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Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell–based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.

Objective * To explore the expression of matrix metalloproteinase 14 (MMP14) in pancreatic cancer tissues and its correlation with clinical characteristics, and analyze its correlation with the characteristics of tumor immune microenvironment in pancreatic cancer. Methods * GEPIA (Gene Expression Profiling Interactive Analysis) platform was used to analyze the MMPs expression in 30 common tumor tissues. R software was used to integrate transcriptomic data of 167 normal pancreatic tissues from GTEx (Genotype-Tissue Expression) database with 178 pancreatic cancer tissues and 4 para-tumor tissues from TCGA (The Cancer Genome Atlas) database to compare the differences of MMP14 expression. GEPIA platform was used to perform survival analysis in the patients with different MMP14 expression levels. Perl and R project software were used to analyze the correlation of MMP14 expression and clinical characteristics. R project software and GSEA v3.0 software were used for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Ontology (GO) functional enrichment analysis. CIBERSORT analysis was used to calculate the proportions of immune cell subsets in the tumor immune microenvironment, and analyze correlation of MMP14 expression and the proportion of immune cell subsets. Six fresh surgical samples of pancreatic cancer tissues and paired para-tumor tissues were collected to detect various immune cell subsets by flow cytometry. t-SNE dimensionality reduction and statistical analysis were used to explore the characteristics of tumor immune microenvironment in pancreatic cancer. A tissue microarray was used to conduct multiplex immunohistochemistry (mIHC) to detect MMP14 expression and the proportions of immune cell subsets to verify bioinformatics analysis results. Results * In the bioinformatics database, compared with the other members of MMPs, MMP14 was highly expressed in a variety of tumors, and MMP14 expression in pancreatic cancer was higher than that in the other cancers. The expression of MMP14 in pancreatic cancer tissues was significantly higher than that in normal pancreatic tissues and para-tumor tissues (P=0.000). The expression of MMP14 in the TNM stage II tumor was higher than that in the stage I tumor (P=0.012). The expressions of MMP14 in the histological grade 2 (G2) and grade 3 (G3) tumors were higher than those in the grade 1 (G1) tumor (P=0.000). The survival prognosis of the patients in MMP14-low expression group was significantly better than that in high expression group (P=0.033). KEGG and GO analysis results showed that MMP14 was enriched in the pancreatic cancer pathway and immune-related pathways. The expression level of MMP14 was negatively correlated with the percentages of CD8+ T cells and monocytes (P<0.05), and positively correlated with the percentage of macrophages (P=0.000). Flow cytometry analysis suggested that tumor microenvironment of pancreatic cancer was immunosuppressive. The results of mIHC showed that MMP14 expression in the tumor tissues was higher than that in the para-tumor tissues (P=0.000). Tumor tissues with higher TNM stage and histological grade expressed relatively higher MMP14 levels (P<0.05). In the tumor tissues with high MMP14 expression level, the percentage of CD8+ T cells decreased (P=0.001) and the percentage of macrophages increased (P= 0.000), which were consistent with bioinformatics analysis results. Conclusion * Compared with normal pancreatic tissues and paratumor tissues, the expression of MMP14 significantly increases in pancreatic tumor tissues and the high expression is associated with poor prognosis of the patients; in the pancreatic tumor tissues with high MMP14 expression, the percentage of CD8+ T cells decreases and the percentage of macrophages increases; with high MMP14 expression, the tumor microenvironment of pancreatic cancer is highly immunosuppressive. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinase 14 (MMP14) has been reported to be upregulated in some types of cancer and to promote cancer cell invasion and metastasis. However, the expression profile and functional role of MMP14 in kidney renal clear cell carcinoma (KIRC) remains unknown. This study investigated the association between MMP14 expression level and prognosis in KIRC., Methods: The messenger RNA (mRNA) expression profile and clinical data (including T stage, N stage, M stage, pathologic stage, gender, race, age, histologic grade, serum calcium, hemoglobin) were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Protein expression was evaluated by immunohistochemistry in the Human Protein Atlas (HPA) database. Correlation analyses between MMP14 and all mRNAs in KIRC were batch calculated, and gene set enrichment analyses (GSEA) were then conducted of Disease Ontology (DO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using R packages. Multivariate logistic regression analysis was used to explore the prognostic factors of KIRC patients., Results: The gene expression of MMP14 was significantly upregulated in KIRC tissues when compared with the normal tissue (P<0.001). The predictive ability of MMP14 as a variable for predicting tumor and normal outcomes had certain accuracy based on the receiver operating characteristic (ROC) model [area under the curve (AUC) =0.881, confidence interval (CI): 0.844-0.917]. When compared with the normal kidney tissue, the protein expression of MMP14 in KIRC got an increased trend, but due to the limited sample size, the difference is not statistically significant (P>0.05). Survival analysis revealed that MMP14 was significantly associated with overall survival in KIRC (P=0.013). GSEA of DO terms indicated high expression of MMP14 was related to KIRC, and GSEA of KEGG pathways showed that MMP14 and its coexpressed genes were significantly positively correlated with pathways in cancer. Signaling pathway GSEA indicated the upregulation of MMP14 in KIRC may activate cancer pathways., Conclusions: MMP14 may be associated with poor prognosis in KIRC and may be a potential prognostic marker for KIRC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-22-619/coif). The authors have no conflicts of interest to declare., (2022 Translational Andrology and Urology. All rights reserved.)

Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients ( n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell-based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14 + cells among intratumoral CAFs (MMP14 + CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14 + CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14 + CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14 + CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target., Competing Interests: HK has received consulting fees from Bristol-Myers Squibb Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., and Taiho Pharmaceutical Co. Ltd.YC honoraria from Bristol-Myers Squibb Co. Ltd., Bayer Yakuhin Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Merck Biopharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Pharmaceutical Industry, Teijin Pharma Ltd., and Taiho Pharmaceutical Co. Ltd.YC lecture fees from Glaxo Smith Kline K.K. and Otsuka Pharmaceutical Co. Ltd.YC and research funding from Chugai Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Kobayashi Pharmaceutical Co. Ltd., and Eisai Co. Ltd. TT has received speaker fees from MSD K.K., Ono Pharmaceutical Co. Ltd., and Bristol-Myers Squibb Co. Ltd. YC has received honoraria from Chugai Pharmaceutical Co. Ltd. KH has received lecture fees from AS ONE Corp., AstraZeneca K.K., Bristol-Myers Squibb Co. Ltd., MSD K.K., and Ono Pharmaceutical Co. Ltd. as well as research funding from AstraZeneca K.K. and MSD K.K. KN has received honoraria from Astellas Pharma Inc., Takeda Pharmaceutical Co. Ltd., Nanzando Co. Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Roche Diagnostics K.K., MSD K.K., Eli Lilly Japan K.K., Nippon Kayaku Co. Ltd., Daiichi Sankyo Co. Ltd., Novartis Pharma K.K., Kyowa Kirin Co. Ltd., Taiho Pharmaceutical Co. Ltd., Pfizer Japan Inc., AbbVie Inc., Bristol-Myers Squibb Co. Ltd., CareNet Inc., Amgen Inc., Medical Review Co. Ltd., Yodosha Co. Ltd., 3H Clinical Trial Inc., Thermo Fisher Scientific K.K., Hisamitsu Pharmaceutical Co. Inc., Nichi-Iko Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Medicus Shuppan Publishers Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Nikkei Business Publications Inc., Yomiuri Telecasting Corp., and Medical Mobile Communications Co. Ltd.YC research funding from MSD K.K., AstraZeneca K.K., Pfizer Japan Inc., ICON Japan K.K., Astellas Pharma Inc., Bayer Yakuhin Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., EPS International Co. Ltd., Bristol Myers Squibb Co. Ltd., CMIC Shift Zero K.K., PRA Health Sciences, Taiho Pharmaceutical Co. Ltd., Eisai Co. Ltd., Merck Biopharma Co. Ltd., Parexel International Corp., Mochida Pharmaceutical Co. Ltd., Covance Japan Inc., Ono Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co. Ltd., Medical Research Support, Sysmex Corp., GlaxoSmithKline K.K., Sanofi K.K., A2 Healthcare Corp., Kyowa Hakko Kirin Co. Ltd., Syneos Health, AbbVie Inc., EPS Corp., Pfizer R&D Japan G.K., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., PPD-SNBL K.K., Nippon Boehringer Ingelheim Co. Ltd., IQVIA Services Japan K.K./Quintiles Inc., Japan Clinical Research Operations, and SymBio Pharmaceuticals Ltd.YC and consulting fees from Astellas Pharma Inc., Takeda Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Kyorin Pharmaceutical Co. Ltd., and Ono Pharmaceutical Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Makutani, Kawakami, Tsujikawa, Yoshimura, Chiba, Ito, Kawamura, Haratani and Nakagawa.)