PDGF-C Mediates the Angiogenic and Tumorigenic Properties of Fibroblasts Associated with Tumors Refractory to Anti-VEGF Treatment

Abstract

Tumor- or cancer-associated fibroblasts (TAFs or CAFs) from different tumors exhibit distinct angiogenic and tumorigenic properties. Unlike normal skin fibroblasts or TAFs from TIB6 tumors that are sensitive to anti-VEGF treatment (TAF-TIB6), TAFs from resistant EL4 tumors (TAF-EL4) can stimulate TIB6 tumor growth even when VEGF is inhibited. We show that platelet-derived growth factor C (PDGF-C) is upregulated in TAFs from resistant tumors. PDGF-C-neutralizing antibodies blocked the angiogenesis induced by such TAFs in vivo, slowed the growth of EL4 and admixture (TAF-EL4 + TIB6) tumors, and exhibited additive effects with anti-VEGF-A antibodies. Hence, our data reveal an additional mechanism for TAF-mediated tumorigenesis and suggest that some tumors may overcome inhibition of VEGF-mediated angiogenesis through upregulation of PDGF-C.

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

“…In support of this latter concept, FGF2 is upregulated in a mouse tumour model of acquired resistance to DC101 (a VEGFR2 inhibitory antibody) and inhibition of FGF2 in combination with DC101 led to improved anti-tumour responses (Casanovas et al, 2005). Moreover, inhibition of PLGF or PDGF has been reported to enhance the anti-tumour efficacy of VEGF pathway inhibitors in some murine tumour models (Bergers et al, 2003;Fischer et al, 2007;Crawford et al, 2009). Another recent study demonstrated that IL-8 is upregulated in sunitinib-resistant tumour xenografts and that inhibition of IL-8 can re-sensitize these resistant tumours to sunitinib (Huang et al, 2010b).…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…The high interstitial pressure measured in the desmoplastic stroma limits tumor blood vessel perfusion and the delivery of chemo and other forms of therapy. Furthermore, CAFs may also mediate resistance to anti‐VEGF therapy, likely via their production of stromal‐cell derived factor‐1 (SDF1, or CXCL12) – a potent chemotactic signal for proangiogenic myeloid cells (Orimo et al., 2005) – or by directly stimulating angiogenesis via their secretion of platelet‐derived growth factor‐C (PDGF‐C) (Crawford et al., 2009) and basic fibroblast growth factor (FGF2) (Pietras et al., 2008). …”

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

“…2). [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Several types of cancers, particularly those derived from the ovary, prostate, breast, lung, brain, skin, and bone, express PDGFRa on the malignant cells themselves (Table 1). 22 In 1 experiment in which a human tumor array was probed with a cross-reactive polyclonal rabbit antibody to PDGFRa, PDGFRa expression was noted in approximately 95% of osteosarcomas and chondrosarcomas, in 77% of prostate cancers, in 52% of ovarian cancers, in 65% of breast cancers, and in 51% of lung cancers (N. Loizos, ImClone Systems, unpublished results).…”

“…PDGFs can influence cancer growth and malignant angiogenesis through several mechanisms, including the activation of PDGFRa expressed on cancer cells, stromal fibroblasts, and vascular endothelial cells and by PDGF-induced production of vascular endothelial growth factor (VEGF) by stromal cells. [45][46][47][48][49][50][51][52][53][54][55]57,60 The asterisk indicates that Table 1 required for the development of malignant stroma, 46 a separate study indicated that the induction of PDGF-CC expression in melanoma cells led to accelerated tumor growth through the activation of PDGFRa. 47 In the latter study, the exclusive expression of PDGFRa on cancerassociated stromal fibroblasts illuminated a paracrine mechanism of stromal-regulated melanoma tumor growth.…”