Lysyl oxidase in colorectal cancer

Abstract

Colorectal cancer is the third most prevalent form of cancer worldwide and fourth-leading cause of cancer-related mortality, leading to ϳ600,000 deaths annually, predominantly affecting the developed world. Lysyl oxidase is a secreted, extracellular matrix-modifying enzyme previously suggested to act as a tumor suppressor in colorectal cancer. However, emerging evidence has rapidly implicated lysyl oxidase in promoting metastasis of solid tumors and in particular colorectal cancer at multiple stages, affecting tumor cell proliferation, invasion, and angiogenesis. This emerging research has stimulated significant interest in lysyl oxidase as a strong candidate for developing and deploying inhibitors as functional efficacious cancer therapeutics. In this review, we discuss the rapidly expanding body of knowledge concerning lysyl oxidase in solid tumor progression, highlighting recent advancements in the field of colorectal cancer. colorectal cancer; extracellular matrix; lysyl oxidase COLORECTAL CANCER (CRC), encompassing both colon and rectal cancer, is the third most prevalent form of cancer worldwide and the fourth-leading cause of cancer-related mortality, leading to ϳ600,000 deaths annually (22). Of note, CRC is most prevalent in developed countries, where cases account for over 60% of the total 1.2 million worldwide diagnoses. The primary treatment for CRC typically involves surgical resection, which remains the gold standard of care for patients. However, greater than 50% of CRC-specific deaths occur as a result of metastatic dissemination, with advanced-stage CRC patients exhibiting a median survival of only 6 -9 mo from diagnosis (63). Thus the early identification of patients harboring metastatic tumors will allow the rapid deployment of adjuvant therapies to help improve their survival. Therefore, understanding the molecular mechanisms behind the spread of CRC is key to stratifying patients for emerging antimetastatic therapies.Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary function is to catalyze the covalent cross-linking of collagens and elastin in the extracellular matrix (ECM). This occurs through the oxidative deamination of peptidyl lysine residues in ECM components (33, 64). The action of LOX is important in establishing the structural integrity and stability of the ECM, thereby contributing to the tensile strength of many tissues. LOX is the classical member of a larger family of proteins consisting of five currently identified paralogs: LOX, LOX-like 1 (LOXL1), LOX-like 2 (LOXL2), LOX-like 3 (LOXL3), and LOX-like 4 (LOXL4). Each of these members shares a high degree of sequence homology within their carboxy terminal region, leading to conservation of including a conserved catalytic domain, copper-binding motif, a lysyl-tyrosyl-quinone (LTQ) cofactor, and cytokine receptor-like (CRL) domain (Fig. 1). The amino terminal regions are more divergent and are thought to be important in protein-protein interactions. The presence of prodomains in LOX and LOXL1 enables th...

Lysyl oxidase: A colorectal cancer biomarker of lung and hepatic metastasis

“…LOX was initially identified as an ECM enzyme that regulated the tensile strength of tissues . Some in vitro studies reported that the LOX gene was a tumor suppressor and its re‐expression could revert H‐Ras‐mediated transformation of NIH 3T3 fibroblasts .…”

“…The LOX multigene family comprises five members (LOX, LOXL1, LOXL2, LOXL3, and LOXL4), all of which share a highly conserved homologue sequence within their carboxy terminal region . LOX is an important ECM whose matrix remodeling function has been studied extensively . Elevated LOX expression is reported to be associated with invasion and metastasis in various types of solid tumors, such as breast, melanoma, and head and neck tumors …”

“…The role of LOX in CRC has recently been comprehensively investigated, but the results reported are conflicting . Csiszar et al .…”

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“…cancers [4,7,8]. In contrast, recent publications have demonstrated the overexpression of LOX in many types of solid cancer, including brain [9], head and neck [10], oral and oropharyngeal squamous cell [11], breast [12] and ovarian cancer [13].…”

“…One explanation for the seemingly paradoxical role of LOX in cancer is likely the existence of multiple forms and differential localisation of LOX. Increasing evidence indicates that the tumour suppressor activity of LOX lies in the cleaved LOX-PP (18-kDa) which can re-enter the nucleus following extracellular cleavage from the mature enzyme and repress oncogenes such as bcl-2 [4,[16][17][18]. On the contrary, the secreted LOX mature enzyme is typically reported to increase ECM stiffness, activate oncogenic signalling pathways and play a tumour promoting role [19,20].…”