title: The pancreatic niche inhibits the effectiveness of sunitinib treatment of pancreatic cancer.
abstract: 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.
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Martínez-Bosch
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Pedro Enrique
authors.initials: PE
authors.lastname: Guerrero
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Anabel
authors.initials: A
authors.lastname: José
authors.affiliation: Pathology Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: Pathology Service, Hospital del Mar, Barcelona, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Munné-Collado
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.|Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Anta
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Gibert
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Orozco
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Vinaixa
authors.affiliation: Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
authors.affiliation: Catalan Institute of Oncology-IDIBELL, Barcelona University, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.affiliation: Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: PDA; acinar carcinoma; fibrosis; pancreatic cancer; sunitinib