Regulation of tumor cell – Microenvironment interaction by the autotaxin-lysophosphatidic acid receptor axis

Abstract

The lipid mediator lysophosphatidic acid (LPA) in biological fluids is primarily produced by cleavage of lysophospholipids by the lysophospholipase D enzyme Autotaxin (ATX). LPA has been identified and abundantly detected in the culture medium of various cancer cell types, tumor effusates, and ascites fluid of cancer patients. Our current understanding of the physiological role of LPA established its role in fundamental biological responses that include cell proliferation, metabolism, neuronal differentiation, angiogenesis, cell migration, hematopoiesis, inflammation, immunity, wound healing, regulation of cell excitability, and the promotion of cell survival by protecting against apoptotic death. These essential biological responses elicited by LPA are seemingly hijacked by cancer cells in many ways; transcriptional upregulation of ATX leading to increased LPA levels, enhanced expression of multiple LPA GPCR subtypes, and the downregulation of its metabolic breakdown. Recent studies have shown that overexpression of ATX and LPA GPCR can lead to malignant transformation, enhanced proliferation of cancer stem cells, increased invasion and metastasis, reprogramming of the tumor microenvironment and the metastatic niche, and development of resistance to chemo-, immuno-, and radiation-therapy of cancer. The fundamental role of LPA in cancer progression and the therapeutic inhibition of the ATX-LPA axis, although highly appealing, remains unexploited as drug development to these targets has not reached into the clinic yet. The purpose of this brief review is to highlight some unique signaling mechanisms engaged by the ATX-LPA axis and emphasize the therapeutic potential that lies in blocking the molecular targets of the LPA system.

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…Tumor-promoting inflammation and decreased acquired immune responses are "hallmarks" of cancer [21,24,69]. In addition, chronic LPA signaling enables cancer cells to evade the immune system [30,32,70]. Recent work shows that this involves increased signaling through LPAR5 on CD8+ T-cells and blocking of T-cell antigen receptor responses [71].…”

Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface

“…These results provide evidence supporting the contention that aberrant expression of LPA receptors, or the enzyme producing LPA, could contribute to the initiation and progression of human breast cancer [26]. Although a high expression of the ATX gene (ENPP2) correlates with a poor outcome in several types of cancer (such as B-cell lymphomas, renal cell carcinomas, liver or pancreatic cancers [27][28][29]), it is now well established that the tumor microenvironment is an essential source of ATX [30]. Our group notably provided evidence that circulating non-tumoral ATX is stored in the α-granules of resting platelets and is eventually released upon tumor cell-induced platelet aggregation, leading to the production of LPA [31,32].…”

Kynurenic acid and cancer: facts and controversies

“…All of these data suggested potential double-edged role of KYNA in carcinogenesis. Taking into consideration an anti-inflammatory potential of KYNA, this compound may be considered as a potent anticancer agent since continuous inflammation is one of the factors which may induce process of carcinogenesis [103,104]. On the other hand, the proper immune response may inhibit the early stages of carcinogenesis or prevent spreading of cancer cells into the whole body [105,106].…”