VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours

Our plain-English summary of VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours, by Y. Ohta, V. Shridhar, R.K. Bright, et al (British Journal of Cancer, 1999).

The study

• Authors: Y. Ohta, V. Shridhar, R.K. Bright, G.P. Kalemkerian, W. Du, M. Carbone, Y. Watanabe, H.I. Pass
• Journal: British Journal of Cancer
• Published: 1999;81(1):54-61
• Cited by: 291 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The vascular endothelial growth factor (VEGF) family is a novel regulator of endothelial cell proliferation. We assessed the mRNA expression of VEGF, VEGF type C (VEGF-C) and their receptors together with the microvessel density (VD) and microlymphatic vessel density (LVD) in pursuit of their connection and prognostic value in malignant pleural mesothelioma (MPM). We used four human MPM cell lines, 54 MPM tumours and five normal pleural tissues. Expression levels for receptors and ligands were assessed by semiquantitative reverse transcriptase polymerase chain reaction analysis. Microvessels were highlighted by immunohistochemical staining for factor VIII. The discrimination of lymphatics was performed by enzyme-histochemistry for 5'-nucleotidase after adequate inhibition of non-specific activity. The expression levels of VEGF, VEGF-C and VEGFRs were high in all MPM cell lines. The percentages of tumours with higher expression compared to the mean values of normal pleural tissues were 31.5% (17/54) for VEGF, 66.7% (36/54) for VEGF-C, 20.4% (11/54) for fms-like tyrosine kinase (flt)-1, 42.6% (23/54) for kinase insert domain-containing recepter (KDR) and 59.3% (32/54) for flt-4. Significant positive correlations were found between VEGF-C and flt-4, VEGF and KDR, VEGF and flt-1 in tumour tissues. The association between LVD and VEGF-C expression level was especially strong (P< 0.0001, r= 0.63). There were also significant correlations between LVD and flt-4, and VD and VEGF. No correlation, however, was found between LVD and nodal metastasis. VD was a negative prognostic indicator in this study. The associations between VEGFNEGF-C and vessel density suggest that these factors play an important role in angiogenesis and lymphangiogenesis in this tumour, and assessment of vascularity may be a useful prognostic indicator for MPM patients.

In plain English

This laboratory study looked at tumour tissue from people with malignant pleural mesothelioma (MPM). It did not study asbestos exposure. The authors measured mRNA expression of two growth factors, VEGF and VEGF-C, and of their receptors (flt-1, KDR and flt-4). They did this in four mesothelioma cell lines, 54 tumour samples from a frozen sample bank, and five normal pleural tissue samples. In the tumours they also counted all small vessels, blood and lymphatic together (VD), and, separately, small lymphatic vessels (LVD). All four cell lines showed high expression. Compared with the normal pleura average, expression was higher in 17 of 54 tumours for VEGF and in 36 of 54 for VEGF-C. VEGF-C levels were associated with lymphatic vessel density, and VEGF levels with overall vessel density. Lymphatic vessel density was not significantly associated with lymph-node metastasis. Among 46 patients with standardized surgery, being male, advanced stage and high VD were independent indicators of poorer survival. The authors concluded that their study suggests VEGF and VEGF-C play an important role in forming blood and lymphatic vessels in these tumours.

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 mesothelioma cell lines, tumour samples and normal pleural tissue, with survival analysis of the patients whose tumours were sampled
• Who was studied: Four human malignant mesothelioma cell lines (H-meso, H2818, H2591, H2595); 54 malignant mesothelioma tumours chosen at random from a bank of snap-frozen samples (44 epithelial, 4 sarcomatous, 6 mixed); five normal pleural tissue samples from patients with non-cancerous disease. Dates and patient locations are not stated.
• Exposure: Not studied. Asbestos appears only in the introduction as background. The study measured mRNA expression of VEGF, VEGF-C and their receptors. It also measured overall microvessel density (VD, blood and lymphatic vessels together, stained for factor VIII) and lymphatic microvessel density (LVD, stained for 5'-nucleotidase) in tumours.
• Main results:
  • All four mesothelioma cell lines showed high mRNA expression of VEGF, VEGF-C and their receptors KDR, flt-1 and flt-4.
  • Share of the 54 tumours with expression higher than the mean of the normal pleural tissues: 31.5% (17/54) for VEGF, 66.7% (36/54) for VEGF-C, 20.4% (11/54) for flt-1, 42.6% (23/54) for KDR and 59.3% (32/54) for flt-4.
  • Two of the five normal pleural samples had a higher VEGF index than the tumour mean, and two had a higher VEGF-C index than the tumour mean.
  • In tumours, the mean VEGF-C index was 0.87 plus or minus 0.15, against 0.16 plus or minus 0.03 in normal pleura. The authors described VEGF-C, flt-4 and KDR levels as tending to be greater in tumours.
  • In tumour tissue, expression levels were positively correlated for VEGF-C and flt-4 (P = 0.0018, r = 0.67), VEGF and KDR (P = 0.0002, r = 0.39), and VEGF and flt-1 (P = 0.0089, r = 0.27).
  • In tumours, lymphatic vessel density (LVD) was strongly associated with VEGF-C expression (P less than 0.0001, r = 0.63).
  • LVD was also associated with flt-4 expression (P = 0.0164, r = 0.64). Overall microvessel density (VD, which counted both blood and lymphatic vessels) was associated with VEGF expression (P = 0.0188, r = 0.33).
  • VD counted both blood and lymphatic vessels, and its mean count was much greater than that for LVD.
  • Among the 47 cases with lymph node information (30 node-positive, 17 node-negative), nodal status showed no significant relationship with LVD (P = 0.1351) or VD (P = 0.8856).
  • In 28 stage III patients with epithelial-type tumours and standardized resections, median survival was 11 months in the high-VD group and 17 months in the low-VD group. One-year survival was 40.0% and 61.5% respectively. This difference was a trend that did not reach statistical significance (P = 0.0866).
  • In multivariate analysis of 46 patients with standardized resections, male gender, advanced stage (III and IV) and high VD were independent negative prognostic indicators. Table 4 gives a hazard ratio of 2.247 for VD (95% CI 1.070 to 4.719, P = 0.0326).
  • In the 46 patients with standardized resections, age, nodal status, histological subtype, VEGF-C, flt-4, the combined VEGF-C factor and LVD had no impact on survival.
• The authors' conclusion: The authors concluded that their study suggests VEGF and VEGF-C play an important role in forming blood and lymphatic vessels in MPM tumours, and that VD has a significant impact on overall survival. They also stated that LVD had no impact on nodal metastasis.
• Limitations the authors state:
  • The authors attribute the result for the combined VEGF factor, whose link with outcome only trended toward significance, to the small sample size.
  • Mesothelioma cells themselves expressed both flt-4 and 5'-nucleotidase. This made it difficult to match flt-4-expressing endothelial cells with those showing 5'-nucleotidase activity.
  • In three cases, non-specific staining stayed high, so LVD was assessed by avoiding those areas.
  • Nodal status was not related to outcome in their samples. This leaves open whether VEGF and VEGF-C relate to prognosis where nodal status matters more.

Topics

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

Medical terms in this study, explained in our Lexicon: Angiogenesis, Malignant Mesothelioma, Pleural Mesothelioma, Immunohistochemistry, Metastasis.

Related studies

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• The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor — P. Cacciotti, L. Strizzi, et al. (2002)
• Combination of onconase and dihydroartemisinin synergistically suppresses growth and angiogenesis of non-small-cell lung carcinoma and malignant mesothelioma — R. Shen, J. Li, et al. (2016)
• Impact of tumor angiogenesis in peritoneal mesothelioma after radical cytoreduction and hyperthermic intraperitoneal chemotherapy — T.C. Chua, P. Yao, et al. (2010)
• Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis — P. Smeele, S.M. d'Almeida, et al. (2018)

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