Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts

Abstract

Summary Loss of pigment epithelium-derived factor (PEDF, SERPINF1) in cancer cells is associated with poor prognosis and metastasis, but the contribution of stromal PEDF to cancer evolution is poorly understood. Therefore, we investigated the role of fibroblast-derived PEDF in melanoma progression. We demonstrate that normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. Accordingly, mice with global PEDF knockout were more susceptible to melanoma metastasis. We also demonstrate that normal fibroblasts in close contact with PEDF-null melanoma cells lost PEDF expression and tumor suppressive properties. Further mechanistic investigations underlying the crosstalk between tumor and stromal cells revealed that melanoma cells produced PDGF-BB and TGF-β, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGF-β-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of interleukin-8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. Collectively, our results demonstrate that PEDF maintains tumor-suppressive functions in fibroblasts to prevent CAF conversion, and illustrate the mechanisms by which melanoma cells silence stromal PEDF to promote malignancy.

A Smart Nano‐Prodrug Platform with Reactive Drug Loading, Superb Stability, and Fast Responsive Drug Release for Targeted Cancer Therapy

“…Hematoxylin and eosin (H&E) staining analyses showed that cRGD‐PS‐DM1 nano‐prodrug did not induce obvious damage to the major organs of treated mice (Figure S4, Supporting Information), corroborating that this nano‐prodrug formulation has a low systemic toxicity. B16F10 melanoma is known as a highly aggressive malignancy . The high treatment efficacy and low side effects of cRGD‐PS‐DM1 nano‐prodrug in B16F10 tumor‐bearing mice suggests that this nanodrug platform has a great potential for cancer chemotherapy.…”

Bidirectional cross talk between patient‐derived melanoma and cancer‐associated fibroblasts promotes invasion and proliferation

“…Previous work established interactions between melanoma cells and the tumor microenvironment via secreted factors in mice (Nwani et al., ). Furthermore, proteome analyses of exosomes released by melanoma cell lines revealed their impact on melanoma invasiveness through interactions between malignant cells and the tumor microenvironment (Lazar et al., ).…”

Reverse of non‐small cell lung cancer drug resistance induced by cancer‐associated fibroblasts via a paracrine pathway

“…This data suggests that the CAF may produce soluble factors in the medium to promote NSCLC cell survival under stress of chemotherapy drugs. To further determine the key factors in the CAF‐secreted cytokines involved in NSCLC drug resistance, we screened the expression of IGF2 , SDF‐1 , HGF , VEGF α, FGF , EGF , PDGF , CTGF , Tenascin , TSP‐1 and Fibronectin in the CAF pre‐co‐cultured with or without LCP1 cells and found that IGF2 , VEGFa and EGF were significantly upregulated, especially the IGF2 (Figure C). Moreover, we used the recombinant IGF2 to pre‐treat LCP1 and A549 cells, followed by cisplatin, etoposide and vinorelbine diatrate treatment.…”