Abstract
Members of the lysyl oxidase (LOX) family are secreted copper-dependent amine oxidases that catalyze the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM), an essential process for the structural integrity of all tissues. LOX enzymes can also remodel the tumor microenvironment and have been implicated in all stages of tumor initiation and progression of many cancer types. Changes in the ECM can influence several cancer cell phenotypes. Integrin adhesion complexes (IACs) physically connect cells with their microenvironment. This review article summarizes the main findings on the role of LOX proteins in modulating the tumor microenvironment, with a particular focus on how ECM changes are integrated by IACs to modulate cells behavior. Finally, we discuss how the development of selective LOX inhibitors may lead to novel and effective therapies in cancer treatment.
Highlights
Members of the lysyl oxidase (LOX) family are secreted copper-dependent amine oxidases that catalyze the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM), an essential process for the structural integrity of all tissues
Results indicate that changes in ECM stiffness regulate the expression of LOX proteins (Figure 2, left)
Increased matrix stiffness induced the expression of LOX enzymes in hepatocellular carcinoma (HCC) cells growing on different stiffness substrates [111,112]
Summary
Metastasis still remains the main cause of mortality amongst cancer patients [1]. During the invasion-metastasis cascade, cancer cells from the primary tumor disseminate and establish metastases in distant tissues. The ECM influences cellular behavior and is required for major developmental processes [11,12,13] Under pathological conditions, such as cancer, tumor cells can modulate the surrounding microenvironment both at primary and secondary sites, and these ECM alterations are considered one of the greatest extrinsic drivers of tumor progression [14]. Cancer cells can alter the surrounding ECM either directly or indirectly, through recruitment and activation of non-malignant stromal cells [15] This process usually results in expansion of the tumor stroma and accumulation of dense fibrotic tissue around the tumor, a phenomenon known as desmoplasia [16]. Cancers 2019, 11, 729 that directly or indirectly alter the ECM structure at secondary sites in other organs, creating permissive conditions (pre-metastatic niches) for subsequent colonization of the cancer cells [17]
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