The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels.
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.
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català D'Oncologia (ICO), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.|Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
Elisenda
E
Alsina-Sanchis
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català D'Oncologia (ICO), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.|Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
Agnès
A
Figueras
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català D'Oncologia (ICO), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.|Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
Álvaro
Á
Lahiguera
Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.|Servei D'Anatomia Patològica, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.|Xenopat S.L, Business Bioincubator, Bellvitge Health Science Campus, L'Hospitalet de Llobregat, Barcelona, Spain.
August
A
Vidal
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català D'Oncologia (ICO), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.|Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
Oriol
O
Casanovas
Laboratori D'Oncologia Molecular, Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Mariona
M
Graupera
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català D'Oncologia (ICO), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.|Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.|Xenopat S.L, Business Bioincubator, Bellvitge Health Science Campus, L'Hospitalet de Llobregat, Barcelona, Spain.
Alberto
A
Villanueva
Program Against Cancer Therapeutic Resistance (ProCURE), Institut Català D'Oncologia (ICO), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.|Institut D'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.|Departament de Ciències Fisiològiques II, Universitat de Barcelona, Avda Feixa Llarga S/N 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Francesc
F
Viñals
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000077216:Carcinoma, Ovarian Epithelial; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011897:Random Allocation; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000597236:IGF1R protein, human; C530108:LY2109761; D011720:Pyrazoles; D011758:Pyrroles; D017451:Receptors, Somatomedin; D016212:Transforming Growth Factor beta; C557414:cixutumumab; D017526:Receptor, IGF Type 1
IGF1R; TGFβ; epithelial ovarian tumors