The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer
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Neus Martínez-Bosch1, Pedro Enrique Guerrero1, Mireia Moreno1, Anabel José2,3, Mar Iglesias4, Jessica Munné-Collado4, Héctor Anta1,5, Joan Gibert1, Carlos Alberto Orozco1, Judith Vinaixa1, Cristina Fillat2,3, Francesc Viñals6, Pilar Navarro1
1Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
2Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Barcelona, Spain
3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
4Pathology Service, Hospital del Mar, Barcelona, Spain
5Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
6Catalan Institute of Oncology-IDIBELL, Barcelona University, Barcelona, Spain
Pilar Navarro, email: [email protected]
Keywords: sunitinib, pancreatic cancer, PDA, acinar carcinoma, fibrosis
Received: January 14, 2016 Accepted: June 06, 2016 Published: June 21, 2016
Current treatments for pancreatic ductal adenocarcinoma (PDA) are ineffective, making this the 4th leading cause of cancer deaths. Sunitinib is a broad-spectrum inhibitor of tyrosine kinase receptors mostly known for its anti-angiogenic effects. We tested the therapeutic effects of sunitinib in pancreatic cancer using the Ela-myc transgenic mouse model. We showed that Ela-myc pancreatic tumors express PDGFR and VEGFR in blood vessels and epithelial cells, rendering these tumors sensitive to sunitinib by more than only its anti-angiogenic activity. However, sunitinib treatment of Ela-myc mice with either early or advanced tumor progression had no impact on either survival or tumor burden. Further histopathological characterization of these tumors did not reveal differences in necrosis, cell differentiation, angiogenesis, apoptosis or proliferation. In stark contrast, in vitro sunitinib treatment of Ela-myc– derived cell lines showed high sensitivity to the drug, with increased apoptosis and reduced proliferation. Correspondingly, subcutaneous tumors generated from these cell lines completely regressed in vivo after sunitinib treatments. These data point at the pancreatic tumor microenvironment as the most likely barrier preventing sunitinib treatment efficiency in vivo. Combined treatments with drugs that disrupt tumor fibrosis may enhance sunitinib therapeutic effectiveness in pancreatic cancer treatment.
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