scholarly journals A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

2018 ◽  
Author(s):  
Arman Jahangiri ◽  
William Chen ◽  
Ankush Chandra ◽  
Alan Nguyen ◽  
Garima Yagnik ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Xenograft Model ◽  
Therapy Resistance ◽  
Gene Signature ◽  
Duration Of Treatment ◽  
Mesenchymal Transition ◽  
Angiogenic Therapy ◽  
Bevacizumab Treatment ◽  
Evolution Of Resistance ◽  
Angiogenic Genes

ABSTRACTBevacizumab treatment of glioblastoma is limited by transient responses and acquired resistance. Because of the lengthy duration of treatment that can precede resistance in patients, in order to study changes underlying the evolution of bevacizumab resistance, we created a novel multigenerational xenograft model of acquired bevacizumab resistance. Glioblastoma xenografts were treated with bevacizumab or IgG, and the fastest growing tumor re-implanted into new mice, generating paired isogeneic responsive or resistant multigenerational xenografts. Microarray analysis revealed significant overexpression across generations of the mesenchymal subtype gene signature, paralleling results from patient bevacizumab-resistant glioblastomas (BRGs) that exhibited increasing mesenchymal gene expression correlating with increased bevacizumab treatment duration. Key mesenchymal markers, including YKL-40, CD44, SERPINE1, and TIMP1 were upregulated across generations, with altered morphology, increased invasiveness, and increased neurosphere formation confirmed in later xenograft generations. Interestingly, YKL-40 levels were elevated in serum of patients with bevacizumab-resistant vs. bevacizumab-naïve glioblastomas. Finally, despite upregulation of VEGF-independent pro-angiogenic genes across xenograft generations, immunostaining revealed increased hypoxia and decreased vessel density with increasing generation of treatment, mirroring our findings in patient BRGs and suggesting tumor growth despite effective devascularization caused by VEGF blockade. Besides identifying novel targets for preventing the evolution of resistance and offering a xenograft model for testing resistance inhibitors, our work suggests YKL-40 as a blood biomarker of bevacizumab resistance worthy of further evaluation.

scholarly journals TMOD-24. A NOVEL XENOGRAFT MODEL REVEALS A GENE CASCADE DEFINING A MESENCHYMAL TRANSITION DURING THE EVOLUTION OF RESISTANCE TO ANTI-ANGIOGENIC THERAPY

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi212-vi212
Author(s):  
Arman Jahangiri ◽  
William Chen ◽  
Garima Yagnik ◽  
Maxim Sidorov ◽  
Jonathan Rick ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Mesenchymal Transition ◽  
Angiogenic Therapy ◽  
Evolution Of Resistance

scholarly journals DRES-01. ZEB1-MEDIATED INVASIVE MESENCHYMAL TRANSITION AT THE SINGLE CELL LEVEL PROMOTES ANTI-ANGIOGENIC THERAPY RESISTANCE IN GLIOBLASTOMA

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi75-vi75
Author(s):  
Ankush Chandra ◽  
Arman Jahangiri ◽  
William Chen ◽  
Garima Yagnik ◽  
Joseph Garcia ◽  
...  
Keyword(s):  
Single Cell ◽  
Therapy Resistance ◽  
Single Cell Level ◽  
Cell Level ◽  
Mesenchymal Transition ◽  
Angiogenic Therapy

scholarly journals Treatment with a new benzimidazole derivative bearing a pyrrolidine side chain overcomes sorafenib resistance in hepatocellular carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fat-Moon Suk ◽  
Chao-Lien Liu ◽  
Ming-Hua Hsu ◽  
Yu-Ting Chuang ◽  
Jack P. Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Benzimidazole Derivative ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Side Chain ◽  
Mesenchymal Transition ◽  
New Compounds ◽  
Line Drug

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Currently, sorafenib is the standard first-line drug for patients with advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity of tumour cells to the drug, leading to acquired resistance. Therefore, developing new compounds to treat sorafenib resistance is urgently needed. Although benzimidazole and its derivatives have been reported to exert antimicrobial and antitumour effects, the anti-drug resistance potential of these molecules is still unknown. In this study, we established sorafenib-resistant (SR) cell lines and an acquired sorafenib resistance xenograft model. We showed that treatment with a benzimidazole derivative bearing a pyrrolidine side chain (compound 9a) inhibited the proliferation of SR cells by blocking the phosphorylation of AKT, p70S6 and the downstream molecule RPS6. In addition, caspase 3/PARP-dependent apoptotic signals were induced in 9a-treated cells. Regarding epithelial-mesenchymal transition (EMT) activities, 9a treatment significantly suppressed the migration of SR cells. In particular, the levels of EMT-related transcription factors (snail, slug and twist) and mesenchymal markers (vimentin and N-cadherin) were downregulated. In the acquired sorafenib resistance xenograft model, compound 9a administration decreased the growth of tumours with acquired sorafenib resistance and the expression of the HCC markers α-fetoprotein, glypican 3 and survivin. In conclusion, treatment with this compound may be a novel therapeutic strategy for patients with sorafenib resistance.

scholarly journals New Insights into Therapy-Induced Progression of Cancer

2020 ◽  
Vol 21 (21) ◽  
pp. 7872
Author(s):  
Polina V. Shnaider ◽  
Olga M. Ivanova ◽  
Irina K. Malyants ◽  
Ksenia S. Anufrieva ◽  
Ilya A. Semenov ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Genetic Alterations ◽  
Therapeutic Interventions ◽  
Molecular Response ◽  
Mesenchymal Transition ◽  
Third Line ◽  
Molecular Aspects

The malignant tumor is a complex heterogeneous set of cells functioning in a no less heterogeneous microenvironment. Like any dynamic system, cancerous tumors evolve and undergo changes in response to external influences, including therapy. Initially, most tumors are susceptible to treatment. However, remaining cancer cells may rapidly reestablish the tumor after a temporary remission. These new populations of malignant cells usually have increased resistance not only to the first-line agent, but also to the second- and third-line drugs, leading to a significant decrease in patient survival. Multiple studies describe the mechanism of acquired therapy resistance. In past decades, it became clear that, in addition to the simple selection of pre-existing resistant clones, therapy induces a highly complicated and tightly regulated molecular response that allows tumors to adapt to current and even subsequent therapeutic interventions. This review summarizes mechanisms of acquired resistance, such as secondary genetic alterations, impaired function of drug transporters, and autophagy. Moreover, we describe less obvious molecular aspects of therapy resistance in cancers, including epithelial-to-mesenchymal transition, cell cycle alterations, and the role of intercellular communication. Understanding these molecular mechanisms will be beneficial in finding novel therapeutic approaches for cancer therapy.

scholarly journals Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo Zhou ◽  
Meng Xia ◽  
Bin Wang ◽  
Niresh Thapa ◽  
Lijuan Gan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Annexin V ◽  
Therapy Resistance ◽  
Tumor Xenograft ◽  
Cancer Cell Growth ◽  
Cisplatin Therapy

Abstract Background Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo. Results We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone. Conclusion Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

scholarly journals A Panel of Emerging EMT Genes Identified in Malignant Mesothelioma

2021 ◽  
Author(s):  
Licun Wu ◽  
Shaheer Amjad ◽  
Hana Yun ◽  
Sendurai Mani ◽  
Marc de Perrot
Keyword(s):  
Malignant Mesothelioma ◽  
Patient Survival ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Gene Signature ◽  
Optimal Model ◽  
Mesenchymal Transition ◽  
Aggressive Cancer ◽  
Immunosuppressive Microenvironment ◽  
Critical Process

Abstract Malignant mesothelioma (MESO) is a highly aggressive cancer with poor prognosis. Epithelial-mesenchymal transition (EMT) is a critical process in malignancies involved in tumor angiogenesis, progression, invasion and metastasis, immunosuppressive microenvironment and therapy resistance. However, there is a lack of specific biomarkers to identify EMT in MESO. Biphasic MESO with dual phenotypes could be an optimal model to study EMT process. Using a powerful EMTome to investigate EMT gene signature, we identified a panel of EMT genes COL5A2, ITGAV, SPARC and ACTA2 in MESO. In combination with TCGA database, Timer2.0 and other resources, we observed that overexpression of these emerging genes is positively correlated with immunosuppressive infiltration, and an unfavorable factor to patient survival in MESO. The expression of these genes was confirmed in our patients and human cell lines. Our findings suggest that these genes may be novel targets for therapeutics and prognosis in MESO and other types of cancers.

scholarly journals Adenylate kinase-4 modulates oxidative stress and stabilizes HIF-1α to drive lung cancer metastasis

2017 ◽  
Author(s):  
Yi-Hua Jan ◽  
Tsung-Ching Lai ◽  
Chih-Jen Yang ◽  
Yuan-Feng Lin ◽  
Ming-Shyan Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adenylate Kinase ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Aerobic Glycolysis ◽  
Xenograft Model ◽  
Gene Signature ◽  
Mesenchymal Transition ◽  
Lung Cancer Metastasis

AbstractDisrupting signaling axes that are essential for tumor metastasis may provide therapeutic opportunity to cure cancer. We previously identified adenylate kinase 4 (AK4) as a biomarker of metastasis in lung cancer. Here we analyze AK4-associated metabolic gene signature and reveal HIF-1α is transcriptionally activated and associated with poor prognosis in lung adenocarcinoma patients. Overexpression of AK4 shifts metabolism towards aerobic glycolysis and elevates intracellular reactive oxygen species (ROS), which stabilizes and exaggerates HIF1-α protein expression and concurrently drives epithelial-to-mesenchymal transition (EMT) in hypoxia. Furthermore, overexpression of AK4 reduces hypoxic necrosis in tumors and promotes liver metastasis in vivo. Connectivity map analysis of AK4 gene signature identifies Withaferin-A as a potential compound to inhibit AK4-HIF-1α signaling axis, which then shows promising anti-metastatic potency in an orthotopic xenograft model of lung cancer. Our findings offer an alternative strategy to impair lung cancer metastasis via targeting AK4-HIF-1α axis.

CDK12 Promotes Breast Cancer Progression and Maintains Stemness by Activating c-myc/β -catenin Signaling

2020 ◽  
Vol 20 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Fang Peng ◽  
Chuansheng Yang ◽  
Yanan Kong ◽  
Xiaojia Huang ◽  
Yanyu Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Lung Metastasis ◽  
Xenograft Model ◽  
Breast Cancer Cell Lines ◽  
Cell Renewal ◽  
Cancer Stemness ◽  
Mesenchymal Transition ◽  
Potential Biomarker

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness. Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway. Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis. Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.

scholarly journals Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 75
Author(s):  
Paula I. Escalante ◽  
Luis A. Quiñones ◽  
Héctor R. Contreras
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Epithelial Mesenchymal Transition ◽  
Late Onset ◽  
Dihydropyrimidine Dehydrogenase ◽  
Acquired Resistance ◽  
Potential Effect ◽  
Mesenchymal Transition ◽  
Folfox Chemotherapy

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

Sign in / Sign up

Export Citation Format

Share Document