Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts
Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts
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DOI：
10.1073/pnas.1416498111
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发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Karin, Michael
中科院分区：
文献类型：
--
作者：
Ammirante, Massimo;Shalapour, Shabnam;Karin, Michael
前列腺癌(PC)是一种进展缓慢的恶性肿瘤，对雄激素消融或化疗的反应通常是变得更具侵袭性，获得神经内分泌表型，并经历转移扩散。我们发现C-X-C基序趋化因子13(CXCL13)募集的B淋巴细胞在PC的恶性进展和转移转移中起重要作用。我们现在描述雄激素消融是如何诱导CXCL13表达的。在同种异体移植和自发的小鼠PC中，CXCL13都是由肿瘤相关的肌成纤维细胞表达的，这些细胞在雄激素去除后通过低氧依赖的机制被激活。化疗后，同样的细胞会产生CXCL13。去雄激素后正常前列腺组织中也存在肌成纤维细胞活化和CXCL13的表达，而人前列腺癌的肌成纤维细胞也表达CXCL13。低氧激活低氧诱导因子1(HIF-1)，诱导自分泌转化生长因子-β信号，从而促进肌成纤维细胞的激活和CXCL13的诱导。除了转化生长因子-β受体激酶抑制剂外，肌成纤维细胞的激活和CXCL13的诱导也被磷酸二酯酶5(PDE5)抑制剂阻断。在转基因小鼠前列腺癌(TRAMP)神经内分泌分化的自发性转移性前列腺癌(TRAMP)模型中，抑制物类型和肌成纤维细胞免疫耗竭均可阻断抗去势前列腺癌的出现。
Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how androgen ablation induces CXCL13 expression. In both allografted and spontaneous mouse PC, CXCL13 is expressed by tumor-associated myofibroblasts that are activated on androgen ablation through a hypoxia-dependent mechanism. The same cells produce CXCL13 after chemotherapy. Myofibroblast activation and CXCL13 expression also occur in the normal prostate after androgen deprivation, and CXCL13 is expressed by myofibroblasts in human PC. Hypoxia activates hypoxia-inducible factor 1 (HIF-1) and induces autocrine TGF-beta signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-beta receptor kinase inhibitors, myofibroblast activation and CXCL13 induction are blocked by phosphodiesterase 5 (PDE5) inhibitors. Both inhibitor types and myofibroblast immunodepletion block the emergence of castration-resistant PC in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous metastatic PC with neuroendocrine differentiation.