Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

Abstract

The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer.

MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA

“…There are increasing reports demonstrating the promising effect of targeting hypoxia-responsive genes, such as LOX , LOXL2 , and VEGFA . For instance, a couple of drugs targeting LOX family members are in the early stage of clinical trials [ 5 ], including pancreatic and colorectal adenocarcinoma [ 10 , 11 ]. Sorafenib was shown to hit the first breakthrough systemic therapy for treating advanced HCC via disrupting VEGF signaling [ 50 ].…”

“…The lysyl oxidase family members are secreted copper-dependent oxidases, including five paralogues: LOX , LOX -like 1–4 ( LOXL 1–4), which act to exert catalytic activity to remodel the cross-linking of the extracellular matrix (ECM) of fibrotic liver and that of a corrupted tumor microenvironment (TME) [ 4 ]. To date, the roles of LOX and LOXL 2 in the clinical significance and therapeutic implication of HCC are mostly studied as compared to the other family members [ 5 ]. The fact that LOX and LOXL 2 serving as critical factors in mediating the formation of a corrupted TME and promoting the progression of metastasis of HCC through activating pathways involved in hypoxia responsive signaling and angiogenesis, and epithelial mesenchymal transition (EMT) has been highlighted [ 5 ].…”

“…To date, the roles of LOX and LOXL 2 in the clinical significance and therapeutic implication of HCC are mostly studied as compared to the other family members [ 5 ]. The fact that LOX and LOXL 2 serving as critical factors in mediating the formation of a corrupted TME and promoting the progression of metastasis of HCC through activating pathways involved in hypoxia responsive signaling and angiogenesis, and epithelial mesenchymal transition (EMT) has been highlighted [ 5 ]. For example, LOX acts to mediate angiogenesis via increasing the secreted vascular endothelial growth factor A ( VEGFA ) from HCC cells [ 6 ] and to augment metastatic behaviors by activating EMT program [ 7 ].…”

“…On the other hand, LOXL 2 was reported to activate the process of angiogenesis through upregulating the HIF-1α/VEGF pathway [ 8 ] and promote HCC metastasis to distant organ via an AKT/fibronectin-dependent pathway [ 9 ]. Given the biological importance of LOX , LOXL 2, and VEGFA in the cancer progression, a variety of targeting drugs has currently been evaluated in clinical trials [ 5 , 10 , 11 , 12 ]. Nonetheless, a treatment approach that can comprehensively targeting these factors to render therapeutic potential for the treatment of HCC is yet to be identified.…”

New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

“…For example, a remodeled, stiff ECM can support angiogenesis with abnormal vasculature, leading to a corrupt TME which promotes tumor dissemination [74]. In this regard, the function of lysyl oxidase (LOX) family members on a pro-tumoral TME of HCC by remodeling the ECM was recently noted [75]. More notably, Wong et al demonstrated that miR-29a acts as a negative regulator on lysyl oxidase like 2 (LOXL2) through interacting with the 3'UTR, thereby impeding the HCC metastasis [64].…”