Lysophosphatidic Acid: Promoter of Cancer Progression and of Tumor Microenvironment Development. A Promising Target for Anticancer Therapies?

Increased expression of the enzyme autotaxin (ATX) and the consequently increased levels of its product, lysophosphatidic acid (LPA), have been reported in several primary tumors. The role of LPA as a direct modulator of tumor cell functions—motility, invasion and migration capabilities as well as resistance to apoptotic death—has been recognized by numerous studies over the last two decades. Notably, evidence has recently been accumulating that shows that LPA also contributes to the development of the tumor microenvironment (TME). Indeed, LPA plays a crucial role in inducing angiogenesis and lymphangiogenesis, triggering cellular glycolytic shift and stimulating intratumoral fibrosis. In addition, LPA helps tumoral cells to escape immune surveillance. Treatments that counter the TME components, in order to deprive cancer cells of their crucial support, have been emerging among the promising new anticancer therapies. This review aims to summarize the latest knowledge on how LPA influences both tumor cell functions and the TME by regulating the activity of its different elements, highlighting why and how LPA is worth considering as a molecular target for new anticancer therapies

Renal and systemic nitric oxide synthesis in rats with renal mass reduction

Renal and systemic nitric oxide synthesis in rats with renal mass reduction. In rats undergoing renal mass reduction (RMR) oral supplementation with the nitric oxide (NO) precursor L-arginine increases glomerular filtration rate and ameliorates signs of glomerular injury, suggesting that chronic renal failure in the rats is a condition of low NO formation in the kidney. On the contrary, data are available that in the systemic circulation of uremics, both rats and human beings, NO is formed in excessive amounts and may contribute to platelet dysfunction and bleeding tendency, well-known complications of uremia. The present study was designed to clarify the pathophysiology of renal and systemic NO synthesis in uremia. We showed that renal ex vivo NO generation, measured as the conversion of [3H] L-arginine to [3H] L-citrulline, was lower than normal in RMR rats, seven days after surgery, and progressively worsened with time in close correlation with signs of renal injury. Consistent with these results, urinary excretion of the stable NO metabolites, NO2−/NO3−, significantly decreased in rats with RMR. To go deeper into the cellular origin and biochemical nature of this abnormality we used two histochemical approaches that could locate either NO synthase (NOS) catalytic activity (NADPH-diaphorase) or NOS isoenzyme expression (immunoperoxidase). NADPH-diaphorase documented a progressive loss of renal NOS activity in RMR rats that co-localized with a strong progressive decrease of inducible NOS isoenzyme (iNOS) immunostaining. At variance with iNOS, endothelial cell NOS (ecNOS) staining was rather comparable in RMR and control kidneys. At variance to the kidney, in the systemic circulation of RMR rats the synthesis of NO increased as reflected by higher than normal plasma NO2−/NO3− concentrations. High systemic NO likely derives from vessels as documented by the increased NOS activity and higher expression of both iNOS and ecNOS in the aorta of RMR rats. Up-regulation of systemic NO synthesis might be an early defense mechanism against hypertension of uremia. On the other hand, more NO available to circulating cells may sustain the bleeding tendency, a well-known complication of uremia

Proteasomal Processing of Albumin by Renal Dendritic Cells Generates Antigenic Peptides

The role of dendritic cells (DC) that accumulate in the renal parenchyma of non–immune-mediated proteinuric nephropathies is not well understood. Under certain circumstances, DC capture immunologically ignored antigens, including self-antigens, and present them within MHC class I, initiating an autoimmune response. We studied whether DC could generate antigenic peptides from the self-protein albumin. Exposure of rat proximal tubular cells to autologous albumin resulted in its proteolytic cleavage to form an N-terminal 24–amino acid peptide (ALB1-24). This peptide was further processed by the DC proteasome into antigenic peptides that had binding motifs for MHC class I and were capable of activating syngeneic CD8+ T cells. In vivo, the rat five-sixths nephrectomy model allowed the localization and activation of renal DC. Accumulation of DC in the renal parenchyma peaked 1 wk after surgery and decreased at 4 wk, concomitant with their appearance in the renal draining lymph nodes. DC from renal lymph nodes, loaded with ALB1-24, activated syngeneic CD8+ T cells in primary culture. The response of CD8+ T cells of five-sixths nephrectomized rats was amplified with secondary stimulation. In contrast, DC from renal lymph nodes of five-sixths nephrectomized rats treated with the proteasomal inhibitor bortezomib lost their capacity to stimulate CD8+ T cells in primary and secondary cultures. These data suggest that albumin can be a source of potentially antigenic peptides upon renal injury and that renal DC play a role in processing self-proteins through a proteasome-dependent pathway