Artículo

Orozco, C.A.; Martinez-Bosch, N.; Guerrero, P.E.; Vinaixa, J.; Dalotto-Moreno, T.; Iglesias, M.; Moreno, M.; Djurec, M.; Poirier, F.; Gabius, H.-J.; Fernandez-Zapico, M.E.; Hwang, R.F.; Guerra, C.; Rabinovich, G.A.; Navarro, P. "Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk" (2018) Proceedings of the National Academy of Sciences of the United States of America. 115(16):E3769-E3778
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Abstract:

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. © 2018 National Academy of Sciences. All Rights Reserved.

Registro:

Documento: Artículo
Título:Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
Autor:Orozco, C.A.; Martinez-Bosch, N.; Guerrero, P.E.; Vinaixa, J.; Dalotto-Moreno, T.; Iglesias, M.; Moreno, M.; Djurec, M.; Poirier, F.; Gabius, H.-J.; Fernandez-Zapico, M.E.; Hwang, R.F.; Guerra, C.; Rabinovich, G.A.; Navarro, P.
Filiación:Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, 08003, Spain
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, C1428ADN, Argentina
Department of Pathology, Autonomous University of Barcelona, Barcelona, 08005, Spain
Centro de Investigación Biomédica en Red de Cáncer, Hospital del Mar, Barcelona, 08005, Spain
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, 28029, Spain
Jacques Monod Institute, Paris Diderot University, UMR CNRS 7592, Paris Cedex 013, 75205, France
Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, Munich, D-80539, Germany
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, United States
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77230, United States
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428, Argentina
Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona, 080036, Spain
Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Campus de Montilivi, Girona, 17003, Spain
Palabras clave:Galectin-1; Pancreatic cancer; Pancreatic stellate cells; Tumor immunity; Tumor microenvironment; galectin 1; galectin; galectin 1; LGALS1 protein, human; small interfering RNA; angiogenesis; animal cell; animal experiment; animal model; animal tissue; BALB/c nude mouse; cancer growth; cancer inhibition; cancer survival; carcinogenesis; cell invasion; cell migration; cell proliferation; controlled study; Gal1 gene; gene deletion; gene expression; genetic analysis; human; human cell; in vitro study; in vivo study; inflammation; lymphocytic infiltration; metastasis; molecular interaction; molecular pathology; mouse; nonhuman; oncogene K ras; pancreas adenocarcinoma; pancreas cancer; pancreatic stellate cell; priority journal; protein function; Review; signal transduction; stroma; transgenic mouse; tumor immunity; tumor invasion; tumor microenvironment; tumor promotion; tumor vascularization; animal; cell division; cell motion; conditioned medium; gene expression regulation; gene knockdown; gene ontology; genetics; immunology; knockout mouse; metabolism; molecularly targeted therapy; neovascularization (pathology); pancreas carcinoma; pancreas tumor; paracrine signaling; physiology; stroma cell; transplantation; tumor associated leukocyte; tumor microenvironment; vascularization; xenograft; Animals; Carcinoma, Pancreatic Ductal; Cell Division; Cell Movement; Culture Media, Conditioned; Galectin 1; Galectins; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene Ontology; Heterografts; Humans; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Knockout; Mice, Transgenic; Molecular Targeted Therapy; Neoplasm Metastasis; Neovascularization, Pathologic; Pancreatic Neoplasms; Pancreatic Stellate Cells; Paracrine Communication; RNA, Small Interfering; Stromal Cells; Tumor Microenvironment
Año:2018
Volumen:115
Número:16
Página de inicio:E3769
Página de fin:E3778
DOI: http://dx.doi.org/10.1073/pnas.1722434115
Título revista:Proceedings of the National Academy of Sciences of the United States of America
Título revista abreviado:Proc. Natl. Acad. Sci. U. S. A.
ISSN:00278424
CODEN:PNASA
CAS:galectin 1, 258495-34-0; Culture Media, Conditioned; Galectin 1; Galectins; LGALS1 protein, human; RNA, Small Interfering
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v115_n16_pE3769_Orozco

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Citas:

---------- APA ----------
Orozco, C.A., Martinez-Bosch, N., Guerrero, P.E., Vinaixa, J., Dalotto-Moreno, T., Iglesias, M., Moreno, M.,..., Navarro, P. (2018) . Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk. Proceedings of the National Academy of Sciences of the United States of America, 115(16), E3769-E3778.
http://dx.doi.org/10.1073/pnas.1722434115
---------- CHICAGO ----------
Orozco, C.A., Martinez-Bosch, N., Guerrero, P.E., Vinaixa, J., Dalotto-Moreno, T., Iglesias, M., et al. "Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk" . Proceedings of the National Academy of Sciences of the United States of America 115, no. 16 (2018) : E3769-E3778.
http://dx.doi.org/10.1073/pnas.1722434115
---------- MLA ----------
Orozco, C.A., Martinez-Bosch, N., Guerrero, P.E., Vinaixa, J., Dalotto-Moreno, T., Iglesias, M., et al. "Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk" . Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 16, 2018, pp. E3769-E3778.
http://dx.doi.org/10.1073/pnas.1722434115
---------- VANCOUVER ----------
Orozco, C.A., Martinez-Bosch, N., Guerrero, P.E., Vinaixa, J., Dalotto-Moreno, T., Iglesias, M., et al. Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk. Proc. Natl. Acad. Sci. U. S. A. 2018;115(16):E3769-E3778.
http://dx.doi.org/10.1073/pnas.1722434115