Dang Yun-Zhi, Chen Xiao-Jiao, Yu Jiao, Zhao Shu-Hong, Cao Xi-Ming, Wang Qing
Department of Radiation Oncology, Shaanxi Provincial People's Hospital, Xi'an, China.
State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China.
Neoplasma. 2023 Feb;70(1):123-135. doi: 10.4149/neo_2023_220726N757.
Since metastasis remains the primary reason for colorectal cancer (CRC) associated death, a better understanding of the molecular mechanism underlying CRC metastasis is urgently needed. Here, we elucidated the role of Cathepsin C (CTSC) in promoting CRC metastasis. The expression of CTSC was detected by real-time PCR and immunohistochemistry in the human CRC cohort. The metastatic capacities of CTSC-mediated metastasis were analyzed by in vivo metastasis model. Elevated CSTC expression was positively associated with tumor differentiation, tumor invasion, lymph node metastasis, and AJCC stage and indicated poor prognosis in human CRC. CTSC overexpression in CRC cells promoted myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) recruitment by the CSF1/CSF1R axis. In contrast, the knockdown of CSF1 reduced CTSC-mediated MDSCs and TAMs infiltration and CRC metastasis. Depletion of either MDSCs or TAMs decreased CTSC-mediated CRC metastasis. In human CRC tissues, CTSC expression was positively associated with intratumoral MDSCs and TAMs infiltration. Furthermore, the combination of CTSC inhibitor AZD7986 and anti-PD-L1 antibody blocked CTSC-induced CRC metastasis. CTSC overexpression promoted MDSCs and TAMs infiltration by CSF1/CSF1R axis. Interruption of this oncogenic loop may provide a promising treatment strategy for inhibiting CTSC-driven CRC metastasis.
由于转移仍然是结直肠癌（CRC）相关死亡的主要原因，因此迫切需要更好地了解CRC转移的分子机制。在此，我们阐明了组织蛋白酶C（CTSC）在促进CRC转移中的作用。通过实时PCR和免疫组织化学检测人CRC队列中CTSC的表达。通过体内转移模型分析CTSC介导的转移的转移能力。CTSC表达升高与肿瘤分化、肿瘤侵袭、淋巴结转移和AJCC分期呈正相关，提示人CRC预后不良。CRC细胞中CTSC的过表达通过CSF1/CSF1R轴促进骨髓来源的抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs）的募集。相反，CSF1的敲低减少了CTSC介导的MDSCs和TAMs浸润以及CRC转移。MDSCs或TAMs的消耗均降低了CTSC介导的CRC转移。在人CRC组织中，CTSC表达与肿瘤内MDSCs和TAMs浸润呈正相关。此外，CTSC抑制剂AZD7986和抗PD-L1抗体的联合使用可阻断CTSC诱导的CRC转移。CTSC过表达通过CSF1/CSF1R轴促进MDSCs和TAMs浸润。中断这种致癌环可能为抑制CTSC驱动的CRC转移提供一种有前景的治疗策略。
