Abstract：
:Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Martínez-Bosch N,Fernández-Barrena MG,Moreno M,Ortiz-Zapater E,Munné-Collado J,Iglesias M,André S,Gabius HJ,Hwang RF,Poirier F,Navas C,Guerra C,Fernández-Zapico ME,Navarro Pdoi
10.1158/0008-5472.CAN-13-3013subject
Has Abstractpub_date
2014-07-01 00:00:00pages
3512-24issue
13eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-13-3013journal_volume
74pub_type
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