Uveal Versus Cutaneous Melanoma; Same Origin, Very Distinct Tumor Types

Abstract

Here, we critically evaluated the knowledge on cutaneous melanoma (CM) and uveal melanoma (UM). Both cancer types derive from melanocytes that share the same embryonic origin and display the same cellular function. Despite their common origin, both CM and UM display extreme differences in their genetic alterations and biological behavior. We discuss the differences in genetic alterations, metastatic routes, tumor biology, and tumor-host interactions in the context of their clinical responses to targeted- and immunotherapy.

Keywords: adaptive immunity; cutaneous melanoma; driver mutations; liver metastases; metastatic uveal melanoma; uveal melanoma.

Figure 1

Signaling pathways and receptors involved in uveal melanoma (UM) and cutaneous melanoma (CM). Three main signaling pathways affected in UM and/or CM patients are depicted. G protein-coupled receptor (GPCR) with its Guanine nucleotide-binding proteins: the first is the Guanine nucleotide binding protein (GNAQ) and subunit alpha-11 (GNA11), which downstream activate Phospholipase C (PLC) and Protein Kinase C (PKC). The second is the mitogen-activated protein kinase (MAPK) signaling pathway, consisting of BRAF-MEK1/2-ERK1/2. Finally, there is the PI3K/Akt/mTOR pathway, which can be influenced by both RAS (from the MAPK signaling pathway) and phosphatase and tensin homolog (PTEN). The previously described chemokine receptors and their influence on the signaling pathways are added: C-X-C chemokine receptor 4 (CXCR4), with its C-X-C Motif Chemokine Ligand 12 (CXCL12), tyrosine-protein kinase Met (c-Met) and its ligand Hepatocyte Growth Factor (HGF), and Insulin-like Growth Factor-1 Receptor (IGF-1R), with Insulin-like Growth Factor-1 (IGF-1). In the nucleus, the ERK1/2 stimulates transcription factors, while both histone deacetylase (HDAC) and mechanistic target of rapamycin (mTOR) inhibit the formation of Reactive Oxygen Species (ROS). Figure was created with BioRender.com.