Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications

Abstract

Background: The classification and prognostic assessment of melanoma is currently based on morphologic and histopathologic biomarkers. Availability of an increasing number of molecular biomarkers provides the potential for redefining diagnostic and prognostic categories and utilizing pharmacogenomics for the treatment of patients. The aim of the present review is to provide a basis that will allow the construction-or reconstruction-of future melanoma research.

Methods: We critically review the common medical databases (PubMed, EMBASE, Scopus and Cochrane CENTRAL) for studies reporting on molecular biomarkers for melanoma. Results are discussed along the hallmarks proposed for malignant transformation by Hanahan and Weinberg. We further discuss the genetic basis of melanoma with regard to the possible stem cell origin of melanoma cells and the role of sunlight in melanoma carcinogenesis.

Results: Melanocyte precursors undergo several genome changes -UV-induced or not- which could be either mutations or epigenetic. These changes provide stem cells with abilities to self-invoke growth signals, to suppress antigrowth signals, to avoid apoptosis, to replicate without limit, to invade, proliferate and sustain angiogenesis. Melanocyte stem cells are able to progressively collect these changes in their genome. These new potential functions, drive melanocyte precursors to the epidermis were they proliferate and might cause benign nevi. In the epidermis, they are still capable of acquiring new traits via changes to their genome. With time, such changes could add up to transform a melanocyte precursor to a malignant melanoma stem cell.

Conclusions: Melanoma cannot be considered a "black box" for researchers anymore. Current trends in the diagnosis and prognosis of melanoma are to individualize treatment based on molecular biomarkers. Pharmacogenomics constitute a promising field with regard to melanoma patients' treatment. Finally, development of novel monoclonal antibodies is expected to complement melanoma patient care while a number of investigational vaccines could find their way into everyday oncology practice.

Keywords: Biomarkers; carcinogenesis; melanoma; melanomagenesis; stem cells; sunlight; ultra violet light exposure.

Figure 1

Melanoma intracellular signaling pathways: A simplified diagram of three of the major genetic networks involved in melanoma carcinogenesis. The SCF/c-KIT signaling network (NRAS, MAPK and PI3 Kinase/AKT pathways), the Wnt/Frizzled signaling network (APC, β-catenin), and the α-MSH/MC1R signaling network (PKA, CREB, MITF) which have been implicated in melanoma proliferation, apoptosis and cell cycle regulation. p16INKA and p14ARF are two separate tumor suppressors both of which are thought to contribute to senescence and tumor growth restriction. The p53 proapoptotic signaling network is also a major contributor to melanoma apoptosis and chemosensitivity and is regulated by many of the oncogenic melanoma pathways. →: designates a positive feedback ⊣: designates a negative feedback

Figure 2

Melanoma: Stem cells, sun exposure and hallmarks of carcinogenesis. Melanoma stem cells undergo several genome changes, either mutations or epigenetic. Melanoma stem cells need to achieve growth self-sufficiency, the ability to suppress anti-growth signals, to avoid apoptosis, to replicate without limit, to invade, proliferate and sustain angiogenesis prior to malignancy development. In the epidermis, stem cells are still capable of acquiring new traits via changes to their genome. A: precursor melanocyte migrating toward the dermis. B and C: precursor melanocytes in the dermis and epidermis respectively. D and E: mature melanocytes in the epidermis and stratum corneum. F: Malignant melanocyte (melanoma stem cell). Malignant transition could be either due to spontaneous mutations (The Hallmarks of Melanoma) or –partially- due to UV-induced genome changes (either mutations or epigenetic). During this process which is anticipated to last several years, some precursor cells might acquire the ability to replicate, invoke own growth signals and avoid apoptosis, being capable of causing benign nevi (G). Further genomic instability, perhaps UV-induced, leads to the development of metastatic melanoma (H), which could cause bloodborne metastases (I)