Urology Department, Xinjiang Medical University Affiliated Tumor Hospital, Ürümqi, Xinjiang, China.
Comprehensive Internal Medicine Department, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, China.
Cell Biol Int. 2021 Oct;45(10):2054-2062. doi: 10.1002/cbin.11630. Epub 2021 Jul 20.
The crosstalk between tumor microenvironment and cancer cells is emerging as a critical determinant in tumor progression. However, the underlying mechanism of tumor microenvironment-induced cancer development remains controversial. Here, our study provides evidence to suggest that tumor-associated macrophage (TAM) enrichment is found in chemoresistant prostatic tumor tissues. Those TAMs are demonstrated to promote chemoresistance and distant metastasis in prostatic cancer through secretion of CCL5. Mechanistically, TAM coculture or additional CCL5 can mediate the STAT3-dependent epithelial-mesenchymal transition process, resulting in distant metastasis in prostatic cancer. Meanwhile, activation of STAT3 induced by CCL5 can mediate upregulation of the transcription factor Nanog, leading to drug resistance. In vivo study further demonstrated that blockade of STAT3 signals significantly reverses chemoresistance and suppresses lung metastasis in colorectal tumor-bearing mice, suggesting a novel strategy for clinical prostatic cancer treatment.
肿瘤微环境与癌细胞之间的串扰正成为肿瘤进展的关键决定因素。然而，肿瘤微环境诱导癌症发展的潜在机制仍存在争议。在这里，我们的研究提供了证据表明，肿瘤相关巨噬细胞（TAM）在耐药性前列腺肿瘤组织中富集。这些 TAMs 通过分泌 CCL5 被证明可促进前列腺癌的化疗耐药性和远处转移。在机制上，TAM 共培养或额外的 CCL5 可以介导 STAT3 依赖性上皮间质转化过程，导致前列腺癌的远处转移。同时，CCL5 诱导的 STAT3 激活可以介导转录因子 Nanog 的上调，导致耐药性。体内研究进一步表明，阻断 STAT3 信号可显著逆转结直肠荷瘤小鼠的化疗耐药性并抑制肺转移，为临床前列腺癌治疗提供了一种新策略。
