Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk
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 microenvi...
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_00278424_v115_n16_pE3769_Orozco |
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todo:paper_00278424_v115_n16_pE3769_Orozco2023-10-03T14:38:16Z Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk 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. 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 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00278424_v115_n16_pE3769_Orozco |
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Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 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 |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
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. |
| author_facet |
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. |
| author_sort |
Orozco, C.A. |
| title |
Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk |
| title_short |
Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk |
| title_full |
Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk |
| title_fullStr |
Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk |
| title_full_unstemmed |
Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk |
| title_sort |
targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk |
| url |
http://hdl.handle.net/20.500.12110/paper_00278424_v115_n16_pE3769_Orozco |
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