1. Department of Biochemistry and Biophysics, Diabetes Center and Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America, 2. Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden, 3 Department of Neurosurgery, University of California San Franciso, San Francisco, California, United States of America
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.
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.
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.
Funding: The research was supported by grants to DH and to GB from the US National Cancer Institute, and by an award to DH from the William F. Bowes Charitable Foundation. DH is an American Cancer Society Research Professor. KP received support from the Swedish Cancer Society, the Swedish Society for Medical Research, the ?ke Wiberg's Foundation, the Royal Swedish Academy of Sciences, and the Swedish Research Council's Linnaeus grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Academic Editor: Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, United States of America
Citation: Pietras K, Pahler J, Bergers G, Hanahan D (2008) Functions of Paracrine PDGF Signaling in the Proangiogenic Tumor Stroma Revealed by Pharmacological Targeting . PLoS Med 5(1): e19 doi:10.1371/journal.pmed.0050019
Received: May 29, 2007; Accepted: December 6, 2007; Published: January 29, 2008
Copyright: © 2008 Pietras et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abbreviations: CAF, cancer-associated fibroblast; CIN, cervical intraepithelial neoplasia; E2, 17?-estradiol; FACS, fluorescence activated cell sorting; FGF, fibroblast growth factor; HPV, human papilloma virus; K14, keratin 14; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; rt, room temperature; RT-PCR, reverse-transcription polymerase chain reaction; SCC, squamous cell carcinoma; VEGF, vascular endothelial growth factor
* To whom correspondence should be addressed. E-mail: kristian.pietras@licr.ki.se (KP); dh@biochem.ucsf.edu (DH)
