Functions of Paracrine PDGF Signaling in the Proangiogenic Tumor Stroma Revealed by Pharmacological Targeting

Memorial Sloan-Kettering Cancer Center, United States of America
PLoS Medicine (Impact Factor: 14.43). 02/2008; 5(1):e19. DOI: 10.1371/journal.pmed.0050019
Source: PubMed


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.

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    • "CAFs play an important role in angiogenesis. When CAF-secreted fibroblast growth factor-2 (FGF-2) is inhibited, angiogenesis is reduced (Pietras et al., 2008). Furthermore, brivanib (a dual VEGF/ FGF tyrosine kinase inhibitor) effectively blocks angiogenesis in a pancreatic neuroendocrine tumor model (Allen et al., 2011). "
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    ABSTRACT: It is well established that the tumour microenvironment contributes to cancer progression. Stromal cells can be divided into mesenchymal, vascular and immune. Signalling molecules secreted by the tumour corrupts these cells to create ‘activated’ stroma. Equally, the extracellular matrix contributes to tumour development and invasion by forming a biologically active scaffold. In this review we describe the key structural, cellular and signalling components of the tumour microenvironment with a perspective on stromal soluble factors and microRNAs.
    Full-text · Article · May 2015 · Frontiers in Cell and Developmental Biology
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    • "The PDGF pathway has been implicated in proliferation and angiogenesis in many malignancies. Indeed, PDGF and/or PDGF receptors are expressed in a variety of malignancies including melanoma [43] colorectal [44], lung [45], colon [46], cervical [47] and breast cancer [48]; in all cases PDGF signaling plays a key role in tumor growth and progression. "
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    ABSTRACT: Luminal, estrogen receptor-positive breast cancers represent more than 70% of cases. Despite initial good prognoses one third of Luminal cancers eventually recur locally or at distant sites and exhibit hormone resistance. Here we demonstrate that factors elaborated by malignant stromal cells can induce Luminal tumor cells proliferation and promote angiogenesis and hormone independence. We recently isolated a malignant mouse mammary gland stromal cell line named BJ3Z that increases proliferation and angiogenesis in estrogen-free xenografted Luminal MCF-7 breast cancer cells. BJ3Z and Normal mouse mammary Fibroblasts (NMFs) were expression profiled using microarray assays. Messenger RNA levels were confirmed by RT-PCR and by immunohistochemistry (IHC). Breast cancer MCF-7, BT-474, BT-20 and MDA-MB-231cell lines and stromal BJ3Z and NMFs were grown for in vitro assays: breast cancer cell lines were treated with stromal cells conditioned media, for three-dimensional (3D) mono and co-cultures in Matrigel, proliferation was measured by Bromo-deoxyuridine (BrdU) incorporation using IHC. Tubule formation in vitro, a proxy for angiogenesis, was assessed using 3D cultured Human Umbilical cord Vascular Endothelial Cells (HUVEC). We show that under estrogen-free conditions, BJ3Z cells but not NMFs increase proliferation of co-cultured Luminal but not basal-like human breast cancer cells in 2D or as 3D Matrigel colonies. Gene expression profiling, RT-PCR analysis and IHC of colony-derived BJ3Z cells and NMFs shows that Platelet Derived Growth Factor ligands (PDGF-A and -B) are elaborated by BJ3Z cells but not NMFs; while PDGF receptors are present on NMFs but not BJ3Z cells. As a result, in colony co-culture assays, BJ3Z cells but not NMFs increase MCF-7 cell proliferation. This can be mimicked by direct addition of PDGF-BB, and blocked by the PDGF receptor inhibitor Imatinib Mesylate. Both normal and malignant stromal cells enhance angiogenesis in an in vitro model. This effect is also due to PDGF and is suppressed by Imatinib. We provide evidence that Luminal breast cancer cells can be targeted by the PDGF signaling pathway leading to estrogen-independent proliferation and angiogenesis. We speculate that stroma-directed therapies, including anti-PDGFR agents like Imatinib, may be useful in combination with other therapies for treatment of luminal cancers.
    Full-text · Article · Oct 2014 · BMC Cancer
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    • "The role of FGF-2 was confirmed in another study in which murine melanoma cells overexpressed PDGF-C, which induced increased TAF content in tumours. The TAFs expressed FGF-2 and the matricellular protein osteopontin[20]. The TAFs promoted increased tumour growth and angiogenesis, through production of the chemokine stromal derived factor 1α (SDF-1α a.k.a. "
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    ABSTRACT: In addition to malignant cells, solid tumours comprise supporting stromal tissue that consists of Extra Cellular Matrix (ECM), connective tissue cells, inflammatory cells and blood vessels. The stromal compartment and the malignant cells together shape the tumour microenvironment that in turn determines tumour progression and efficacy of anti-tumour treatments. It is now recognized that the host microenvironment undergoes extensive change during the evolution and progression of cancer. This involves the generation of Tumour-Associated Fibroblasts (TAFs), which, through release of growth factors and cytokines, lead to enhanced angiogenesis, increased tumour growth and invasion. It has also been demonstrated that TAFs may modulate the Cancer Stem Cell (CSC) phenotype, which has therapeutic implications. Understanding the various components in the tumour microenvironment may afford us the opportunity to develop new drugs that target these reversible nonmutational events in the prevention and treatment of cancer.
    Full-text · Article · Sep 2013
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