The tumor stroma is being increasingly recognized as an important component for tumor development, progression and metastasis. Cancer-associated fibroblasts (CAFs), one of the most abundant cell types the tumor stroma, produce many cancer-promoting factors. Microarray gene expression analyses and qRT-PCR of micro-dissected normal and cancer human prostate tissue revealed up-regulation of GDF15/MIC-1, a member of the TGFβ/BMP-family, in tumor stroma. Up-regulation of GDF15/MIC-1 mRNA was demonstrated in situ in fibroblasts of prostate cancer stroma and in primary cultures of prostate cancer fibroblasts. When expressed in fibroblasts, GDF15/MIC-1 exerted autocrine effects on fibroblasts and prominent paracrine effects on prostate cancer cell migration, invasion and in vivo tumor growth. Importantly, beside this local pro-tumoral activity, GDF15-expressing fibroblasts also stimulated the outgrowth of distant, otherwise indolent, prostate cancer cells in mice. The findings reveal stromal cells as a previously unrecognized source of GDF15/MIC-1 in human prostate cancer, demonstrate that the tumor-instigation potency can be governed by the tumor microenvironment, and reinforce the role of GDF15/MIC-1 as a biomarker of worse prognosis and potential therapeutic target in prostate cancer.