Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth.

Autor: Resovi A; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Persichitti P; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Brunelli L; Department of Environmental Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Minoli L; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Borsotti P; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Garattini G; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Tironi M; Department of Biomedical Engineering, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy., Dugnani E; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy., Redegalli M; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., De Simone G; Department of Environmental Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Pastorelli R; Department of Environmental Science, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Bani MR; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Piemonti L; Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy., Mosher DF; Departments of Biomolecular Chemistry and Medicine, University of Wisconsin, Madison, WI, USA., Giavazzi R; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Taraboletti G; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy., Belotti D; Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy. dorina.belotti@marionegri.it.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2023 Aug 09; Vol. 42 (1), pp. 201. Date of Electronic Publication: 2023 Aug 09.
DOI: 10.1186/s13046-023-02778-y
Abstrakt: Background: The pancreatic microenvironment has a defensive role against cancer but it can acquire tumor-promoting properties triggered by multiple mechanisms including alterations in the equilibrium between proteases and their inhibitors. The identification of proteolytic events, targets and pathways would set the basis for the design of new therapeutic approaches.
Methods and Results: Here we demonstrate that spheroids isolated from human and murine healthy pancreas and co-transplanted orthotopically with pancreatic ductal adenocarcinoma (PDAC) in mouse pancreas inhibited tumor growth. The effect was mediated by trypsin-generated fibronectin (FN) fragments released by pancreatic spheroids. Tumor inhibition was observed also in a model of acute pancreatitis associated with trypsin activation. Mass spectrometry proteomic analysis of fragments and mAb against different FN epitopes identified the FN type III domain as responsible for the activity. By inhibiting integrin α5β1, FAK and FGFR1 signaling, the fragments induced tumor cell detachment and reduced cell proliferation. Consistent with the mutual relationship between the two pathways, FGF2 restored both FGFR1 and FAK signaling and promoted PDAC cell adhesion and proliferation. FAK and FGFR inhibitors additively inhibited PDAC growth in vitro and in orthotopic in vivo models.
Conclusions: This study identifies a novel role for pancreatic trypsin and fibronectin cleavage as a mechanism of protection against cancer by the pancreatic microenvironment. The finding of a FAK-FGFR cross-talk in PDAC support the combination of FAK and FGFR inhibitors for PDAC treatment to emulate the protective effect of the normal pancreas against cancer.
(© 2023. Italian National Cancer Institute ‘Regina Elena’.)
Databáze: MEDLINE
Externí odkaz: