Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma

Our plain-English summary of Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma, by L. Strizzi, A. Catalano, G. Vianale, et al (The Journal of Pathology, 2001).

The study

• Authors: L. Strizzi, A. Catalano, G. Vianale, S. Orecchia, A. Casalini, G. Tassi, R. Puntoni, L. Mutti, A. Procopio
• Journal: The Journal of Pathology
• Published: 2001;193(4):468-75
• Cited by: 277 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Vascular endothelial growth factor (VEGF), a potent mitogen for vascular endothelium, is expressed in malignant pleural mesothelioma (MM). The present report examines the effect of VEGF on MM growth. Four MM cell lines produced significantly higher VEGF levels than normal mesothelial cells (1946+/-14 pg/ml vs. 180+/-17 pg/ml; p<0.001). In addition, MM cells expressed the tyrosine kinase-related VEGF receptors Flt-1 and KDR. Recombinant human VEGF phosphorylated both Flt-1 and KDR and increased proliferation of all four MM cell lines in a dose-dependent fashion. Neutralizing antibodies against either VEGF, Flt-1 or KDR significantly reduced MM cellular proliferation. In addition, expression of VEGF, Flt-1, and KDR was observed in MM biopsies. Moreover, higher VEGF levels were found in the pleural effusions of MM patients than in the effusions of patients with non-malignant pleural disease (1885.7+/-894.9 pg/ml vs. 266.9+/-180.5 pg/ml; p<0.001). Linear regression analysis showed a significant inverse correlation between serum VEGF levels and MM patient survival (r=0.72; p<0.01). No correlation was found between tumour vessel density and either serum (r=0.26; p=0.42) or pleural effusion (r=0.35; p=0.26) VEGF levels. These results indicate that VEGF, via activation of its tyrosine kinase receptors, may be a key regulator of MM growth. In addition, VEGF production could have an impact on patient survival, not only by promoting tumour angiogenesis but also by directly stimulating tumour growth.

Copyright 2001 John Wiley & Sons, Ltd.

In plain English

This laboratory study from Italy asked whether vascular endothelial growth factor (VEGF), a protein known to stimulate blood-vessel cells, also directly drives the growth of malignant pleural mesothelioma cells. Asbestos exposure was not studied. The authors used four mesothelioma cell lines and normal mesothelial cells. They also used pleural fluid and serum collected retrospectively from 12 mesothelioma patients and 10 patients with non-malignant pleural disease, and biopsies from the mesothelioma patients. After 96 hours, the mesothelioma cell lines released 852 to 1946 pg/ml of VEGF, compared with 180 pg/ml for normal cells. Added VEGF increased growth of all four lines in a dose-dependent way. Antibodies blocking VEGF or its receptors Flt-1 and KDR reduced growth of the MPP89 line. Pleural fluid from mesothelioma patients held more VEGF than fluid from the comparison patients (1885.7 vs 266.9 pg/ml), but serum levels did not differ significantly. Among the 12 mesothelioma patients, higher serum VEGF was reported to correlate with shorter survival. VEGF levels were not significantly linked with tumour blood-vessel density. The authors concluded that VEGF acts as a self-stimulating growth signal in mesothelioma cells, and said a larger series was under study.

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 human mesothelioma cell lines, combined with retrospective analysis of patient pleural fluid and serum samples and of mesothelioma biopsy samples
• Who was studied: Four malignant mesothelioma cell lines (IST-Mes1, IST-Mes2, IST-Mes3, MPP89), and normal mesothelial cells taken from pleural fluid of patients with congestive heart failure. Pleural fluid and serum came from 12 patients with malignant pleural mesothelioma and 10 patients with non-malignant pleural disease at Italian institutions. Archival biopsy specimens from the mesothelioma patients were used for staining. Collection dates were not given.
• Exposure: Not an asbestos exposure study. The factor studied was VEGF in three forms: VEGF made by the cells and found in patient fluids, recombinant human VEGF added to cells at 0.1, 1.0 and 10 ng/ml, and neutralizing antibodies against VEGF, Flt-1 and KDR.
• Main results:
  • After 96 hours, VEGF in culture media from the four mesothelioma cell lines ranged from 852 plus or minus 207 to 1946 plus or minus 14 pg/ml. Normal mesothelial cells released 180 plus or minus 17 pg/ml (p less than 0.001).
  • Added VEGF increased cell proliferation in a dose-dependent way in all four mesothelioma cell lines. In the MPP89 line, cell number rose about four-fold at the highest VEGF concentration compared with untreated cells: 16.3 plus or minus 2.0 vs 4.0 plus or minus 1.0, times 10 to the 4th cells per well (p less than 0.001).
  • In MPP89 cells, an antibody neutralizing VEGF significantly reduced proliferation compared with a control antibody: 42.0 plus or minus 3.0 vs 83.0 plus or minus 8.0, times 10 to the 3rd cells per well (p less than 0.05).
  • In MPP89 cells, DNA synthesis (thymidine uptake) rose with added VEGF compared with controls: 75.5 plus or minus 6.7 vs 50.7 plus or minus 5.1, times 10 to the 3rd dpm (p less than 0.05). Uptake fell about 60% with anti-VEGF antibody (32.0 plus or minus 1.0). It also fell with antibodies against Flt-1 (40.7 plus or minus 8.2) and KDR (27.2 plus or minus 10.9) (p less than 0.05).
  • Added VEGF caused a dose-dependent increase in activation (phosphorylation) of its receptors Flt-1 and KDR in the mesothelioma cells.
  • Staining detected VEGF, Flt-1 and KDR in mesothelioma biopsy samples.
  • Pleural fluid VEGF was significantly higher in mesothelioma patients than in patients with non-malignant pleural disease: 1885.7 plus or minus 894.9 vs 266.9 plus or minus 180.5 pg/ml (p less than 0.001).
  • Serum VEGF did not differ significantly between mesothelioma patients and patients with non-malignant pleural disease: 617.5 plus or minus 189.7 vs 576.4 plus or minus 249.2 pg/ml (p greater than 0.05).
  • Among the 12 mesothelioma patients, serum VEGF showed a significant inverse correlation with survival (r=0.72 as printed; p less than 0.01).
  • Pleural fluid VEGF did not correlate with survival in mesothelioma patients (r=0.07; p=0.83).
  • Serum and pleural fluid VEGF correlated only weakly, and not significantly, with tumour blood-vessel density (serum r=0.26, p=0.42; pleural fluid r=0.35, p=0.26).
• The authors' conclusion: The authors concluded that their findings show a VEGF-dependent autocrine loop that stimulates mesothelioma cell growth through activation of VEGF's receptors. They also concluded that the pleural fluid and serum results suggest possible diagnostic and prognostic uses of VEGF levels in mesothelioma.
• Limitations the authors state:
  • The authors said a larger series of patients was being studied to confirm the possible diagnostic and prognostic uses of VEGF levels.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Pleural Mesothelioma, Mesothelial Cells, Pleural Effusion, Angiogenesis.

Related studies

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• VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours — Y. Ohta, V. Shridhar, et al. (1999)
• Endothelial nitric oxide synthase is strongly expressed in malignant mesothelioma but does not associate with vascular density or the expression of VEGF, FLK1 or FLT1 — Y. Soini, A. Puhakka, et al. (2001)
• Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor — E. Nakataki, S. Yano, et al. (2006)
• The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells — A. Catalano, R. Lazzarini, et al. (2009)
• Clinical significance of serum vascular endothelial growth factor in malignant pleural mesothelioma — A. Yasumitsu, C. Tabata, et al. (2010)

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