Abstract
PDGF-C, which is abundant in the malignant breast tumor microenvironment, plays an important role in cell growth and survival. Because tumor-associated macrophages (TAMs) contribute to cancer malignancy, macrophage survival mechanisms are an attractive area of research into controlling tumor progression. In this study, we investigated PDGF-C-mediated signaling pathways involved in anti-apoptotic effects in macrophages. We found that the human malignant breast cancer cell line MDA-MB-231 produced high quantities of PDGF-C, whereas benign MCF-7 cells did not. Recombinant PDGF-C induced PDGF receptor α chain phosphorylation, followed by Akt and Bad phosphorylation in THP-1-derived macrophages. MDA-MB-231 culture supernatants also activated macrophage PDGF-Rα. PDGF-C prevented staurosporine-induced macrophage apoptosis by inhibiting the activation of caspase-3, -7, -8, and -9 and cleavage of poly(ADP-ribose) polymerase. Finally, TAMs isolated from the PDGF-C knockdown murine breast cancer cell line 4T1 and PDGF-C knockdown MDA-MB-231-derived tumor mass showed higher rates of apoptosis than the respective WT controls. Collectively, our results suggest that tumor cell-derived PDGF-C enhances TAM survival, promoting tumor malignancy.
Highlights
Aggressive breast tumor cells secrete platelet-derived growth factor C (PDGF-C)
The PDGF-C contents of the supernatants were assayed by Western blotting under reducing and nonreducing conditions (Fig. 1). Reducing proteins of both the fulllength monomer of PDGF-C at 48 kDa and the processed GFD monomer (GFD-M) expression at 17 kDa were detected in only the MDA-MB-231 culture supernatant (Fig. 1A)
Western blotting under non-reducing conditions confirmed the full-length dimer of PDGF-C (85 kDa), full-length monomer (48 kDa), and Reanalysis of MDA-MB-231 vs. MCF-7 breast cancer cell line microarray data
Summary
Aggressive breast tumor cells secrete platelet-derived growth factor C (PDGF-C). Significance: PDGF-C secreted from malignant tumor cells could affect the survival of tumor-associated macrophages. PDGF-C, which is abundant in the malignant breast tumor microenvironment, plays an important role in cell growth and survival. We found that the human malignant breast cancer cell line MDA-MB-231 produced high quantities of PDGF-C, whereas benign MCF-7 cells did not. Our results suggest that tumor cell-derived PDGF-C enhances TAM survival, promoting tumor malignancy. Effect of PDGF-C on Macrophage Survival greater number of malignant cells can produce chemoattractants as well as survival signals for monocytes/macrophages; these leukocytes increase the levels of factors that enhance the aggressiveness of tumor cells. We report that PDGF-C mediates anti-apoptotic effects through Akt/Bad phosphorylation, underlining the importance of the survival mechanisms of macrophages resident in tumors
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