Maxwell Pamela J, Neisen Jessica, Messenger Johanna, Waugh David J J
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
Oncotarget. 2014 Jul 15;5(13):4895-908. doi: 10.18632/oncotarget.2052.
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.
PTEN功能受损是侵袭性前列腺癌（CaP）的遗传特征，且与CXCL8表达及信号传导增加相关。当前的目标是进一步明确CXCL8促进PTEN缺失型前列腺癌进展的生物学反应及机制，重点是明确CXCL8与前列腺肿瘤微环境中其他促疾病趋化因子之间潜在的相互作用。自分泌CXCL8刺激（i）增加了PTEN缺陷型CaP细胞中CXCR1和CXCR2的表达，提示存在自我增强信号轴，以及（ii）在PTEN野生型和PTEN缺失型CaP细胞中诱导CXCR4和CCR2的表达。相反，旁分泌CXCL8信号诱导前列腺基质WPMY-1成纤维细胞和单核巨噬细胞样THP-1细胞表达并分泌趋化因子CCL2和CXCL12。体外研究证明肿瘤来源的CXCL8与基质来源的趋化因子存在功能协同作用。CXCL12诱导PC3细胞迁移以及CCL2诱导前列腺癌细胞增殖依赖于前列腺癌细胞内的固有CXCL8信号。例如，在共培养实验中，CXCL12/CXCR4信号而非CCL2/CCR2信号支持成纤维细胞介导的PC3细胞迁移，而CXCL12/CXCR4和CCL2/CCR2信号则是单核细胞增强PC3细胞迁移的基础。联合抑制CXCL8和CXCL12信号在抑制成纤维细胞促进的细胞运动方面更有效，而抑制CXCL8则减弱了CCL2促进的前列腺癌细胞增殖。我们得出结论，PTEN缺陷型肿瘤细胞来源的CXCL8信号通过同时上调癌细胞中的受体表达并诱导基质趋化因子合成，增加了CaP细胞对基质趋化因子的敏感性和反应性。可能需要联合靶向趋化因子来抑制它们在促进侵袭性CaP侵袭和增殖方面的多方面作用。
