Targeting the TGFβ pathway in uterine carcinosarcoma.

IF 4.1 Q2 CELL BIOLOGY

Cell Stress Pub Date : 2020-08-25 DOI:10.15698/cst2020.11.234

Shailendra Kumar Dhar Dwivedi, Geeta Rao, Anindya Dey, Megan Buechel, Yushan Zhang, Min Zhang, Da Yang, Priyabrata Mukherjee, Resham Bhattacharya

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引用次数: 8

Abstract

Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. Interestingly, GLT sensitizes UCS cells to chemotherapy both in vitro and in in vivo preclinical tumor model. Hence, targeting TGFβ signaling, in combination with standard chemotherapy, may be exploited as an important strategy to manage the clinically challenging UCS.

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靶向子宫癌肉瘤中TGFβ通路。

子宫癌肉瘤（UCS）是一种相对罕见但极具侵袭性的子宫内膜恶性肿瘤。尽管手术和化疗已经改善了结果，但由于缺乏靶向治疗和双相（上皮和间充质）性质，使肿瘤具有侵袭性且难以控制，总生存率（OS）仍然令人沮丧。在此，我们报道了转化生长因子-β（TGFβ）在UCS中维持上皮-间质转化（EMT）表型和侵袭性的作用。使用3D培养系统，我们评估了转化生长因子-β受体-I（TGFβR1）激酶抑制剂Galuniserib（GLT）单独使用和与用于治疗UCS的标准化疗药物联合使用的疗效。我们证明，GLT通过抑制转化生长因子-β1（TGFβ1）发出的经典和非经典信号降低了细胞活力、侵袭、克隆生长和分化。有趣的是，GLT在体外和体内临床前肿瘤模型中都能使UCS细胞对化疗敏感。因此，靶向TGFβ信号传导，结合标准化疗，可以作为治疗临床挑战性UCS的重要策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)

CiteScore

13.50

自引率

0.00%

发文量

审稿时长

15 weeks

期刊介绍： Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.