The incidence of melanoma cases is increasing faster than that of any other cancer. Understanding the molecular mechanisms of the initiation and progression of melanoma would create new opportunities for developing novel therapeutic strategies for this potentially lethal disease. A crucial question in the development of melanoma is the identification of the cell type capable of sustaining neoplastic growth. It has been demonstrated that melanoma contains cancer stem cells (CSCs) considered the source of the primary tumor mass and responsible for drug resistance and cancer recurrence. Preliminary data from this Research Unit (RU) demonstrate that CSCs can be isolated from melanoma cells, being identified by the expression of specific biomarkers of staminality, such as CXCR6.
It is also clear that the progression of melanoma phase depends on the interaction of cancer cells with the surrounding microenvironment, specifically with endothelial vascular cells.
Epidemiologic and experimental observations support the hypothesis that melanoma can be classified as an estrogen-responsive tumor. Clinical observations indicate that estrogen-receptor-beta (ERbeta), endowed with a strong antiproliferative activity, is the predominant ER type in melanomas and its expression markedly decreases during the progression of melanoma towards its metastatic phase.
It is known that receptors for Gonadotropin-Releasing Hormone (GnRHRs) are expressed in different tumors, including melanoma. This RU has demonstrated that GnRH agonists exert a dual antiangiogenic activity in melanoma, both by reducing VEGF-A secretion from tumor cells and by counteracting the direct proangiogenic activity of VEGF-A on endothelial cells.
At least one of the five somatostation receptors (SSTRs) was found to be expressed in melanoma cells and SRIF analogs inhibit melanoma cell proliferation. Moreover, several microenvironment events may also be modulated by SSTRs activation in melanoma cells and in associated inflammatory and vascular cells.
Finally, ultraviolet (UV) radiation, in particular UVB, has been linked to cutaneous melanoma. Experimental data show that UV incites melanomagenesis not only through DNA mutagenesis, but also by altering interactions between melanocytes and their microenvironment to regulate remodelling of UV-damaged skin. Specifically, UVB recruits macrophages producing IFN-gamma which plays a crucial role in aberrant melanocyte transformation.
The proposed research will be organized into five Tasks aimed at:
1) Isolating and characterizing human melanoma cancer stem cells (CSCs). In CSCs and corresponding melanoma cells it will be investigated: the capability to growth in immunodeficient mice; the capability to transmigrate "in vitro"; the capability to organize a pseudovascular network;
2) Investigating the role of ERbeta in melanoma development and in tumor-microenvironment interaction: expression and function of ERbeta in melanoma development and its role in the process of neoangiogenesis; expression and role of ERbeta in melanoma CSCs; translation of the informations obtained above in preclinical models;
3) Giving insights on the role of GnRHRs in melanoma development and in tumor-microenvironment interaction: role of GnRHR in melanoma neoangiogenesis; expression and role of GnRHRs in melanoma CSCs; role of GnRHR as a target for novel antitumor strategies; translation of the informations obtained above in preclinical models;
4) Defining the role of SSTRs in melanoma development and in tumor-microenvironment interaction: role of SSTRs in melanoma angiogenesis; expression and role of SRIF receptors in melanoma CSCs; translation of the informations obtained above in preclinical models.
5) Analyzing the effects of UVB induced inflammation on: the microenvironment of tumoral melanocytes at different stages of differentiation; the effect of the inflammatory microenvironment on tumoral melanocytes proliferation and metastatization.