Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells
| Autor: | Johanna Messenger, Pamela J. Maxwell, David Waugh, Jessica Neisen |
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| Rok vydání: | 2014 |
| Předmět: |
Male
PTEN Chemokine POTENTIATION Apoptosis MICROENVIRONMENT PROGRESSION Receptors Interleukin-8B Receptors Interleukin-8A Prostate cancer 0302 clinical medicine Cell Movement CXC chemokine receptors Chemokine CCL2 IN-VIVO 0303 health sciences biology Reverse Transcriptase Polymerase Chain Reaction Cell Cycle CXCL12 prostate cancer Cell biology Gene Expression Regulation Neoplastic CHEMOKINES Oncology ERG 030220 oncology & carcinogenesis CXCL8 CCL2 Research Paper Signal Transduction EXPRESSION musculoskeletal diseases Stromal cell Cell Survival MIGRATION Immunoblotting Cell Line 03 medical and health sciences Paracrine signalling SDG 3 - Good Health and Well-being Cell Line Tumor medicine Humans Neoplasm Invasiveness Autocrine signalling 030304 developmental biology CXCR4 Tumor microenvironment CXCR2 Interleukin-8 PTEN Phosphohydrolase Prostatic Neoplasms medicine.disease Chemokine CXCL12 HEK293 Cells Cancer cell biology.protein Cancer research Stromal Cells |
| Zdroj: | Maxwell, P J, Neisen, J, Messenger, J & Waugh, D J J 2014, ' Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells ', Oncotarget, vol. 5, no. 13, pp. 4895-4908 . Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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