inhibition as a superior therapy to target stemness, providing a foundation for a potential personalized strategy to reduce breast cancer progression.

Interferon regulatory factor-1 reverses chemoresistance by downregulating the expression of P-glycoprotein in gastric cancer Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Jingsheng Yuan, Zhijie Yin, Lulu Tan, Wenzhong Zhu, Kaixiong Tao, Guobing Wang, Wenjia Shi, Jinbo Gao Abstract The emergence of multiple drug resistance (MDR) is the main cause of chemotherapy failure in gastric cancer. In this study, to generate MDR gastric cancer cell lines, we exposed MKN45 and AGS gastric cancer cells to cisplatin, fluorouracil, and adriamycin. Through transcriptome sequencing, we found that interferon regulatory factor-1 (IRF-1) was expressed at significantly lower levels in the MDR cell lines than in the parental cell lines. We then established stable clones of MKN45 and SGC7901 cells with a doxycycline-inducible IRF-1 expression system and confirmed that IRF-1 overexpression efficiently reversed the MDR. Further analyses indicated that IRF-1 suppresses P-glycoprotein (P-gp) expression in vitro and in vivo, leading to an increase in chemotherapy drug retention. The results showed that IRF-1 bound to the promoter regions of P-gp gene and inhibited P-gp transcription. IFN-γ induced IRF-1-mediated downregulation of P-gp in gastric cancer cells. Finally, we demonstrated that the clinical correlation between IRF-1 and P-gp expression and that IRF-1 serves as an independent prognostic factor for patients with gastric cancer. We conclude that IRF-1 reverses the MDR trait of gastric cancer by downregulating P-gp, and this mechanism has potential treatment implications and is clinically actionable.

BIRC5 is a target for molecular imaging and detection of human pancreatic cancer Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Shi-He Liu, Yeahwa Hong, Stephen Markowiak, Robbi Sanchez, Justin Creeden, John Nemunaitis, Andrea Kalinoski, James Willey, Paul Erhardt, Jason Lee, Michael van Dam, F. Charles Brunicardi Abstract Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer mortality with a dismal overall survival rate and an urgent need for detection of minute tumors. Current diagnostic modalities have high sensitivity and specificity for larger tumors, but not for minute PDAC. In this study, we test the feasibility of a precision diagnostic platform for detecting and localizing minute human PDAC in mice. This platform includes: 1) defining BIRC5 as an early PDAC-upregulated gene and utilizing an enhanced BIRC5 super-promoter to drive expression of dual Gaussia luciferase (GLuc) and sr39 thymidine kinase (sr39TK) reporter genes exponentially and specifically in PDAC; 2) utilizing a genetically-engineered AAV2RGD to ensure targeted delivery of GLuc and sr39TK specifically to PDAC; 3) using serologic GLuc and sr39TK microPET/CT imaging to detect and localize minute human PDAC in mice. The study demonstrates feasibility of a precision diagnostic platform using an integrated technology through a multiple-stage amplification strategy of dual reporter genes to enhance the specificity and sensitivity of detection and localization of minute PDAC tumors and currently undetectable disease.

Tumor vasculature remodeling by radiation therapy increases doxorubicin distribution and efficacy Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Vincent Potiron, Karen Clément-Colmou, Emmanuel Jouglar, Manon Pietri, Sophie Chiavassa, Grégory Delpon, François Paris, Stéphane Supiot Abstract The tumor microenvironment regulates cancer initiation, progression and response to treatment. In particular, the immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. We and others have shown that radiation therapy (RT) induces pericyte recruitment, resembling vascular normalization. Here, we asked whether radiation-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy. First, RT induced vascular remodeling, accompanied by decreased hypoxia and/or increased Hoechst perfusion in prostate PC3 and LNCaP and Lewis lung carcinoma. These results were independent of the RT regimen, respectively 10 × 2 Gy and 2 × 12 Gy, suggesting a common effect. Next, using doxorubicin as a fluorescent reporter, we observed that RT improves intra-tumoral chemotherapy distribution. These effects were not hindered by anti-angiogenic sunitinib. Moreover, sub-optimal doses of doxorubicin had almost no effect alone, but significantly delayed tumor growth after RT. These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution, and could be an alternative chemosensitizing strategy.

PD-1/PD-L1 blockade in paediatric cancers: What does the future hold? Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Julia Moreno-Vicente, Stephen A. Beers, Juliet C. Gray Abstract Checkpoint blockade (CPB) immunotherapy has shown unprecedented success in a wide range of adult malignancies, and is increasingly being employed in the treatment of advanced cancers. However, the experience in the paediatric population remains limited and the small number of single agent studies reported have shown disappointing response rates. Paediatric cancers offer unique challenges that can hinder the translation of CPB into the paediatric clinic, and combinational therapies are likely to be needed to achieve therapeutic success. As the number of paediatric trials using CPB rapidly increases, understanding the challenges that these agents may encounter in this population is of special significance to allow the design of optimal combinatorial strategies for each tumour type. Here, we offer an overview of the unique biological and immunological features of paediatric cancers as compared to adult malignancies, and how these might impact the overall success of CPB in the paediatric population. We review the growing body of pre-clinical and clinical experiences to date, and discuss future strategies involving the combination of CPB with traditionally used therapies (chemotherapy and radiotherapy) or with other newly developed immunotherapies.

A tRNA fragment, 5′-tiRNAVal, suppresses the Wnt/β-catenin signaling pathway by targeting FZD3 in breast cancer Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Dongping Mo, Pan Jiang, Yining Yang, Xuelian Mao, Xuyan Tan, Xun Tang, Da Wei, Bing Li, Xiaoming Wang, Li Tang, Feng Yan Abstract tRNA-derived fragments offer a recently identified group of non-coding single-stranded RNAs that are often as abundant as microRNAs in cancer cells and play important roles in carcinogenesis. However, the biological functions of them in breast cancer are still unclear. Hence, we focused on investigating whether tiRNAs could play a key role in the progression of breast cancer. We have identified 5′-tiRNAVal with significantly low expression in breast cancer tissues. The down-regulation of serum 5′-tiRNAVal was positively correlated with stage progression and lymph node metastasis. Overexpression of 5′-tiRNAVal suppressed cells malignant activities. FZD3 was confirmed to be a direct target of 5′-tiRNAVal in breast cancer. In addition, FZD3, β-Catenin, c-myc and cyclinD1 levels in 5′-tiRNAVal overexpressing cells were downregulated while APC was inversely upregulated. Moreover, 5′-tiRNAVal inhibited the FZD3-mediated Wnt/β-Catenin signaling pathway in breast cancer cells. Finally, 5′-tiRNAVal levels differentiated breast cancer from healthy controls with a sensitivity of 90.0% and specificity of 62.7%. This is the first study to show that 5′-tiRNAVal as a new tumor-suppressor through inhibition of FZD3/Wnt/β-Catenin signaling pathway, which could be as a potential diagnostic biomarker for breast cancer.

Management of immune related adverse events induced by immune checkpoint inhibition Publication date: 1 August 2019 Source: Cancer Letters, Volume 456 Author(s): Andreas Teufel, Tianzuo Zhan, Nicolai Härtel, Jan Bornschein, Matthias P. Ebert, Nadine Schulte Abstract In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy and these drugs have already become essential for the treatment of various non-curable tumors. Compared to conventional chemotherapy or tyrosine kinase inhibitors, ICIs generally exhibit a favorable side effect profile further promoting their increasing prescription rate. However, increasing use of these substance made clear that ICI induced activation of the immune system may also lead to immune-related adverse events (irAEs). Common irAEs are dermatological, gastrointestinal, or endocrine side effects but further tissue types and organ systems may also be affected. A detailed knowledge of these potential side effects is important as early recognition is the key to successful treatment, reversibility of organ dysfunction and in some cases even prevention of fatal outcome. In more severe irAEs, immunosuppression may be necessary to cope with these side effects. To increase awareness of irAEs and support immediate and successful management, we provide a comprehensive review on most common irAEs of ICIs, their diagnosis, and treatment.

Immune checkpoint modulators in cancer immunotherapy: Recent advances and combination rationales Publication date: 1 August 2019 Source: Cancer Letters, Volume 456 Author(s): Li Fan, Yue Li, Jia-Yu Chen, Yong-Fa Zheng, Xi-Ming Xu Abstract As a new hallmark of cancer, immune surveillance evading plays a critical role in carcinogenesis. Through modulating the immune checkpoints, immune cells in tumor microenvironment can be harnessed to battle cancer cells. In recent years, the administration of anti-CTLA or/and anti-PD-1/L1 antibody has exhibited unexpected antitumor effect in multiple types of cancer, motivating the researchers to find more potential immune checkpoints as clinical targets. A wealth of clinical trials have been done to evaluate the safety and efficacy of monotherapy or combination therapy with immune checkpoint modulators. However, there still exist problems such as low response rate and adverse events in the clinical, which in turn leads us to the basic study. The better understanding of the crosstalk between the immune cells and the cancer cells within the microenvironment may inspire us new ideas for cancer treatment. In this review, we mainly summarize the recent advances in application of immune checkpoint modulators and the combination rationales, and discuss the problems existing in the precision therapy with immune checkpoint modulators.

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