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The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels
Author(s) -
AlsinaSanchis Elisenda,
Figueras Agnès,
Lahiguera Álvaro,
Vidal August,
Casanovas Oriol,
Graupera Mariona,
Villanueva Alberto,
Viñals Francesc
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30233
Subject(s) - insulin like growth factor 1 receptor , ovarian cancer , cancer research , cell growth , transforming growth factor , ovarian tumor , transforming growth factor beta , growth factor , signal transduction , insulin like growth factor receptor , cancer , biology , receptor , medicine , endocrinology , microbiology and biotechnology , genetics
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.