The role of chemokine CXCL12 in obesity induced PCa progression
Prostate cancer (PCa) is the second leading cause of cancer in men, in the United States. Several studies have shown that overweight or obesity increases PCa progression and PCa mortality. However, the mechanisms underlying this association are not clear. White adipose tissue (WAT) consists of mature adipocytes and a host of other cells generally referred to as the stromal vascular fraction (SVF), which secrete chemokines, cytokines and pro-inflammatory molecules. Adipose stromal cells (ASCs) are stem/progenitor cells that are part of this SVF. It is reported that recruitment of ASCs to peri-tumoral WAT is higher in obese mice. In our study, we used several approaches to evaluate the role of ASC-derived CXCL12 in PCa growth and progression. Using the HiMyc PCa mouse model, we found that obesity enhanced PCa growth and progression by changing the surrounding tumor microenvironment, especially the WAT. The chemokine CXCL12 and its receptor CXCR4 were highly upregulated in the SVF of peri prostatic (pp)WAT from obese HiMyc mice. Using HMVP2 PCa cells derived from HiMyc mice in an allograft tumor model yielded similar results. Furthermore, we showed that treating HMVP2 cells with CXCL12 increased activation of oncogenic signaling proteins associated with cancer migration and invasion such as STAT3, NFkB and AKT. These effects were abolished when CXCR4 and CXCR7 were knocked down or when HMVP2 cells were treated with AMD3100, a CXCR4 antagonist. Further in vivo study confirmed that CXCL12/CXCR4/CXCR7 signaling plays an important role in obesity-induced PCa progression. Treatment with AMD3100 and CCX771 reversed EMT associated protein expression and proliferation in HMVP2 prostate tumors from obese mice. Depleting ASC, the source of CXCL12, produced similar inhibition of tumor progression and EMT related changes. in both control diet and obese mice. Combining ASC depletion with CXCR4 inhibition produced a synergistic inhibition of tumor growth and progression. Several signaling pathways including AKT, ERK, STAT3 and FOXO1a were inhibited by the combination treatment. Furthermore, in prostate specific CXCR4 knockout mice, we found that CXCR4 knockout inhibited adenocarcinoma formation and decreased expression of of both EMT and stem cells markers. Overall, these data demonstrate that CXCL12/CXCR4/CXCR7 pathway as a novel therapeutic target to offset the effecst of obesity on PCa progression.