VEGF-null cells require PDGFR α signaling-mediated stromal fibroblast recruitment for tumorigenesis

Abstract

We generated VEGF‐null fibrosarcomas from VEGF‐loxP mouse embryonic fibroblasts to investigate the mechanisms of tumor escape after VEGF inactivation. These cells were found to be tumorigenic and angiogenic in vivo in spite of the absence of tumor‐derived VEGF. However, VEGF derived from host stroma was readily detected in the tumor mass and treatment with a newly developed anti‐VEGF monoclonal antibody substantially inhibited tumor growth. The functional significance of stroma‐derived VEGF indicates that the recruitment of stromal cells is critical for the angiogenic and tumorigenic properties of these cells. Here we identified PDGF AA as the major stromal fibroblast chemotactic factor produced by tumor cells, and demonstrated that disrupting the paracrine PDGFR α signaling between tumor cells and stromal fibroblasts by soluble PDGFR α‐IgG significantly reduced tumor growth. Thus, PDGFR α signaling is required for the recruitment of VEGF‐producing stromal fibroblasts for tumor angiogenesis and growth. Our findings highlight a novel aspect of PDGFR α signaling in tumorigenesis.

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cancers, in 52% of ovarian cancers, in 65% of breast cancers, and in 51% of lung cancers (N. Loizos, ImClone Systems, unpublished results).…”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.…”

“…45,57 It also has been established that an intact PDGF/ PDGFRa axis is required for vascular endothelial growth factor (VEGF) production by tumor stroma and for the regulation of malignant angiogenesis in tumors that are resistant to antiangiogenic treatment. [52][53][54] The former was demonstrated in an elegant experiment in which VEGF-null fibrosarcomas grown in mice required the recruitment of PDGFRa-expressing stromal fibroblasts for VEGF production, angiogenesis, and tumorigenesis. 52 The recruitment of PDGFRa-expressing stromal fibroblasts depended on paracrine stimulation by PDGF-AA produced from the tumor cells.…”

“…[52][53][54] The former was demonstrated in an elegant experiment in which VEGF-null fibrosarcomas grown in mice required the recruitment of PDGFRa-expressing stromal fibroblasts for VEGF production, angiogenesis, and tumorigenesis. 52 The recruitment of PDGFRa-expressing stromal fibroblasts depended on paracrine stimulation by PDGF-AA produced from the tumor cells. When the PDGF/ PDGFRa axis was disrupted, both angiogenesis and tumorigenesis were reduced significantly.…”

The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells

“…A common cellular component of both tissues is fibroblasts, which generate ECM components and paracrine factors (Kalluri and Zeisberg, 2006). In tumors, stromal fibroblasts as well as cancer cells are a significant source of VEGF promoting angiogenesis (Hlatky et al, 1994;Fukumura et al, 1998;Dong et al, 2004). Although the phenotypic changes in tumor fibroblasts are considered responsible for the angiogenic properties as distinct from those of normal fibroblasts (Orimo et al, 2005;Kalluri and Zeisberg, 2006), fibroblasts from normal tissues also produce VEGF (Berse et al, 1992;Hlatky et al, 1994).…”