Angiogenesis, vasculogenic mimicry and vascular invasion in cutaneous malignant melanoma – implications for therapeutic strategies and targeted therapies

Abstract

Angiogenesis, defined as new vessel growth from a pre-existing vessel, has been shown to be crucial for tumor survival and growth in several lineage-unrelated malignancies including melanoma. The concept of vasculogenic mimicry, a highly patterned microcirculation independent of angiogenesis, has also been described in melanoma. The prognostic value of vascular invasion, characterized by the presence of tumor cells within vascular channels, in melanoma remains controversial as in the current American Joint Committee on Cancer-staging system for melanoma vascular invasion is not included for microscopic staging purposes. This review summarizes contemporary understanding of these three processes i.e. angiogenesis, vasculogenic mimicry, and vascular invasion in an effort to uncover putative targets as therapeutic strategies in melanoma.

Keywords::

• angiogenesis
• anti-angiogenesis
• lymphovascular invasion
• melanoma
• vascular invasion
• vasculogenic mimicry

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Conflicting reports exist regarding the potential utility of VEGF as a prognosticator in melanoma.

• Although basic FGF is an important mitogenic GF for melanoma, autocrine basic FGF stimulation has been shown to be insufficient for the induction of transformed melanocytes.

• Angiopoietin-2 appears to be a promising biomarker for disease monitoring at least in stage IV.

• Expression of MMP-9 is an early event in melanomagenesis, as it is found exclusively during the horizontal growth phase, but not during the vertical growth phase.

• The lack of endothelial cells lining vasculogenic mimicry channels may partially explain the lack of response of select tumors to treatment by inhibitors such as angiostatin and endostatin.

• The lack of universal markers to detect vasculogenic mimicry in various tumors has hindered clinical use and future research.

• The use of immunohistochemical stains significantly enhances the detection of lymphovascular invasion and appears to correlate with select established histopathologic prognosticators, although the clinical relevance of the same remains disputable.

• Although there is some evidence for the therapeutic use of anti-angiogenic agents in melanoma, the jury is still out regarding their efficacy in advanced disease.