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.
Highlights
Uterine carcinosarcoma (UCS) is a highly aggressive tumor that constitutes 3-4% of uterine cancers [1, 2]
Role of transforming growth factor-β1 (TGFβ1) in mediating an aggressive UCS phenotype Based on our previous report on the significance of transforming growth factor-β (TGFβ) signaling in UCS [26] and other studies demonstrating am
Plification of the TGFβ locus in UCS, [31] we evaluated the mRNA expression of TGFβ1, TGFβ2, TGFβR1 and TGFβR2 using reverse transcription quantitative real time polymerase chain reaction (RT-qPCR). mRNA for TGFβ1, TGFβ2, TGFβR1 and TGFβR2 could be detected in both the CS-99 and UMMT-ARK1 cell lines (Fig. 1A)
Summary
Uterine carcinosarcoma (UCS) is a highly aggressive tumor that constitutes 3-4% of uterine cancers [1, 2]. In non-malignant epithelial tissues, TGFβ1 plays an essential role in maintaining homeostasis by its ability to inhibit cell cycle progression and by promoting apoptosis [13,14,15,16,17,18,19,20,21,22,23,24]. The role of TGFβ1 in tumorigenesis is complex and its tumor promoting functions are closely linked to the initiation of an EMT program [25]. Aberrant TGFβ1 signaling in UCS [26] and other carcinomas of the breast and pancreas endow tumor cells with a selective advantage of enhanced motility and resistance to chemotherapeutics with an expansion of cancer-initiating stem-like cells [2729]. The MatrigelTM based 3D culture system supports anchorage-independent growth and provides an acellular scaffold composed of collagen and other extracellular matrix (ECM) components, which, in part, recapitulate the tumor microenvironment [30]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
