CTHRC1 诱导胰腺星状细胞 (PSC) 转化为肌成纤维细胞样癌症相关成纤维细胞 (myCAF)。,Cancers

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CTHRC1 诱导胰腺星状细胞 (PSC) 转化为肌成纤维细胞样癌症相关成纤维细胞 (myCAF)。
Cancers ( IF 4.5 ) Pub Date : 2023-06-27 , DOI: 10.3390/cancers15133370
Min Kyung Kang _{1,

2} , Fen Jiang ₂ , Ye Ji Kim ₁ , Kyoungjin Ryu _{1,

2} , Atsushi Masamune ₃ , Shin Hamada ₃ , Yun-Yong Park ₂ , Sang Seok Koh ₁

Affiliation

[背景] 胶原蛋白三螺旋重复序列包含 1 (CTHRC1) 是一种分泌蛋白，有助于包括胰腺癌在内的各种癌症的进展。肿瘤组织中 CTHRC1 的较高表达与较差的生存结果相关。然而，其在肿瘤细胞外基质（ECM）重塑中的具体作用仍不清楚。我们的研究旨在调查 CTHRC1 对胰腺星状细胞 (PSC) 的影响，胰腺星状细胞是胰腺癌 ECM 产生的主要来源。[方法与结果]通过对公开的胰腺癌患者数据的分析发现，CTHRC1主要表达于癌基质中，并与ECM相关基因高度相关。一项体外研究表明，超过 40% 的这些基因可以被 CTHRC1 上调。CTHRC1 特异性激活 PSC 转化为肌成纤维细胞样癌症相关成纤维细胞 (myCAF)，其特征是 POSTN 基因表达显着上调。Periostin（由 POSTN 基因编码）在 CTHRC1-PSC-癌症转移轴中发挥核心作用。此外，与直接刺激相比，CTHRC1 通过 PSC 激活更大程度地促进胰腺癌细胞增殖。概念验证实验表明，CTHRC1 的长期（4 周）抑制导致显着的肿瘤抑制和 ECM 减少，并且还导致 CAF 亚型从 myCAF 意外转变为炎性 CAF（iCAF）。[结论] PSC激活被证明是CTHRC1促肿瘤作用的关键分子机制，CTHRC1 在 CAF 亚型分化和肿瘤微环境 (TME) 重塑中发挥关键作用。抑制 CTHRC1 作为治疗胰腺癌的治疗策略值得进一步研究。

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CTHRC1 Induces Pancreatic Stellate Cells (PSCs) into Myofibroblast-like Cancer-Associated Fibroblasts (myCAFs).

[BACKGROUND] Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that contributes to the progression of various cancers, including pancreatic cancer. The higher expression of CTHRC1 in tumor tissues is associated with poorer survival outcomes. However, its specific roles in tumor extracellular matrix (ECM) remodeling remain unclear. Our study aims to investigate the influences of CTHRC1 on pancreatic stellate cells (PSCs), a main source of ECM production in pancreatic cancer. [METHODS AND RESULTS] The analyses of the publicly available pancreatic cancer patient data revealed that CTHRC1 is mainly expressed in cancer stroma and highly correlated with ECM-related genes. An in vitro study showed that more than 40% of these genes can be upregulated by CTHRC1. CTHRC1 specifically activated PSC into myofibroblast-like cancer-associated fibroblasts (myCAFs), which are characterized by a significantly upregulated POSTN gene expression. Periostin (coded by the POSTN gene) has a central role in the CTHRC1-PSCs-cancer metastasis axis. Furthermore, CTHRC1 promoted pancreatic cancer cell proliferation through PSC activation to a greater extent than via direct stimulation. Proof-of-concept experiments showed that the long-term (4-week) inhibition of CTHRC1 led to significant tumor suppression and ECM reduction, and also resulted in an unexpected shift in the CAF subtype from myCAFs to inflammatory CAFs (iCAFs). [CONCLUSION] PSC activation was demonstrated to be the key molecular mechanism responsible for the tumor-promoting effects of CTHRC1, and CTHRC1 has a critical role in CAF subtype differentiation and tumor microenvironment (TME) remodeling. The inhibition of CTHRC1 as a therapeutic strategy for the treatment of pancreatic cancer warrants further investigation.

更新日期：2023-06-27

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