title: Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells.
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.
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors: Pamela J
authors: PJ
authors: Maxwell
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors: Jessica
authors: J
authors: Neisen
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors: Johanna
authors: J
authors: Messenger
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors: David J J
authors: DJ
authors: Waugh
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D054377:Chemokine CXCL12; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human