Genetic factors in metastatic progression of cutaneous melanoma: the future role of circulating melanoma cells in prognosis and management

Abstract

The greatest potential for improvement of outcome for patients with Cutaneous Malignant Melanoma lies in the prevention of systemic metastasis. Despite extensive investigation, current prognostic indicators either alone or in combination, although related to melanoma progression, are not sufficient to accurately predict the pattern of progression and outcome for any individual patient. Metastasis related death has been recorded in patients initially diagnosed with early stage tumour as well as in patients many years after initial tumour removal. The trouble finding a predictable pattern in the puzzle of melanoma progression may be linked to the fact that most of the material studied for prognosis is either, cutaneous primaries or metastatic deposits, rather than the melanoma cells in the circulatory system which are responsible for disease progression. In this review article we discuss the potential use of circulating tumour cell (CTC) detection and quantification for identifying patients at risk of metastatic deposits. We also discuss current therapies for the treatment of metastatic melanoma and analyse how CTCs may be used to evaluate the effectiveness of current therapies and to pinpoint patients who require further treatment.

Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma

“…The high CMC numbers suggested high sensitivity for CMC enrichment and detection considering the no, or occasional low, positive count in healthy controls. CMC numbers were an order of magnitude higher than those reported using other devices or studies with other types of cancer [10, 11, 18, 19]. …”

Pathways and therapeutic targets in melanoma

“…CTCs have been shown to serve as seeds for metastatic lesions, and therefore their presence could be interpreted as a prognostic marker. In addition, monitoring of CTC levels could serve as a marker of disease progression and treatment success or failure (reviewed by Ireland et al and Tanaka et al[324, 325]). Molecular profiling of CTC could become a “liquid biopsy”, and could reflect genetic heterogeneity, both intratumoral or between multiple metastatic tumors.…”

Circulating Melanoma Cells in the Diagnosis and Monitoring of Melanoma: An Appraisal of Clinical Potential

“…In addition, CMCs can avoid detection by natural killer cells, which induce apoptosis by targeting the NKG2D ligand expressed on the surface of certain cells. CMC internalize the NKGD2 natural killer cell target ligand in order to evade damage from natural killer cells (34). …”

“…These cells are able to survive in the circulatory system and may aggregate to form microemboli or clumps of metastatic cells protected by a collection of surrounding of platelets and/or leukocytes (1, 36, 37) (Figure 1). Due to the sheer size of microemboli, they can become entrapped in small capillaries and CMC within the mix subsequentially invade into susceptible tissue to establish metastases (34, 38). …”