From Melanocyte to Malignant Metastatic Melanoma

Malignant melanoma is one of the most aggressive malignancies in human and is responsible for almost 60% of lethal skin tumors. Its incidence has been increasing in white population in the past two decades. There is a complex interaction of environmental (exogenous) and endogenous, including genetic, risk factors in developing malignant melanoma. 8–12% of familial melanomas occur in a familial setting related to mutation of the CDKN2A gene that encodes p16. The aim of this is to brieﬂy review the microanatomy and physiology of the melanocytes, epidemiology, risk factors, clinical presentation, historical classiﬁcation and histopathology and, more in details, the most recent discoveries in biology and genetics of malignant melanoma. At the end, the ﬁnal version of 2009 AJCC malignant melanoma staging and classiﬁcation is presented. The rising proportion of melanomas diagnosed at an early pathologic stage is commonly ascribed to better public education. However in the US SEER program of cancer registration it has been found that the rates for in situ melanomas are closely related by a log linear relationship to the incidence of invasive melanomas and that this relationship is unrelated to calendar year or gender or patient age. This relationship is su ﬃ ciently strong to leave little room for other factors. The relationship may be di ﬀ erent in populations with di ﬀ erent melanoma rates and responses to them. It is suggested that the results are due to variations within populations of individual response to melanoma cell proliferation. In tumor growth, angiogenesis, the process of new-formation of blood vessels from pre-existing ones, is uncontrolled and unlimited in time. The vascular phase is characterized by the new-formation of vascular channels that enhances tumor cell proliferation, local invasion and hematogenous metastasis. Human malignant melanoma is a highly metastatic tumor with poor prognosis, and high resistance to treatment. Parallel with progression, melanoma acquires a rich vascular network, whereas an increasing number of tumor cells express the laminin receptor, which enables their adhesion to the vascular wall, favouring tumor cell extravasation and metastases. Melanoma neovascularization has been correlated with poor prognosis, overall survival, ulceration and increased rate of relapse. Secretion of various angiogenic cytokines, i.e. VEGF-A, FGF-2, PGF-1 and -2, IL-8, and TGF-1 by melanoma cells promote the angiogenic switch and has been correlated to transition from the radial to the vertical growth phase, and to the metastatic phase. Moreover, melanoma cells overexpress α v β 3, α v β 5, α 2 β 1 and α 5 β 1 integrins and release, together with stromal cells, higher amount of metalloproteases that increasing their invasive potential and angiogenesis. Basing on these observations, di ﬀ erent molecular targets of antiangiogenic molecules has be recognized and various antiangiogenic agents are currently in preclinical and clinical trials for melanoma. Cutaneous melanoma and uveal melanoma both derive from melanocytes but show remarkable di ﬀ erences in tumorigenesis, mode of metastatic spread, genetic alterations, and therapeutic response. In this review we discuss the di ﬀ erences and similarities along with the genetic research techniques available and the contribution to our current understanding of melanoma. The several chromosomal aberrations already identiﬁed prove to be very strong predictors of decreased survival in CM and UM patients. Especially in UM, where the overall risk of metastasis is high (45%), genetic research might aid clinicians in selecting high-risk patients for future systemic adjuvant therapies. Our research, inspired by the pioneering works of Isaac Witz in the 1980s, established that 40% of human metastatic melanomas express ectopically inhibitory Fc gamma receptors (Fc γ RIIB), while they are detected on less than 5% of primary cutaneous melanoma and not on melanocytes. We demonstrated that these tumoral Fc γ RIIB act as decoy receptors that bind the Fc portion of antimelanoma IgG, which may prevent Fc recognition by the e ﬀ ector cells of the immune system and allow the metastatic melanoma to escape the humoral/natural immune response. The Fc γ RIIB is able to inhibit the ADCC (antibody dependent cell cytotoxicity) in vitro. Interestingly, the percentage of melanoma expressing the Fc γ RIIB is high (70%) in organs like the liver, which is rich in patrolling NK (natural killer) cells that exercise their antitumoral activity by ADCC. We found that this tumoral Fc γ RIIB is fully functional and that its inhibitory potential can be triggered depending on the speciﬁcity of the anti-tumor antibody with which it interacts. Together these observations elucidate how metastatic melanomas interact with and potentially evade humoral immunity and provide direction for the improvement of anti-melanoma monoclonal antibody therapy. The incidence of melanoma, the most aggressive type of cutaneous malignant tumor, is currently on the rise. Treatment in advanced stages is still unsuccessful compared with other malignant tumors, thus it is important to indentify the key mechanisms responsible for melanoma progression and metastasis. Genetic and molecular components, in particular, that are up- or downregulated in melanoma cells, a ﬀ ect the invasive potential of melanoma. Another possible important cofactor highlighted by recent studies is chronic stress, involving environmental and psychological factors, which can be an important cofactor in not only cancer progression in general but also in melanoma spreading. The negative e ﬀ ects of chronic stress have been evaluated epidemiologically in patients with breast and prostate cancer. In particular, the e ﬀ ects of stress mediators, namely, catecholamines have been studied on various human malignancies, including melanoma and have highlighted a signiﬁcant increase of progression-related molecules. As such, this could be the starting point for a new approach in the treatment of advanced melanoma, in which the negative e ﬀ ects of stress are reduced or blocked.