Functional relevance of the switch of VEGF receptors/co-receptors during peritoneal dialysis-induced mesothelial to mesenchymal transition

Our plain-English summary of Functional relevance of the switch of VEGF receptors/co-receptors during peritoneal dialysis-induced mesothelial to mesenchymal transition, by M.L. Pérez-Lozano, P. Sandoval, A. Rynne-Vidal, et al (PloS One, 2013).

The study

• Authors: M.L. Pérez-Lozano, P. Sandoval, A. Rynne-Vidal, A. Aguilera, J.A. Jiménez-Heffernan, P. Albar-Vizcaíno, P.L. Majano, J.A. Sánchez-Tomero, R. Selgas, M. López-Cabrera
• Journal: PloS One
• Published: 2013;8(4):e60776
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Vascular endothelial growth factor (VEGF) is up-regulated during mesothelial to mesenchymal transition (MMT) and has been associated with peritoneal membrane dysfunction in peritoneal dialysis (PD) patients. It has been shown that normal and malignant mesothelial cells (MCs) express VEGF receptors (VEGFRs) and co-receptors and that VEGF is an autocrine growth factor for mesothelioma. Hence, we evaluated the expression patterns and the functional relevance of the VEGF/VEGFRs/co-receptors axis during the mesenchymal conversion of MCs induced by peritoneal dialysis. Omentum-derived MCs treated with TGF-β1 plus IL-1β (in vitro MMT) and PD effluent-derived MCs with non-epithelioid phenotype (ex vivo MMT) showed down-regulated expression of the two main receptors Flt-1/VEGFR-1 and KDR/VEGFR-2, whereas the co-receptor neuropilin-1 (Nrp-1) was up-regulated. The expression of the Nrp-1 ligand semaphorin-3A (Sema-3A), a functional VEGF competitor, was repressed throughout the MMT process. These expression pattern changes were accompanied by a reduction of the proliferation capacity and by a parallel induction of the invasive capacity of MCs that had undergone an in vitro or ex vivo MMT. Treatment with neutralizing anti-VEGF or anti-Nrp-1 antibodies showed that these molecules played a relevant role in cellular proliferation only in naïve omentum-derived MCs. Conversely, treatment with these blocking antibodies, as well as with recombinant Sema-3A, indicated that the switched VEGF/VEGFRs/co-receptors axis drove the enhanced invasion capacity of MCs undergoing MMT. In conclusion, the expression patterns of VEGFRs and co-receptors change in MCs during MMT, which in turn would determine their behaviour in terms of proliferation and invasion in response to VEGF.

In plain English

This laboratory study from Madrid, Spain, did not study asbestos or mesothelioma. It examined mesothelial cells, the cells lining the abdomen, in people on peritoneal dialysis, a kidney treatment. The authors studied how these cells change into a more fibrous form (mesothelial to mesenchymal transition) and the role of a growth factor, VEGF, and the receptors it binds to. They used cells from the omentum (abdominal tissue) of 31 surgical donors, which they treated in the laboratory with two signalling proteins (TGF-beta1 and IL-1beta). They also used cells drained in dialysis fluid from 51 patients, grouped as epithelioid (30) or non-epithelioid (21). In changed cells, two VEGF receptors (VEGFR-1 and VEGFR-2) fell, the co-receptor neuropilin-1 rose, and Sema-3A, a protein that competes with VEGF, fell. Changed cells grew less but invaded through a collagen layer more. Blocking VEGF clearly reduced growth only in untreated omentum cells. Blocking VEGF or neuropilin-1, or adding Sema-3A, reduced invasion. The authors concluded that VEGF binding to neuropilin-1 may have a role in mesothelial cell invasion.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of cultured human mesothelial cells. It used omentum-derived cells changed in vitro and cells from dialysis effluent studied ex vivo, together with patient clinical data and peritoneal biopsies.
• Who was studied: 51 clinically stable peritoneal dialysis patients (30 men, 21 women, aged 25 to 78) in Madrid, Spain. Their effluent cells were classed as epithelioid (n = 30) or non-epithelioid (n = 21). The study also used omentum from 31 healthy donors (11 for PCR, 20 for proliferation, invasion and immunofluorescence assays), effluent cells from 15 additional PD patients, and biopsies from 5 PD patients and 4 controls. Study dates are not given.
• Exposure: No asbestos exposure was studied. The exposures were peritoneal dialysis fluids in patients and, in the laboratory, 72-hour treatment of omentum cells with TGF-beta1 (0.5 ng/mL) plus IL-1beta (2 ng/mL).
• Main results:
  • In omentum cells from 11 donors treated with TGF-beta1 plus IL-1beta, VEGFR-1 (p = 0.005) and VEGFR-2 (p = 0.0005) expression went down and neuropilin-1 went up (p = 0.004).
  • Non-epithelioid effluent cells, compared with epithelioid effluent cells, showed significantly lower VEGFR-1 and VEGFR-2 and higher neuropilin-1. VEGFR-3 and Nrp-2 showed no statistical differences.
  • VEGF levels were higher in dialysis effluents from patients draining non-epithelioid cells (n = 11) than epithelioid cells (n = 16), p = 0.04.
  • Sema-3A levels were significantly lower in effluents draining non-epithelioid cells (16 epithelioid, 11 non-epithelioid; p = 0.02).
  • Blocking VEGF with an antibody significantly inhibited proliferation of untreated omentum cells. Proliferation of changed cells was not affected or only marginally affected. An anti-neuropilin-1 (Np-1b) antibody reduced proliferation by 25 to 30% in cells of both types.
  • Treatment with recombinant Sema-3A significantly reduced the invasion capacity of the mesothelial cells. Anti-VEGF and anti-Np-1b antibodies also inhibited invasion.
  • 62% of patients with non-epithelioid cells (13 of 21) had a creatinine mass transfer coefficient of 11 mL/min or more, compared with 30% of patients with epithelioid cells (9 of 30), p = 0.04.
  • Nine of the 11 patients who had peritonitis drained non-epithelioid cells (p = 0.03).
• The authors' conclusion: The authors concluded that their results strongly suggest that VEGF interacting with neuropilin-1 may have a role in mesothelial cell invasion.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelial Cells, Mesothelioma, Omentum, Non-epithelioid.

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