The Role of the Microenvironment – Models for the Study of Melanoma

Melanoma is a progressive disease that claims many lives each year due to lack of therapeutics effective for the long-term treatment of patients. Currently, the best treatment option is early detection followed by surgical removal. Cutaneous melanoma continues to represent both a challenge and a big paradox among solid tumors: though considerable prognostic markers are available, little is known about their biological significance. Recent data on the effect of an anti-melanoma target therapy, ipilimumab (Hodi et al, 2010) and new anti-BRAF molecules (Flaherty, 2010) raised hope on the treatment of melanoma. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress on the treatment of both early and advanced melanoma may depend on identifying additional molecular targets and on understanding the mechanisms leading to response or resistance. Animal models have been critical in the study of the molecular mechanisms of cancer and in the development of new therapeutic agents; nevertheless, there is still much room for improvement. The most widely used in vivo model involves the injection of tumor cells in the flank of mice. The relevance of each particular model depends on how close it replicates the histology, physiological effects, biochemical pathways and metastatic pattern observed in the same human tumor type. Numerous models have been developed to study human tumorigenesis and its properties, such as proliferation, migration, invasion, neoangiogenesis, and metastasis, as well as for the study of anti-cancer treatments. Among others, these include in vitro systems such as focus formation in tumor cell culture explants and continuous cell lines grown on tissue culture plates, or, alternatively, anchorage-independent growth in soft agar. The foregoing experimental models are suitable for studying molecular pathways in cell-cell and cell-extracellular matrix interactions that would be difficult to dissect in the animal. However they will encounter their limitation in terms that they are not particularly amenable to the investigation of interactions of tumor cells with the surrounding microenvironment of adjacent normal human cell tissues and structures. It has