Kang Min Kyung, Jiang Fen, Kim Ye Ji, Ryu Kyoungjin, Masamune Atsushi, Hamada Shin, Park Yun-Yong, Koh Sang Seok
Department of Biomedical Sciences, Dong-A University, Busan 49315, Republic of Korea.
Prestige BioPharma IDC Co., Ltd., Busan 46726, Republic of Korea.
Cancers (Basel). 2023 Jun 27;15(13):3370. doi: 10.3390/cancers15133370.
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. 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). 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.
含胶原蛋白三螺旋重复序列-1（CTHRC1）是一种分泌蛋白，它促进包括胰腺癌在内的多种癌症的进展。肿瘤组织中CTHRC1的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。我们的研究旨在探讨CTHRC1对胰腺星状细胞（PSC）的影响，PSC是胰腺癌中ECM产生的主要来源。对公开可用的胰腺癌患者数据的分析显示，CTHRC1主要在癌基质中表达，并且与ECM相关基因高度相关。一项体外研究表明，这些基因中有40%以上可被CTHRC1上调。CTHRC1特异性地将PSC激活为肌成纤维细胞样癌相关成纤维细胞（myCAF），其特征是POSTN基因表达显著上调。骨膜蛋白（由POSTN基因编码）在CTHRC1-PSC-癌症转移轴中起核心作用。此外，CTHRC1通过激活PSC促进胰腺癌细胞增殖的程度大于直接刺激。概念验证实验表明，长期（4周）抑制CTHRC1可导致显著的肿瘤抑制和ECM减少，还导致CAF亚型意外地从myCAF转变为炎性CAF（iCAF）。PSC激活被证明是CTHRC1促肿瘤作用的关键分子机制，并且CTHRC1在CAF亚型分化和肿瘤微环境（TME）重塑中起关键作用。抑制CTHRC1作为治疗胰腺癌的策略值得进一步研究。
