Revisiting the role of lysophosphatidic acid in stem cell biology

Abstract

Stem cells possess unique biological characteristics such as the ability to self-renew and to undergo multilineage differentiation into specialized cells. Whereas embryonic stem cells (ESC) can differentiate into all cell types of the body, somatic stem cells (SSC) are a population of stem cells located in distinct niches throughout the body that differentiate into the specific cell types of the tissue in which they reside in. SSC function mainly to restore cells as part of normal tissue homeostasis or to replenish cells that are damaged due to injury. Cancer stem-like cells (CSC) are said to be analogous to SSC in this manner where tumor growth and progression as well as metastasis are fueled by a small population of CSC that reside within the corresponding tumor. Moreover, emerging evidence indicates that CSC are inherently resistant to chemo- and radiotherapy that are often the cause of cancer relapse. Hence, major research efforts have been directed at identifying CSC populations in different cancer types and understanding their biology. Many factors are thought to regulate and maintain cell stemness, including bioactive lysophospholipids such as lysophosphatidic acid (LPA). In this review, we discuss some of the newly discovered functions of LPA not only in the regulation of CSC but also normal SSC, the similarities in these regulatory functions, and how these discoveries can pave way to the development of novel therapies in cancer and regenerative medicine.

Pancreatic cancer cells upregulate LPAR4 in response to isolation stress to promote an ECM-enriched niche and support tumour initiation

“…'Isolation stress' (1) downregulates the expression of miR-139-5p (2), which releases a brake on LPAR4 expression (3 and 4). Even in the absence of microenvironmental LPA, LPAR4 is sufficient to activate AKT/CREB signalling (5), driving the expression of ECMrelated genes, including FN1 (6). The deposited FN1 matrix protein ligates with its cell surface integrins α5β1 and/or αVβ3 (7), endowing cells with several selfsufficient traits, including 3D growth and stress tolerance, ultimately promoting tumour initiation and cancer stemness (8).…”

“…Such features are not only derived from intrinsic stem-like traits but can be influenced by tumour stroma-derived immune cell factors within a cancer stem cell (CSC) niche 3 . One such factor is lysophosphatidic acid (LPA) 4 , a bioactive lipid that regulates cell fate transitions for a variety of stem cell types, including CSCs 5,6 .…”

The Emerging Role of LPA as an Oncometabolite

“…On the other hand, circular LPAR3 RNA targets Jupiter microtubule-associated homolog 1 (JPT1) to decrease the radiosensitivity of prostate tumour cells [141]. Similar effects of circular LPAR3 RNA have been noted in ovarian cancer, where this circular RNA enhances cisplatin resistance Another important function of LPA is its role in regulating stemness properties [127,128]. For example, in triple-negative aldehyde dehydrogenase-positive (ALDH + ) breast cancer cells, LPA/LPAR3 induces Ca 2+ signalling through the transient receptor potential cation channel subfamily C member 3 (TRPC3) channel to induce cancer stem cell populations [129].…”

Designing Dual Inhibitors of Autotaxin-LPAR GPCR Axis

“…LPA induces several cellular responses, including cell proliferation, migration, survival, invasion, metastasis, and production of cytokines, by modulating six distinct LPA G-protein coupled receptors (LPAR) ( Figure 1 ) [ 1 , 2 , 3 , 4 , 5 , 6 ]. Activation of the ATX-LPA-LPAR signaling pathway is critical for the maintenance of stemness in pluripotent somatic and cancer stem cells [ 7 , 8 ], the development of neurological systems, the generation of blood vessels, wound healing, and tissue repair [ 4 , 5 ]. Consequently, dysregulation of this signaling pathway is often linked to metabolic and inflammatory disorders, including cancer, tumor immunity [ 9 , 10 , 11 , 12 ], fibrosis, neuropathic pain and neurodegeneration [ 13 , 14 , 15 ], inflammation, autoimmune diseases, and metabolic syndrome [ 4 , 5 , 16 ].…”