Lysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule by binding to and activating at least five known G protein-coupled receptors (GPCRs): LPA(1)-LPA(5). They are encoded by distinct genes named LPAR1-LPAR5 in humans and Lpar1-Lpar5 in mice. The biological roles of LPA are diverse and include developmental, physiological, and pathophysiological effects. This diversity is mediated by broad and overlapping expression patterns and multiple downstream signaling pathways activated by cognate LPA receptors. Studies using cloned receptors and genetic knockout mice have been instrumental in uncovering the significance of this signaling system, notably involving basic cellular processes as well as multiple organ systems such as the nervous system. This has further provided valuable proof-of-concept data to support LPA receptors and LPA metabolic enzymes as targets for the treatment of medically important diseases that include neuropsychiatric disorders, neuropathic pain, infertility, cardiovascular disease, inflammation, fibrosis, and cancer.

https://www.scripps.edu/chun/PDFs/Choi%20Ann%20Rev%20Pharmacol%20Toxicol%202010.pdf

LPA Receptors: Subtypes and Biological Actions

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1–4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer—an aggressive malignancy that is refractory to standard treatments and current immunotherapies5–8—induces endoplasmic reticulum stress and activates the IRE1α–XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α–XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α–XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α–XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts. In human and mouse models of ovarian cancer, endoplasmic reticulum stress and the activation of the IRE1α–XBP1 pathway decreases the metabolic fitness of T cells and limits their anti-tumour functions.

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IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity

Background Lysophosphatidic acid (LPA) acts through the cell surface G protein – coupled receptors, LPA1, LPA2, or LPA3, to elicit a wide range of cellular responses. It is present at high levels in intraperitoneal effusions of human ovarian cancer increasing cell survival, proliferation, and motility as well as stimulating production of neovascularizing factors. LPA2 and LPA3 and enzymes regulating the production and degradation of LPA are aberrantly expressed by ovarian cancer cells, but the consequences of these expression changes in ovarian cancer cells were unknown. Methods Expression of LPA1, LPA2, or LPA3 was inhibited or increased in ovarian cancer cells using small interfering RNAs (siRNAs) and lentivirus constructs, respectively. We measured the effects of changes in LPA receptor expression on cell proliferation (by crystal violet staining), cell motility and invasion (using Boyden chambers), and cytokines (interleukin 6 [IL-6], interleukin 8 [IL-8], and vascular endothelial growth factor [VEGF]) production by enzyme-linked immunosorbent assay. The role of LPA receptors in tumor growth, ascites formation, and cytokine production was assessed in a mouse xenograft model. All statistical tests were two-sided. Results SKOV-3 cells with increased expression of LPA receptors showed increased invasiveness, whereas siRNA knockdown inhibited both migration ( P < .001, Student t test) and invasion. Knockdown of the LPA2 or LPA3 receptors inhibited the production of IL-6, IL-8, and VEGF in SKOV-3 and OVCAR-3 cells. SKOV-3 xenografts expressing LPA receptors formed primary tumors of increased size and increased ascites volume. Invasive tumors in the peritoneal cavity occurred in 75% (n = 4) of mice injected with LPA1 expressing SKOV-3 and 80% (n = 5) of mice injected with LPA2 or LPA3 expressing SKOV-3 cells. Metastatic tumors expressing LPA1, LPA2, and LPA3 were identified in the liver, kidney, and pancreas; tumors expressing LPA2 and LPA3 were detected in skeletal muscle; and tumors expressing LPA2 were also found in the cervical lymph node and heart. The percent survival of mice with tumors expressing LPA2 or LPA3 was reduced in comparison with animals with tumors expressing � -galactosidase. Conclusions Expression of LPA2 or LPA3 during ovarian carcinogenesis contributes to ovarian cancer aggressiveness, suggesting that the targeting of LPA production and action may have potential for the treatment of ovarian cancer.

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Lysophosphatidic Acid Receptors Determine Tumorigenicity and Aggressiveness of Ovarian Cancer Cells

Purpose Plasma levels of lysophospholipids were evaluated as potential biomarkers for colorectal cancer (CRC), where a highly reliable and minimally invasive blood test is lacking. Patients and Methods Patients with CRC (n 133) and control subjects (n 125) were recruited through the Cleveland Clinic. Preoperative plasma samples were analyzed for lysophospholipid levels using liquid chromatography mass spectrometry in a blinded fashion. Participants were randomly divided in a 2:1 ratio into a “training set” (TS) and a “validation set” (VS). Logistic regression models were used in the TS to identify markers that best discriminated between CRC and controls. A cutoff point for the final discriminating model was developed using the receiver operating characteristic curve to achieve 95% specificity. All analyses were then independently validated in the VS. Results Plasma levels of several lysophosphatidylcholines (LPCs), including 18:1- and 18:2-LPC, were significantly decreased in CRC patients compared with controls (P .001). A model based on total saturated LPC and the difference between the proportional amounts of 18:2-LPC and 18:1-LPC in the unsaturated LPC fraction was derived from the TS. This model achieved a sensitivity and specificity of 82% and 93%, respectively, in the VS. Overall, 118 (94%) of 125 control subjects and 113 (85%) of 133 CRC cases were correctly identified, including eight (89%) of nine CRC cases with stage T1 disease.

/pdf/plasma-lysophosphatidylcholine-levels-potential-biomarkers-315w05p1fo.pdf

Plasma Lysophosphatidylcholine Levels: Potential Biomarkers for Colorectal Cancer

The reciprocal interplay of cancer cells and host cells is an indispensable perquisite for tumor growth and progression. Cells of both the innate and adaptive immune system, in particular tumor-associated macrophages (TAMs) and T cells, as well as cancer-associated fibroblasts enter into a malicious liaison with tumor cells to create a tumor promoting and immunosuppressive tumor microenvironment (TME). Ovarian cancer, the most lethal of all gynecological malignancies, is characterized by a unique TME that enables specific and efficient metastatic routes, impairs immune surveillance and mediates therapy resistance. A characteristic feature of the ovarian cancer TME is the role of resident host cells, in particular activated mesothelial cells, which line the peritoneal cavity in huge numbers, as well as adipocytes of the omentum, the preferred site of metastatic lesions. Another crucial factor is the peritoneal fluid, which enables the transcoelomic spread of tumor cells to other pelvic and peritoneal organs, and occurs at more advanced stages as a malignancy-associated effusion. This ascites is rich in tumor-promoting soluble factors, extracellular vesicles, detached cancer cells as well as large numbers of T cells, TAMs and other host cells, which cooperate with resident host cells to support tumor progression and immune evasion. In this review we summarize and discuss our current knowledge of the cellular and molecular interactions that govern this interplay with a focus on signaling networks formed by cytokines, lipids and extracellular vesicles, the pathophysiologial roles of TAMs and T cells, the mechanism of transcoelomic metastasis and the cell type selective processing of signals from the TME.

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The Unique Molecular and Cellular Microenvironment of Ovarian Cancer.

Lysophosphatidic acid (LPA) is elevated in ascites of ovarian cancer patients and stimulates growth and other activities of ovarian cancer cells in vitro . Tissue hypoxia is a critical factor for tumor aggressiveness and metastasis in cancers. We tested whether the ascites of ovarian cancer is hypoxic and whether hypoxia influences the effects of LPA on ovarian cancer cells. We found that ovarian ascitic fluids were hypoxic in vivo . Enhanced cellular responsiveness to LPA, including migration and/or invasion of ovarian cancer cells, was observed under hypoxic conditions. This enhancement could be completely blocked by geldanamycin or a small interfering RNA targeting hypoxia-inducible factor 1α (HIF1α). LPA-induced cell migration required cytosolic phospholipase A 2 (cPLA 2 ) and LPA stimulates cPLA 2 phosphorylation in a HIF1α-dependent manner under hypoxia conditions. Furthermore, we show for the first time that exogenous LPA enhances tumor metastasis in an orthotopic ovarian cancer model and HIFα expression in tumors. 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (an inhibitor of the heat shock protein 90) effectively blocked LPA-induced tumor metastasis in vivo. Together, our data indicate that hypoxic conditions are likely to be pathologically important for ovarian cancer development. HIF1α plays a critical role in enhancing and/or sensitizing the role of LPA on cell migration and invasion under hypoxic conditions, where cPLA 2 is required for LPA-induced cell migration. (Cancer Res 2006; 66(16): 7983-90)

https://cancerres.aacrjournals.org/content/canres/66/16/7983.full.pdf

Kwan Sik Kim

Papers

Hypoxia Enhances Lysophosphatidic Acid Responsiveness in Ovarian Cancer Cells and Lysophosphatidic Acid Induces Ovarian Tumor Metastasis In vivo