By Ze’ev Ronai, PhD, Burnham Institute for Medical Research, La Jolla, USA www.ronailab.net
"Malignant melanoma is one of the most highly invasive and metastatic tumors. Correspondingly, the primary clinical barriers to effective melanoma treatment are the high propensity for tumors to metastasize and the strong resistance of tumors to available treatments.
A significant advance in understanding melanoma biology was made over recent years when genetic changes along the MAPK signaling pathway (B-Raf and N-Ras mutations) were identified. Identification of these types of mutations in many melanoma tumors has significantly increased our understanding of genetic changes underlying melanoma. Yet, it is critical to note that identical genetic changes do not always underlie different melanoma subtypes. For example, mutations seen in melanomas associated with sun exposure differ from those seen in other subtypes, and some melanoma subtypes exhibit mutations in signaling pathways other than MAPK kinase. For example, c-Kit mutations were found in about 30% of mucosal, acral and other melanomas developing on chronically sun-exposed skin, conditions in which mutations in MAPK pathway components were not seen. Thus, while we have greatly advanced our understanding melanoma as a cancer marked by deregulation of well-defined signaling pathways, it is now clear that changes in multiple pathways exist among melanoma subtypes. Understanding these differences will dictate how selective therapies are developed and applied.
Adding to the complexity is the growing recognition that pathways are re-wired in melanoma. In tumors, MAPK-related pathways intersect with and influence regulatory pathways not thought to be linked in normal cells. Thus, the molecular analysis of changes in melanoma will require extensive dissection of multiple pathways influenced by deregulated genes. For example, further understanding of mechanisms underlying deregulated AKT signaling in melanoma awaits characterization.
Equally important is the growing realization that central to the etiology of melanoma is a small but potent population of melanoma initiating (stem?) cells. This exciting topic is receiving growing attention and should provide important insight into the handful of cells capable of initiating a tumor. Although currently only a few groups are dedicating their efforts to this exciting observation, an emerging theme in cancer research is that melanoma initiating cells may be as complex as melanoma tumors are.
Understanding tumor microenvironment has been and will remain critical to our understanding of melanoma progression, given that a hallmark of melanoma is its metastatic potential. The development of mouse models and better technologies to study tumor microenvironment (from 3D cultures to lymph-angiogenesis) provides tools necessary for identifying mechanisms underlying melanoma metastasis and finding selective means to halt it, as well as models to assess possible therapeutic approaches."
The rest of the article can be found at:
http://www.pigment.org/virtual.asp
Pigment Cell & Melanoma
Jimmy B
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