Platelet-derived growth factor-C (PDGF-C) activation by serine proteases: implications for breast cancer progression

Abstract

The PDGF family members are potent mitogens for cells of mesenchymal origin and serve as important regulators of cell migration, survival, apoptosis, and transformation. Tumor-derived PDGF ligands are thought to function in both autocrine and paracrine manners, activating receptors on tumor and surrounding stromal cells. PDGF-C and -D are secreted as latent dimers, unlike PDGF-A and -B. Cleavage of the CUB domain from the PDGF-C and -D dimers is required for their biological activity. At present, little is known about the proteolytic processing of PDGF-C, the rate-limiting step in the regulation of PDGF-C activity. Here we show that the breast carcinoma cell line, MCF7, engineered to overexpress PDGF-C, produces proteases capable of cleaving PDGF-C to its active form. Increased PDGF-C expression enhances cell proliferation, anchorage independent cell growth, and tumor cell motility by autocrine signaling. In addition, MCF7-produced PDGF-C induces fibroblast cell migration in a paracrine manner. Interestingly, PDGF-C enhances tumor cell invasion in the presence of fibroblast, suggesting a role of tumor-derived PDGF-C in tumor-stromal interactions. In the present study, we identify tissue plasminogen activator (tPA) and matriptase as major proteases for processing of PDGF-C in MCF7 cells. In in vitro studies, we also show that urokinase plasminogen activator (uPA) is able to process PDGF-C. Furthermore, by site-directed mutagenesis, we identify the cleavage site for these proteases in PDGF-C. Lastly, we provide evidence suggesting a 2-step proteolytic processing of PDGF-C involving creation of a hemidimer, followed by growth factor domain dimer (GFD-D) generation.

The wound healing, chronic fibrosis, and cancer progression triad

“…Hence, PDGF-induced cell proliferation could very well sustain a desmoplastic reaction while supporting tumor progression, thus fueling a protumorigenic vicious cycle (20). Some studies suggest that PDGF could sustain or even initiate desmoplasia in breast cancer (148,326), while others point to the fact that PDGF is a promigratory factor (67) as well as an EMT regulator (388). Furthermore, PDGF expression can also affect other growth factors, as inhibition of stromal PDGF receptors in a murine model of cervical cancer was shown to alter the levels of expression of the fibroblast growth factors (FGF)-2 and -7 (287).…”

Pericellular proteolysis in cancer

“…While the PDGF ligands A and B are secreted as active heterodimers or homodimers, PDGF ligands C and D are secreted as latent homodimers that require proteolytic activation (Li et al 2000;Bergsten et al 2001). tPA, uPA, and matriptase have been shown to proteolytically activate PDGF-C and PDGF-D (Hurst et al 2012). Pericellular activation of HGF is mediated by the serine proteases matriptase and hepsin (Owen et al 2010).…”

Platelet-derived growth factor-C functions as a growth factor in mouse embryonic stem cells and human fibrosarcoma cells

“…In colorectal tumors, PDGF-C overexpression is significantly associated with worse overall and relapse-free survival [31]. The enforced expression of PDGF-C has also been shown to promote the growth of breast cancer cells [34]. In this study, we demonstrated that PDGF-C promotes the growth of fibrosarcoma cells and ES cells.…”