Correlation of Vascular Endothelial Growth Factor subtypes and their receptors with melanoma progression: A next-generation Tissue Microarray (ngTMA) automated analysis

PLoS One. 2018 Nov 8;13(11):e0207019. doi: 10.1371/journal.pone.0207019. eCollection 2018.

Abstract

Introduction: Finding new markers to assess prognosis of melanoma without the necessity to perform a surgical interventions is an important goal in melanoma research. The current study aimed to assess the correlation of clinical course and prognosis of primary and metastatic melanoma with expression of VEGF family and their receptors.

Methods: A ngTMA block was made from the randomly selected paraffin tissue blocks of the patients with melanocytic nevi, primary and metastatic melanoma. Then sections cut from ngTMA-block were immunohistochemically stained with proper antibodies. Expression of these proteins was investigated using automated image analysis and compared among the study groups.

Results: We analyzed the tissue of 238 patients with following diagnoses: 101 (42.4%) with a diagnosis of nevus, 86 (36.1%) Malignant melanoma and 51 (21.4%) metastasis. Median follow-up time for the malignant lesions was 5.71 years. Among the tested antigen, VEGF-C (p = 0.016), VEGF-R2 (p<0.001) and VEGF-R3 (p = 0.002) were significantly higher expressed in the metastatic tissues. When these scores were assessed in multiple regression models, the only independent factor linked to patient's diagnosis was VEGF-R2 (p<0.001). In addition, groups of highly correlated variables (VEGF-C and VEGF-R3, VEGF-A and VEGF-R1) were found to form separate sub-clusters. On the other side, high values of VEGF-C were associated with both overall and disease-free survival with a statically significant HR of 2.76 (95% CI: 1.27, 5.98; p = 0.01) and 2.82 (95%CI: 1.62, 4.91; p<0.001), respectively.

Conclusions: This study shows that VEGF-C and VEGF-R2 might represent new prognostic marker in MM. However, further prospective studies are warranted to test their real efficacy as a prognostic marker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Automation
  • Biomarkers, Tumor / metabolism*
  • Disease-Free Survival
  • Female
  • Humans
  • Image Interpretation, Computer-Assisted
  • Kaplan-Meier Estimate
  • Logistic Models
  • Male
  • Melanoma / diagnosis*
  • Melanoma / mortality
  • Melanoma / pathology
  • Middle Aged
  • Neoplasm Metastasis
  • Nevus, Pigmented / diagnosis
  • Nevus, Pigmented / pathology
  • Principal Component Analysis
  • Protein Isoforms / metabolism
  • Receptors, Vascular Endothelial Growth Factor / metabolism*
  • Tissue Array Analysis / methods*
  • Vascular Endothelial Growth Factors / metabolism*

Substances

  • Biomarkers, Tumor
  • Protein Isoforms
  • Vascular Endothelial Growth Factors
  • Receptors, Vascular Endothelial Growth Factor

Grants and funding

This study was supported by Swiss National Science Foundation (grant 310030_166473), Bern Cancer League, the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 642295 (MEL-PLEX).