TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer
| العنوان: | TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer |
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| المؤلفون: | Artemiy Golden, Moshe Elkabets, Manu Prasad, Liron Levin, Ben-Zion Joshua, Ksenia M. Yegodayev, Orr Dimitstein, Sankar Jagadeeshan, Ekaterina Khrameeva, Jonathan Zorea, Ofra Novoplansky, Limor Cohen |
| المصدر: | Cancers Volume 12 Issue 2 Cancers, Vol 12, Iss 2, p 339 (2020) |
| بيانات النشر: | Multidisciplinary Digital Publishing Institute, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Stromal cell, therapy resistance, cancer-associated fibroblast, Cetuximab, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, In vivo, TGF beta signaling pathway, Medicine, tumor microenvironment, Epidermal growth factor receptor, neoplasms, Tumor microenvironment, biology, integumentary system, business.industry, Head and neck cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, digestive system diseases, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Cancer-Associated Fibroblasts, head and neck cancer, business, medicine.drug |
| الوصف: | Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epidermal growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms of cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the transforming growth factor-beta (TGF-beta) signaling pathway was upregulated in the stromal cells of PDXs that progressed on cetuximab treatment (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab (CetuximabSen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs) of CetuximabProg-PDX. These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of CetuximabProg-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| DOI: | 10.3390/cancers12020339 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::78b42c9b2f4d9f5ad49ca17581e6759d |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....78b42c9b2f4d9f5ad49ca17581e6759d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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| DOI: | 10.3390/cancers12020339 |