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Title: The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels
Author: Alsina Sanchís, Elisenda
Figueras i Amat, Agnès
Lahiguera, Álvaro
Vidal-Bel, August
Casanovas i Casanovas, Oriol
Graupera i Garcia-Milà, Mariona
Villanueva Garatachea, Alberto
Viñals Canals, Francesc
Keywords: Factors de creixement
Càncer d'ovari
Proliferació cel·lular
Cèl·lules epitelials
Receptors d'insulina
Growth factors
Ovarian cancer
Cell proliferation
Epithelial cells
Insulin receptors
Issue Date: 15-Oct-2016
Publisher: Wiley
Abstract: In a search for new therapeutic targets for treating epithelial ovarian cancer, we analyzed the Transforming Growth Factor Beta (TGFβ) signaling pathway in these tumors. Using a TMA with patient samples we found high Smad2 phosphorylation in ovarian cancer tumoral cells, independently of tumor subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human ovarian cancer orthotopically grown in nude mice (OVAs). Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumor size in all these models, affecting cell proliferation rate. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumor cell proliferation. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC-A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. When IGF1R levels were decreased by shRNA treatment, LY2109761 lost its capacity to block tumoral ovarian cell proliferation. At the molecular level TGFβ induced mRNA IGF1R levels. Overall, our results suggest an important role for the TGFβ signaling pathway in ovarian tumor cell growth through the control of IGF1R signaling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition.
Note: Versió postprint del document publicat a:
It is part of: International Journal of Cancer, 2016, vol. 139, num. 8, p. 1894-1903
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ISSN: 0020-7136
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Fisiològiques)

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