Angiogenesis in melanoma

Abstract

The process of angiogenesis is crucial for progression and metastasis of the majority of solid tumors including melanomas. The current review summarizes existing knowledge of the mechanisms of angiogenesis in melanoma, as well as current anti-angiogenic therapeutic strategies and their targets. We focus primarily on the role of key growth factors that are secreted by melanoma cells and known to trigger angiogenic responses, and their receptors as expressed on both endothelial and melanoma cells. Many of these growth factors function in synergy with receptors for extracellular matrix, integrins, and matrix metalloproteinases (MMPs). All of these systems of molecules are activated during major stages of angiogenesis such as endothelial migration, proliferation, and reorganization of surrounding extracellular matrix. The blockade of these molecules and their downstream pathways leads to inhibition of melanoma vascularization. Thus, these classes of molecules are essential for melanoma angiogenesis and, therefore, might serve as promising targets for therapeutic intervention. Many recently developed compounds targeting key pathways in angiogenesis are in their final stages of clinical trials.

Figure 1. Malignant progression of melanoma

Aberrant proliferation of normal melanocytes leads to formation of benign naevus. The rapidly proliferating transformed melanocytes form dysplastic naevi, which are asymmetric with irregular borders. This is followed by a rapid radial growth phase, which is characterized by intraepidermal growth. The last step in benign melanoma growth is the vertical growth phase. It is also called the dermal invasion phase. Malignant melanomas develop vasculature very rapidly providing a route for further metastasis.

Figure 2. Cell surface receptor mimicry between malignant melanoma cells and endothelial cells

Malignant melanoma cells express VEGFR-2, VEGFR-1 and co-receptor neuropilin-1/2 which are commonly not expressed on most of the cancer cells. Therefore, VEGF is able to induce similar intracellular signaling responses in both endothelial and melanoma cells. Placental growth factor can independently bind to VEGFR-1 and neuropilin-1/2 to induce intracellular signaling. PIGF also form heterodimeric complexes with VEGF and interact with VEGFR-2. Other receptors expressed on both melanoma and endothelial cells include uPA receptor, CXCR-1/2 and FGFR-1. Therefore, there is a spectrum of growth factors/chemokines which are able to induce similar signaling responses in both cell types.

Figure 3. Regulation of integrin signaling by ECM proteins and growth factor receptors

Integrins and their ligand expression are up-regulated in most of the human melanomas. Ligand binding to the extracellular domain of specific integrin leads to initiation of signaling events required for a broad spectrum of processes such as cellular proliferation, survival, and actin cytoskeleton regulation. Integrin interactions with its ligands are the prerequisites for cellular adhesion, invasion and migration. Growth factors, via receptors expressed on endothelial cells or melanoma cells, are able to regulate integrin function activity, i.e. its affinity and avidity of interactions with ECM proteins. The process of functional crosstalk between growth factor receptors and integrins is regulated by several intracellular signaling molecules which are able to shuffle between growth factor receptors and integrin cytoplasmic domains.