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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 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.

SUBMITTER: Gong L

PROVIDER: S-EPMC9592791 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Inhibition of lysyl oxidase-like 2 overcomes adhesion-dependent drug resistance in the collagen-enriched liver cancer microenvironment.

Gong Lanqi L Zhang Yu Y Yang Yuma Y Yan Qian Q Ren Jifeng J Luo Jie J Tiu Yuen Chak YC Fang Xiaona X Liu Beilei B Lam Raymond Hiu Wai RHW Lam Ka-On KO Lee Anne Wing-Mui AW Guan Xin-Yuan XY

Hepatology communications 20220727 11

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 dete ...[more]

PMID: 35894804

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Project description:The inability to recapitulate native tissue biomechanics, especially tensile properties, hinders progress in regenerative medicine. To address this problem, strategies have focused on enhancing collagen production. However, manipulating collagen cross-links, ubiquitous throughout all tissues and conferring mechanical integrity, has been underinvestigated. A series of studies examined the effects of lysyl oxidase (LOX), the enzyme responsible for the formation of collagen cross-links. Hypoxia-induced endogenous LOX was applied in multiple musculoskeletal tissues (i.e., cartilage, meniscus, tendons, ligaments). Results of these studies showed that both native and engineered tissues are enhanced by invoking a mechanism of hypoxia-induced pyridinoline (PYR) cross-links via intermediaries like LOX. Hypoxia was shown to enhance PYR cross-linking 1.4- to 6.4-fold and, concomitantly, to increase the tensile properties of collagen-rich tissues 1.3- to 2.2-fold. Direct administration of exogenous LOX was applied in native cartilage and neocartilage generated using a scaffold-free, self-assembling process of primary chondrocytes. Exogenous LOX was found to enhance native tissue tensile properties 1.9-fold. LOX concentration- and time-dependent increases in PYR content (∼ 16-fold compared with controls) and tensile properties (approximately fivefold compared with controls) of neocartilage were also detected, resulting in properties on par with native tissue. Finally, in vivo subcutaneous implantation of LOX-treated neocartilage in nude mice promoted further maturation of the neotissue, enhancing tensile and PYR content approximately threefold and 14-fold, respectively, compared with in vitro controls. Collectively, these results provide the first report, to our knowledge, of endogenous (hypoxia-induced) and exogenous LOX applications for promoting collagen cross-linking and improving the tensile properties of a spectrum of native and engineered tissues both in vitro and in vivo.

Dataset Information

Inhibition of lysyl oxidase-like 2 overcomes adhesion-dependent drug resistance in the collagen-enriched liver cancer microenvironment.

Publications

Inhibition of lysyl oxidase-like 2 overcomes adhesion-dependent drug resistance in the collagen-enriched liver cancer microenvironment.

Similar Datasets

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