Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

The interaction between cancer cells and microenviron-ment has a critical role in tumor development andprogression. Although microRNAs regulate all the majorbiological mechanisms, their influence on tumor micro-environment is largely unexplored. Here, we investigatethe role of microRNAs in the tumor-supportive capacity ofstromal cells. We demonstrated that miR-15 and miR-16are downregulated in fibroblasts surrounding the prostatetumors of the majority of 23 patients analyzed. Suchdownregulation of miR-15 and miR-16 in cancer-asso-ciated fibroblasts (CAFs) promoted tumor growth andprogression through the reduced post-transcriptionalrepression of Fgf-2 and its receptor Fgfr1, which acton both stromal and tumor cells to enhance cancer cellsurvival, proliferation and migration. Moreover, recon-stitution of miR-15 and miR-16 impaired considerably thetumor-supportive capability of stromal cells in vitro andin vivo. Our data suggest a molecular circuitry in whichmiR-15 and miR-16 and their correlated targets cooperateto promote tumor expansion and invasiveness through theconcurrent activity on stromal and cancer cells, thusproviding further support to the development of therapiesaimed at reconstituting miR-15 and miR-16 in advancedprostate cancer.Oncogene (2011) 30, 4231–4242; doi:10.1038/onc.2011.140;published online 2 May 2011Keywords: miRNA; microenvironment; cancer progres-sionIntroductionThe prostate microenvironment is a variegate compart-ment in which the epithelial cells interact with mesench-ymal and inflammatory cells in the presence ofextracellular matrix (ECM) and soluble molecules(Bhowmick et al., 2004; De Marzo et al., 2007; Joyceand Pollard, 2009). The epithelial–stromal interactionhas a fundamental role in organ formation and tissuehomeostasis. However, during cancer developmentand progression, the tumor and its microenvironmentco-evolve and contribute equally to the acquisition ofthe metastatic phenotype (Chung and Cunha, 1983;Cunha et al., 1983; Chung et al., 1989; Tuxhorn et al.,2002; Risbridger and Taylor, 2008; Thiery et al., 2009).In this context, the stroma acquires tumor-enhancingproperties and is defined as ‘reactive’ (Tuxhorn et al.,2002; Josson et al., 2010). It has been suggested that adysfunctional microenvironment can turn a prostatichypertrophy into a prostate tumor through a processthat involves vessel neo-formation and acquisition ofandrogen insensitivity (Chung et al., 1989; Wu et al.,1994; Hayward et al., 2001; Ao et al., 2007). Among thecell types cohabitating a reactive stroma, carcinoma-associated fibroblasts (CAFs) are thought to be the mainactors, even though it is still unclear if these cellsundergo irreversible alterations or epigenetic changesduring tumor progression. A complex signaling andmany growth factors connect stroma and cancer,including the vascular endothelial growth factor(VEGF-A), bone morphogenetic proteins (BMPs),insulin-like growth factors (IGFs), transforming growthfactor- b(TGF ), wingless-type ligand family (WNT),platelet-derived growth factor (PDGF) and fibroblastgrowth factors (FGFs) (van Moorselaar and Voest,2002). In early tumor lesions, aberrant FGF-2 produc-tion and expression of its receptor (FGFR1) can alterthe epithelial/stromal communication, which ensures thebalance between growth and renewal of the epithelialcompartment under physiological conditions (Kwabi-Addo et al., 2004). Moreover, FGF-2 production byboth stromal and tumor cells promotes increasedproliferation and metastasis formation in prostatecancer (PCa) (Cronauer et al., 1997; Giri et al., 1999;Yang et al., 2008). Thus, the FGF-2/FGFR axis is anattractive target for cancer therapy, in terms of bothligand sequestration and receptor inhibition (Smithet al., 2001; He et al., 2003). In the recent years,considerable attention has been devoted to the study of