KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages
Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment rem...
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MDPI AG
2022-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/24/4101 |
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| author | Yo Sep Hwang Hee Jun Cho Eun Sun Park Jeewon Lim Hyang Ran Yoon Jong-Tae Kim Suk Ran Yoon Haiyoung Jung Yong-Kyung Choe Yong-Hoon Kim Chul-Ho Lee Yong Tae Kwon Bo Yeon Kim Hee Gu Lee |
| author_facet | Yo Sep Hwang Hee Jun Cho Eun Sun Park Jeewon Lim Hyang Ran Yoon Jong-Tae Kim Suk Ran Yoon Haiyoung Jung Yong-Kyung Choe Yong-Hoon Kim Chul-Ho Lee Yong Tae Kwon Bo Yeon Kim Hee Gu Lee |
| author_sort | Yo Sep Hwang |
| collection | DOAJ |
| description | Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to determine the role of KLK6 in the tumor microenvironment. Here, we uncovered the mechanism underlying KLK6-mediated cross-talk between cancer cells and macrophages. Compared with wild-type mice, KLK6−/− mice showed less tumor growth and metastasis in the B16F10 melanoma and Lewis lung carcinoma (LLC) xenograft model. Mechanistically, KLK6 promoted the secretion of tumor necrosis factor-alpha (TNF-α) from macrophages via the activation of protease-activated receptor-1 (PAR1) in an autocrine manner. TNF-α secreted from macrophages induced the release of the C-X-C motif chemokine ligand 1 (CXCL1) from melanoma and lung carcinoma cells in a paracrine manner. The introduction of recombinant KLK6 protein in KLK6−/− mice rescued the production of TNF-α and CXCL1, tumor growth, and metastasis. Inhibition of PAR1 activity suppressed these malignant phenotypes rescued by rKLK6 in vitro and in vivo. Our findings suggest that KLK6 functions as an important molecular link between macrophages and cancer cells during malignant progression, thereby providing opportunities for therapeutic intervention. |
| first_indexed | 2024-03-09T17:12:03Z |
| format | Article |
| id | doaj.art-1af1ee17fb2842c29dbef30351045c9d |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T17:12:03Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-1af1ee17fb2842c29dbef30351045c9d2023-11-24T13:55:52ZengMDPI AGCells2073-44092022-12-011124410110.3390/cells11244101KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and MacrophagesYo Sep Hwang0Hee Jun Cho1Eun Sun Park2Jeewon Lim3Hyang Ran Yoon4Jong-Tae Kim5Suk Ran Yoon6Haiyoung Jung7Yong-Kyung Choe8Yong-Hoon Kim9Chul-Ho Lee10Yong Tae Kwon11Bo Yeon Kim12Hee Gu Lee13Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaProtein Metabolism Medical Research Center, Department of Biomedical Science, College of Medicine, Seoul National University, Seoul 110-799, Republic of KoreaAnticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheong won, Cheongju 28116, Republic of KoreaImmunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of KoreaKallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to determine the role of KLK6 in the tumor microenvironment. Here, we uncovered the mechanism underlying KLK6-mediated cross-talk between cancer cells and macrophages. Compared with wild-type mice, KLK6−/− mice showed less tumor growth and metastasis in the B16F10 melanoma and Lewis lung carcinoma (LLC) xenograft model. Mechanistically, KLK6 promoted the secretion of tumor necrosis factor-alpha (TNF-α) from macrophages via the activation of protease-activated receptor-1 (PAR1) in an autocrine manner. TNF-α secreted from macrophages induced the release of the C-X-C motif chemokine ligand 1 (CXCL1) from melanoma and lung carcinoma cells in a paracrine manner. The introduction of recombinant KLK6 protein in KLK6−/− mice rescued the production of TNF-α and CXCL1, tumor growth, and metastasis. Inhibition of PAR1 activity suppressed these malignant phenotypes rescued by rKLK6 in vitro and in vivo. Our findings suggest that KLK6 functions as an important molecular link between macrophages and cancer cells during malignant progression, thereby providing opportunities for therapeutic intervention.https://www.mdpi.com/2073-4409/11/24/4101KLK6PAR1tumor microenvironmentmacrophagemetastasis |
| spellingShingle | Yo Sep Hwang Hee Jun Cho Eun Sun Park Jeewon Lim Hyang Ran Yoon Jong-Tae Kim Suk Ran Yoon Haiyoung Jung Yong-Kyung Choe Yong-Hoon Kim Chul-Ho Lee Yong Tae Kwon Bo Yeon Kim Hee Gu Lee KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages Cells KLK6 PAR1 tumor microenvironment macrophage metastasis |
| title | KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages |
| title_full | KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages |
| title_fullStr | KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages |
| title_full_unstemmed | KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages |
| title_short | KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages |
| title_sort | klk6 par1 axis promotes tumor growth and metastasis by regulating cross talk between tumor cells and macrophages |
| topic | KLK6 PAR1 tumor microenvironment macrophage metastasis |
| url | https://www.mdpi.com/2073-4409/11/24/4101 |
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