Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.

<h4>Background</h4>Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory...

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Autores principales:	Kristian Pietras, Jessica Pahler, Gabriele Bergers, Douglas Hanahan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R
Acceso en línea:	https://doaj.org/article/9c65748b24e944daa7f342557e9cccfa
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spelling	oai:doaj.org-article:9c65748b24e944daa7f342557e9cccfa2021-11-25T05:37:07ZFunctions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.1549-12771549-167610.1371/journal.pmed.0050019https://doaj.org/article/9c65748b24e944daa7f342557e9cccfa2008-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18232728/?tool=EBIhttps://doaj.org/toc/1549-1277https://doaj.org/toc/1549-1676<h4>Background</h4>Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory cells. Fibroblasts have long been recognized inside carcinomas and are increasingly implicated as functional participants. The stroma is prominent in cervical carcinoma, and distinguishable from nonmalignant tissue, suggestive of altered (tumor-promoting) functions. We postulated that pharmacological targeting of putative stromal support functions, in particular those of cancer-associated fibroblasts, could have therapeutic utility, and sought to assess the possibility in a pre-clinical setting.<h4>Methods and findings</h4>We used a genetically engineered mouse model of cervical carcinogenesis to investigate platelet-derived growth factor (PDGF) receptor signaling in cancer-associated fibroblasts and pericytes. Pharmacological blockade of PDGF receptor signaling with the clinically approved kinase inhibitor imatinib slowed progression of premalignant cervical lesions in this model, and impaired the growth of preexisting invasive carcinomas. Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects. A ligand trap for the FGFs impaired the angiogenic phenotype similarly to imatinib. Thus PDGF ligands expressed by cancerous epithelia evidently stimulate PDGFR-expressing stroma to up-regulate FGFs, promoting angiogenesis and epithelial proliferation, elements of a multicellular signaling network that elicits functional capabilities in the tumor microenvironment.<h4>Conclusions</h4>This study illustrates the therapeutic benefits in a mouse model of human cervical cancer of mechanism-based targeting of the stroma, in particular cancer-associated fibroblasts. Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.Kristian PietrasJessica PahlerGabriele BergersDouglas HanahanPublic Library of Science (PLoS)articleMedicineRENPLoS Medicine, Vol 5, Iss 1, p e19 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R
spellingShingle	Medicine R Kristian Pietras Jessica Pahler Gabriele Bergers Douglas Hanahan Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.
description	<h4>Background</h4>Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory cells. Fibroblasts have long been recognized inside carcinomas and are increasingly implicated as functional participants. The stroma is prominent in cervical carcinoma, and distinguishable from nonmalignant tissue, suggestive of altered (tumor-promoting) functions. We postulated that pharmacological targeting of putative stromal support functions, in particular those of cancer-associated fibroblasts, could have therapeutic utility, and sought to assess the possibility in a pre-clinical setting.<h4>Methods and findings</h4>We used a genetically engineered mouse model of cervical carcinogenesis to investigate platelet-derived growth factor (PDGF) receptor signaling in cancer-associated fibroblasts and pericytes. Pharmacological blockade of PDGF receptor signaling with the clinically approved kinase inhibitor imatinib slowed progression of premalignant cervical lesions in this model, and impaired the growth of preexisting invasive carcinomas. Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects. A ligand trap for the FGFs impaired the angiogenic phenotype similarly to imatinib. Thus PDGF ligands expressed by cancerous epithelia evidently stimulate PDGFR-expressing stroma to up-regulate FGFs, promoting angiogenesis and epithelial proliferation, elements of a multicellular signaling network that elicits functional capabilities in the tumor microenvironment.<h4>Conclusions</h4>This study illustrates the therapeutic benefits in a mouse model of human cervical cancer of mechanism-based targeting of the stroma, in particular cancer-associated fibroblasts. Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.
format	article
author	Kristian Pietras Jessica Pahler Gabriele Bergers Douglas Hanahan
author_facet	Kristian Pietras Jessica Pahler Gabriele Bergers Douglas Hanahan
author_sort	Kristian Pietras
title	Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.
title_short	Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.
title_full	Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.
title_fullStr	Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.
title_full_unstemmed	Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.
title_sort	functions of paracrine pdgf signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/9c65748b24e944daa7f342557e9cccfa
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Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting.

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