Abstract
BackgroundImportant 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.Methods and FindingsWe 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.ConclusionsThis 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.
Highlights
It is increasingly accepted that cancer results from the concerted performance of genetically altered tumor cells interacting with ostensibly normal cell types that together constitute the tumor microenvironment [1]
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
In keratin 14 (K14)-HPV type 16 (HPV16) female transgenic mice whose estrogen levels are maintained by time-release implants (HPV/E2 mice), incipient neoplasias first appear in the transformation zone, arising out of the human papilloma viruses (HPV)-16 oncogene-expressing squamous epithelium; the progressive neoplastic lesions are associated with an aberrant (‘‘reactive’’) stroma [28]
Summary
It is increasingly accepted that cancer results from the concerted performance of genetically altered tumor cells interacting with ostensibly normal cell types that together constitute the tumor microenvironment [1]. In addition to the endothelial cells forming the tumor vasculature, attention is focused on other elements of the stromal compartment, i.e. carcinoma-associated fibroblasts (CAFs), vascular pericytes, and infiltrating inflammatory cells These cell types are being implicated as functionally important for tumorigenesis, by providing proliferative and antiapoptotic regulatory factors, supporting tumor angiogenesis, and facilitating invasion [2,3,4,5,6,7]. The stroma contains endothelial cells and pericytes (which line the inside and coat the outside, respectively, of blood vessels), cancer-associated fibroblasts, and some immune system cells Together, these cells support angiogenesis (the formation of a blood supply, which feeds the tumor), produce factors that stimulate tumor cell growth, and facilitate tumor cell invasion into surrounding tissues. Some of these early lesions, which are known as cervical intraepithelial neoplasias (CINs), develop into invasive cervical cancer, which is treated by surgery followed by chemotherapy or radiotherapy
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