Abstract
Impaired PTEN function is a genetic hallmark of aggressive prostate cancers (CaP) and is associated with increased CXCL8 expression and signaling. The current aim was to further characterize biological responses and mechanisms underpinning CXCL8-promoted progression of PTEN-depleted prostate cancer, focusing on characterizing the potential interplay between CXCL8 and other disease-promoting chemokines resident within the prostate tumor microenvironment. Autocrine CXCL8-stimulation (i) increased expression of CXCR1 and CXCR2 in PTEN-deficient CaP cells suggesting a self-potentiating signaling axis and (ii) induced expression of CXCR4 and CCR2 in PTEN-wild-type and PTEN-depleted CaP cells. In contrast, paracrine CXCL8 signaling induced expression and secretion of the chemokines CCL2 and CXCL12 from prostate stromal WPMY-1 fibroblasts and monocytic macrophage-like THP-1 cells. In vitro studies demonstrated functional co-operation of tumor-derived CXCL8 with stromal-derived chemokines. CXCL12-induced migration of PC3 cells and CCL2-induced proliferation of prostate cancer cells were dependent upon intrinsic CXCL8 signaling within the prostate cancer cells. For example, in co-culture experiments, CXCL12/CXCR4 signaling but not CCL2/CCR2 signaling supported fibroblast-mediated migration of PC3 cells while CXCL12/CXCR4 and CCL2/CCR2 signaling underpinned monocyte-enhanced migration of PC3 cells. Combined inhibition of both CXCL8 and CXCL12 signaling was more effective in inhibiting fibroblast-promoted cell motility while repression of CXCL8 attenuated CCL2-promoted proliferation of prostate cancer cells. We conclude that tumor-derived CXCL8 signaling from PTEN-deficient tumor cells increases the sensitivity and responsiveness of CaP cells to stromal chemokines by concurrently upregulating receptor expression in cancer cells and inducing stromal chemokine synthesis. Combined chemokine targeting may be required to inhibit their multi-faceted actions in promoting the invasion and proliferation of aggressive CaP.
Highlights
Large scale sequencing and molecular pathology analysis is providing deeper insight into the genetic underpinnings of prostate cancer, heightening anticipation of near-term and widespread access to precisionbased therapy of prostate cancer [1]
Immunoblotting confirmed the CXCL8-stimulated increase in CXCR1 and CXCR2 receptor expression in PC3 and LNCaP cells (Fig 1B). These initial experiments suggest that CXCL8 signaling can potentiate expression of the receptors transducing its biological activity in PTENdeficient prostate carcinoma cells
Loss of PTEN function concurrently increased the expression of CXCL8 receptors (CXCR1 and CXCR2), with the resulting elevated autocrine CXCL8 signaling acting to sustain the viability of these PTEN-deficient prostate cancer cells [20]
Summary
Large scale sequencing and molecular pathology analysis is providing deeper insight into the genetic underpinnings of prostate cancer, heightening anticipation of near-term and widespread access to precisionbased therapy of prostate cancer [1]. One of the best characterized common genetic events in prostate cancer relates to the impaired function of PTEN, a haploinsufficient tumor suppressor gene, whose primary cellular activity is to regulate the phosphatidylinositol3-kinase (PI3K)/Akt signaling pathway. A recently published longitudinal molecular pathology analysis indicated that mutation of PTEN was associated with the lethal phenotype of prostate cancer [9]. While pre-clinical and clinical evidence suggests that increased signaling of the PTEN/PI3K/Akt pathway is considered to be a sustaining drive in the development and progression of this disease, our understanding of the key biological mediators and microenvironment responses that underpin and define the more aggressive behavior of PTEN-depleted prostate cancer remains to be fully defined
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