Cancer Institute, Shanghai Urological Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, P. R. China.
Department of Radiotherapy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China.
Cell Death Dis. 2022 Jul 19;13(7):624. doi: 10.1038/s41419-022-05086-z.
Prostate cancer (PCa) is a malignant tumor that seriously threatens men's health worldwide. Recently, stromal cells in the tumor microenvironment (TME) have been reported to contribute to the progression of PCa. However, the role and mechanism of how PCa cells interact with stromal cells to reshape the TME remain largely unknown. Here, using a spontaneous prostate adenocarcinoma (PRAD) model driven by the loss of Pten and Hic1, we found that M2 macrophages markedly infiltrated the stroma of Pten and Hic1 double conditional knockout (dCKO) mice compared with those in control (Ctrl) mice due to higher TGF-β levels secreted by HIC1-deleted PCa cells. Mechanistically, TGF-β in TME promoted the polarization of macrophages into "M2" status by activating the STAT3 pathway and modulating c-Myc to upregulate CXCR4 expression. Meanwhile, TGF-β activated the fibroblasts to form cancer-associated fibroblasts (CAFs) that secrete higher CXCL12 levels, which bound to its cognate receptor CXCR4 on M2 macrophages. Upon interaction with CAFs, M2 macrophages secreted more CXCL5, which promoted the epithelial-mesenchymal transition (EMT) of PCa via CXCR2. Moreover, using the TGF-β receptor I antagonist, galunisertib, significantly inhibited the tumor growth and progression of the TRAMP-C1 cell line-derived subcutaneous tumor model. Finally, we confirmed that the stromal microenvironment was shaped by TGF-β in HIC1-deficient PCa and was associated with the progression of PCa.
前列腺癌（PCa）是一种严重威胁全球男性健康的恶性肿瘤。最近，有研究报道肿瘤微环境（TME）中的基质细胞有助于 PCa 的进展。然而，PCa 细胞与基质细胞相互作用重塑 TME 的作用和机制在很大程度上仍然未知。在这里，我们使用由 Pten 和 Hic1 缺失驱动的自发性前列腺腺癌（PRAD）模型，发现与对照（Ctrl）小鼠相比，由于 HIC1 缺失的 PCa 细胞分泌的 TGF-β 水平较高，M2 巨噬细胞大量浸润 Pten 和 Hic1 双条件敲除（dCKO）小鼠的基质中。在机制上，TME 中的 TGF-β 通过激活 STAT3 通路和调节 c-Myc 来上调 CXCR4 表达，从而促进巨噬细胞向“M2”状态极化。同时，TGF-β 激活成纤维细胞形成癌相关成纤维细胞（CAFs），CAFs 分泌更高水平的 CXCL12，与 M2 巨噬细胞上的同源受体 CXCR4 结合。M2 巨噬细胞与 CAFs 相互作用后，分泌更多的 CXCL5，通过 CXCR2 促进 PCa 的上皮间质转化（EMT）。此外，使用 TGF-β 受体 I 拮抗剂 galunisertib 可显著抑制 TRAMP-C1 细胞系衍生的皮下肿瘤模型的肿瘤生长和进展。最后，我们证实 HIC1 缺失的 PCa 中的基质微环境由 TGF-β 塑造，并与 PCa 的进展相关。
