MT4‐MMP in tumor‐associated macrophages is linked to hepatocellular carcinoma aggressiveness and recurrence

Abstract

Dear Editor, Hepatocellular carcinoma (HCC) is among the deadliest human cancers, ranking as the fifth most common primary cancer and the third most common cancer-associated cause of death. 1 The tumor microenvironment has been proposed in recent years to be closely related to resistance and tumor recurrence. 2 It includes inflammatory cells, cancer cells, and extracellular matrix (ECM). 3 Polarization and phenotypic transition of macrophages are the primary features of tumor-associated chronic inflammation. 4 Tumor-associated macrophages (TAMs) show an M2-like phenotype and are closely involved in tumorigenesis, metastasis, ECM remodeling, and poor prognosis. 5 MT4-MMP (also named MMP17), as a member of the MMP family of ECM remodelers, is membrane anchored by a glycosylphosphatidylinositol anchor (GPI) 6 and directly resolves a specific set of substrates, such as fibrinogen, proTNF, ADAMTS4, and αM integrin. 7 MT4-MMP has been reported to be expressed by macrophages and to be associated with inflammation and angiogenesis. 8 In particular, the MT4-MMP transcript was recently observed in gastrointestinal adenocarcinomas, prostate cancer, osteosarcomas, leukemias, lung carcinomas, glioblastomas, cervical carcinomas, melanomas, and breast cancer. 9 However, the role of MT4-MMP in HCC is still poorly understood. We explored the MT4-MMP expression profile in human HCC. Forty-three and 12 pairs peritumoral and tumor tissues, respectively, were analyzed by qPCR and western blot. Overall survival (OS) was the time from surgery to death or final follow-up, while recurrencefree survival (RFS) was defined as the interval between surgery and recurrence. Data revealed that the MT4-MMP mRNA and protein level was obviously upregulated in peritumoral tissues over tumor tissues (Figure 1A and B). Next, 316 paired peritumoral and tumor tissues were further analyzed for MT4-MMP expression by immunohistochemistry (Figure 1C). Patient clinical and demographic characteristics are compiled in Table S1. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

A newly defined basement membrane-related gene signature for the prognosis of clear-cell renal cell carcinoma

“…MMP17, as a member of the MMP family of ECM remodelers, is capable of directly cleaving nearly all ECM components ( Sohail et al, 2008 ; Yip et al, 2019 ). Overexpression of MMP17 was shown to be strongly associated with HCC recurrence and aggressiveness in Qi’s research, making it a viable biomarker for prognosis prediction ( Qi et al, 2020 ).…”

Molecular Mechanisms Driven by MT4-MMP in Cancer Progression

“…One of the most important aspects of tumor cell resistance and recurrence is the microenvironmental changes that occur during tumorigenesis [ 60 ]. This involves the transformation of the pericellular ECM by different cell types, including fibroblasts, neuroendocrine and immune cells, as well as changes in the blood vessels and lymphatic network to orchestrate the precise conditions for tumor development [ 61 ].…”

Molecular Mechanisms Driven by MT4-MMP in Cancer Progression

“…One of the most important issues in tumor cell resistance and recurrence is the microenvironmental changes that occur during tumorigenesis [58]. This involves pericellular ECM transformation by distinct types of cells including fibroblasts, neuroendocrine and immune cells as well as changes in the blood vessels and the lymphatic network to orchestrate the precise conditions for tumor development [59].…”

“…MT4-MMP is also expressed in tumor-associated macrophages (TAMs) [58]. In peritumoral and tumoral samples of hepatocellular carcinoma, MT4-MMP-positive cells colocalized with macrophages expressing M2 phenotypic markers, while is absent in tumor cells, fibroblasts or M1 macrophages [58].…”

“…MT4-MMP is also expressed in tumor-associated macrophages (TAMs) [58]. In peritumoral and tumoral samples of hepatocellular carcinoma, MT4-MMP-positive cells colocalized with macrophages expressing M2 phenotypic markers, while is absent in tumor cells, fibroblasts or M1 macrophages [58]. In addition, MT4-MMP-positive TAMs reduced, in a paracrine manner, E-cadherin expression in favor of mesenchymal N-cadherin and vimentin in hepatocellular carcinoma cells which is characteristic of the epithelial-mesenchymal transition (EMT) necessary for tumor metastasis [58].…”