期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 16, 页码 E3769-E3778出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1722434115
关键词
pancreatic cancer; galectin-1; tumor microenvironment; tumor immunity; pancreatic stellate cells
资金
- Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER Grants [PI14/00125, PI17/00199]
- Carmen Delgado/Miguel Perez-Mateo Asociacion Espanola de Pancreatologia/Asociacion Cancer de Pancreas Grant
- Generalitat de Catalunya Grant [2014/SGR/143]
- Mayo Clinic Pancreatic Specialized Program of Research Excellence Grant [P50 CA102701]
- Mayo Clinic Center for Cell Signaling in Gastroenterology Grant [P30 DK84567]
- International PhD Studies Fellowship Creditos Beca Francisco Jose de Caldas from the Colombian Administrative Department of Science, Technology and Innovation (Colciencias)
- La Caixa International Fellowship Program
- Argentinean Agency for Promotion of Science and Technology Grant [PICT 2014-3687]
- University of Buenos Aires
- Sales Foundation
- Bunge and Born Foundation
- Argentine National Scientific and Technical Research Council
Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53(-/-)) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.
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