Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironment
Abstract The tumor microenvironment (TME) is considered to be one of the vital mediators of tumor progression. Extracellular matrix (ECM), infiltrating immune cells, and stromal cells collectively constitute the complex ecosystem with varied biochemical and biophysical properties. The development of...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health/LWW
2022-11-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1966 |
| _version_ | 1797760540076933120 |
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| author | Lanqi Gong Yu Zhang Yuma Yang Qian Yan Jifeng Ren Jie Luo Yuen Chak Tiu Xiaona Fang Beilei Liu Raymond Hiu Wai Lam Ka‐On Lam Anne Wing‐Mui Lee Xin‐Yuan Guan |
| author_facet | Lanqi Gong Yu Zhang Yuma Yang Qian Yan Jifeng Ren Jie Luo Yuen Chak Tiu Xiaona Fang Beilei Liu Raymond Hiu Wai Lam Ka‐On Lam Anne Wing‐Mui Lee Xin‐Yuan Guan |
| author_sort | Lanqi Gong |
| collection | DOAJ |
| description | Abstract The tumor microenvironment (TME) is considered to be one of the vital mediators of tumor progression. Extracellular matrix (ECM), infiltrating immune cells, and stromal cells collectively constitute the complex ecosystem with varied biochemical and biophysical properties. The development of liver cancer is strongly tied with fibrosis and cirrhosis that alters the microenvironmental landscape, especially ECM composition. Enhanced deposition and cross‐linking of type I collagen are frequently detected in patients with liver cancer and have been shown to facilitate tumor growth and metastasis by epithelial‐to‐mesenchymal transition. However, information on the effect of collagen enrichment on drug resistance is lacking. Thus, the present study has comprehensively illustrated phenotypical and mechanistic changes in an in vitro mimicry of collagen‐enriched TME and revealed that collagen enrichment could induce 5‐fluorouracil (5FU) and sorafenib resistance in liver cancer cells through hypoxia‐induced up‐regulation of lysyl oxidase‐like 2 (LOXL2). LOXL2, an enzyme that facilitates collagen cross‐linking, enhances cell adhesion‐mediated drug resistance by activating the integrin alpha 5 (ITGA5)/focal adhesion kinase (FAK)/phosphoinositide 3‐kinase (PI3K)/rho‐associated kinase 1 (ROCK1) signaling axis. Conclusion: We demonstrated that inhibition of LOXL2 in a collagen‐enriched microenvironment synergistically promotes the efficacy of sorafenib and 5FU through deterioration of focal adhesion signaling. These findings have clinical implications for developing LOXL2‐targeted strategies in patients with chemoresistant liver cancer and especially for those patients with advanced fibrosis and cirrhosis. |
| first_indexed | 2024-03-12T19:00:04Z |
| format | Article |
| id | doaj.art-2417c7107cde4ecc955f2f98a29b0b82 |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T19:00:04Z |
| publishDate | 2022-11-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-2417c7107cde4ecc955f2f98a29b0b822023-08-02T06:40:17ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2022-11-016113194321110.1002/hep4.1966Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironmentLanqi Gong0Yu Zhang1Yuma Yang2Qian Yan3Jifeng Ren4Jie Luo5Yuen Chak Tiu6Xiaona Fang7Beilei Liu8Raymond Hiu Wai Lam9Ka‐On Lam10Anne Wing‐Mui Lee11Xin‐Yuan Guan12Department of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaDepartment of Clinical Oncology Li Ka Shing Faculty of Medicine Hong Kong ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaDepartment of Colorectal Surgery Guangdong Institute Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat‐sen University Guangzhou ChinaDepartment of Biomedical Engineering City University of Hong Kong Hong Kong ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaDepartment of Clinical Oncology Li Ka Shing Faculty of Medicine Hong Kong ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaDepartment of Biomedical Engineering City University of Hong Kong Hong Kong ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaAbstract The tumor microenvironment (TME) is considered to be one of the vital mediators of tumor progression. Extracellular matrix (ECM), infiltrating immune cells, and stromal cells collectively constitute the complex ecosystem with varied biochemical and biophysical properties. The development of liver cancer is strongly tied with fibrosis and cirrhosis that alters the microenvironmental landscape, especially ECM composition. Enhanced deposition and cross‐linking of type I collagen are frequently detected in patients with liver cancer and have been shown to facilitate tumor growth and metastasis by epithelial‐to‐mesenchymal transition. However, information on the effect of collagen enrichment on drug resistance is lacking. Thus, the present study has comprehensively illustrated phenotypical and mechanistic changes in an in vitro mimicry of collagen‐enriched TME and revealed that collagen enrichment could induce 5‐fluorouracil (5FU) and sorafenib resistance in liver cancer cells through hypoxia‐induced up‐regulation of lysyl oxidase‐like 2 (LOXL2). LOXL2, an enzyme that facilitates collagen cross‐linking, enhances cell adhesion‐mediated drug resistance by activating the integrin alpha 5 (ITGA5)/focal adhesion kinase (FAK)/phosphoinositide 3‐kinase (PI3K)/rho‐associated kinase 1 (ROCK1) signaling axis. Conclusion: We demonstrated that inhibition of LOXL2 in a collagen‐enriched microenvironment synergistically promotes the efficacy of sorafenib and 5FU through deterioration of focal adhesion signaling. These findings have clinical implications for developing LOXL2‐targeted strategies in patients with chemoresistant liver cancer and especially for those patients with advanced fibrosis and cirrhosis.https://doi.org/10.1002/hep4.1966 |
| spellingShingle | Lanqi Gong Yu Zhang Yuma Yang Qian Yan Jifeng Ren Jie Luo Yuen Chak Tiu Xiaona Fang Beilei Liu Raymond Hiu Wai Lam Ka‐On Lam Anne Wing‐Mui Lee Xin‐Yuan Guan Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironment Hepatology Communications |
| title | Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironment |
| title_full | Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironment |
| title_fullStr | Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironment |
| title_full_unstemmed | Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironment |
| title_short | Inhibition of lysyl oxidase‐like 2 overcomes adhesion‐dependent drug resistance in the collagen‐enriched liver cancer microenvironment |
| title_sort | inhibition of lysyl oxidase like 2 overcomes adhesion dependent drug resistance in the collagen enriched liver cancer microenvironment |
| url | https://doi.org/10.1002/hep4.1966 |
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