LOX-1 and cancer: an indissoluble liaison

Abstract

Recently, a strong correlation between metabolic disorders, tumor onset, and progression has been demonstrated, directing new therapeutic strategies on metabolic targets. OLR1 gene encodes the LOX-1 receptor protein, responsible for the recognition, binding, and internalization of ox-LDL. In the past, several studied, aimed to clarify the role of LOX-1 receptor in atherosclerosis, shed light on its role in the stimulation of the expression of adhesion molecules, pro-inflammatory signaling pathways, and pro-angiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. In recent years, LOX-1 upregulation in different tumors evidenced its involvement in cancer onset, progression and metastasis. In this review, we outline the role of LOX-1 in tumor spreading and metastasis, evidencing its function in VEGF induction, HIF-1alpha activation, and MMP-9/MMP-2 expression, pushing up the neoangiogenic and the epithelial-mesenchymal transition process in glioblastoma, osteosarcoma prostate, colon, breast, lung, and pancreatic tumors. Moreover, our studies contributed to evidence its role in interacting with WNT/APC/β-catenin axis, highlighting new pathways in sporadic colon cancer onset. The application of volatilome analysis in high expressing LOX-1 tumor-bearing mice correlates with the tumor evolution, suggesting a closed link between LOX-1 upregulation and metabolic changes in individual volatile compounds and thus providing a viable method for a simple, non-invasive alternative monitoring of tumor progression. These findings underline the role of LOX-1 as regulator of tumor progression, migration, invasion, metastasis formation, and tumor-related neo-angiogenesis, proposing this receptor as a promising therapeutic target and thus enhancing current antineoplastic strategies.

Fig. 1. Intracellular molecular mechanisms leading to metabolic reprogramming and cell transformation, mediated by LOX-1 overexpression.

Ox-LDL binding to LOX-1 increases ROS formation and NO release reduction, alternatively it can activate the PI3K/AKT/GSK3β cascade. The activation of both pathways results in the triggering of transcription factors associated to epithelial to mesenchymal transition (EMT-TFs) and of NF-kB. The NO release reduction can also activate the inflammatory signaling (IL-6, IL-8, and IL-1β). The final result is the activation of hypoxia pathways (VEGF, HIF-1α) and the enhancement of mesenchymal markers expression (MMP-2 and MMP-9). The outcome of all these processes determines cell transformation, angiogenesis, and the epithelial to mesenchymal transition.

Fig. 2. experimental setup for the volatolome measurement of xenografted mice.

Each individual animal was kept in a cage during the measurement. The volatile compounds were sampled with an SPME fiber for the GC-MS analysis. Electronic nose measurements were performed conveying with a pump the air from the cage to the sensors.

Fig. 3. COSMIC data on somatic OLR1 mutations.

A chart showing an overview of the different somatic mutations detected in OLR1 gene.