title: Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts.
abstract: 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 TGFβ, 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 TGFβ-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 IL8, 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. Cancer Res; 76(8); 2265-76. ©2016 AACR.
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Nkechiyere G
authors.initials: NG
authors.lastname: Nwani
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Madrid, Spain. Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain. Instituto de Investigación I+12, Madrid, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Deguiz
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Madrid, Spain. Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid, Spain. Instituto de Investigación I+12, Madrid, Spain.
authors.forename: Benilde
authors.initials: B
authors.lastname: Jimenez
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Elena
authors.initials: E
authors.lastname: Vinokour
authors.affiliation: Northwestern University Center for Developmental Therapeutics, Evanston, Illinois.
authors.forename: Oleksii
authors.initials: O
authors.lastname: Dubrovskyi
authors.affiliation: Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ugolkov
authors.affiliation: Northwestern University Center for Developmental Therapeutics, Evanston, Illinois. Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois. Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Northwestern University Center for Developmental Therapeutics, Evanston, Illinois. Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois. Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Feinberg Cardiovascular Institute at Northwestern University Feinberg School of Medicine, Chicago, Illinois Illinois. olgavolp@northwestern.edu.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005136:Eye Proteins / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D015843:Serpins / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D016212:Transforming Growth Factor beta; D000099174:Pigment Epithelium-Derived Factor