Why does melanoma metastasize into the brain? Genes with pleiotropic effects might be the key

Melanoma is the most aggressive type of skin cancer. It is the seventh most common type of cancer among men and the eighth most common among women with a lifetime risk about 2% (Feng et al., 2011). The incidence of melanoma is rising faster than that of any other cancer type in the US (Tsao et al., 2004). Melanoma is a multifactorial disease whose risk depends on genetic susceptibility (around 10% of melanoma cases have a family history of the disease) as well as on external factors, among which an exposure to ultraviolet (UV) radiation and sunburn play an important role. 
 
Brain metastases is a major challenge in melanoma and one of the least understood aspects of this disorder (Skibber et al., 1996; Fidler et al., 1999). Average survival in advanced metastatic melanoma is only 6–10 months with <5% of patients living 5 years after diagnosis (Jemal et al., 2002). More than half of all melanoma deaths occur from brain metastasis. A key event in brain metastasis is the migration of cancer cells through the blood brain barrier (BBB) (Arshad et al., 2010). The BBB is formed by specialized endothelial cells lining capillaries in the central nervous system. Brain capillary walls are more difficult to penetrate due to a tight layer of endothelial cells, tight junctions (TJs), and other structures that restrict the diffusion of microscopic objects (e.g., bacteria) and large or hydrophilic molecules into the cerebrospinal fluid. 
 
In order to allow the melanoma cell to metastasize into the brain, the integrity of the BBB has to be compromised. This suggests that some germ line mutations contributing to metastatic melanoma may also increase the permeability of the BBB. Finding such mutations and understanding the mechanisms of their action could make substantial contributions to reducing mortality from melanoma. Currently, very little is known about the molecular mechanisms by which melanoma cells can penetrate the BBB. 
 
The literature on germ line mutations contributing to melanoma and its metastases provides some clues about relevant genes and their functions. Udart et al. (2001) gave evidence that a number of genes which are likely to play a role in melanoma and metastases are located on chromosome 7. The list includes the EGFR gene encoding the epidermal growth factor receptor; the BRAF gene, which is a member of the Raf kinase family of serine/threonine-specific protein kinases involved in the MAP kinase/ERKs signaling implicated in many cancers (Wangari-Talbot and Chen, 2012); the PDGF-A gene encoding for platelet-derived growth factor alpha; the PAI-1 encoding for plasminogen activator inhibitor type 1; the MET proto-oncogene, encoding for a membrane receptor protein with tyrosine–protein kinase activity, and others. The PDGF-A is expressed in primary and malignant melanoma and might function as an autocrine growth factor as well as an angiogenesis factor in tumor development. The PAI-1 is expressed in highly invasive metastatic human melanoma cell lines. The EGFR gene and the MET gene were independently amplified in human glioma. In malignant melanoma, the MET gene was shown to be expressed in metastatic lesions. 
 
The permeability of this BBB is essentially regulated by TJ, the intercellular junction, in which the outer cell membranes are joined tightly together by rows of membrane proteins. TJ regulates the flow of ions, nutrients, and cells into the brain (Dejana, 2004; Abbott et al., 2006). The germ line mutation in genes involved in TJ regulation could disrupt BBB functioning. A number of recent studies strongly support the connection between melanoma metastasizing and TJ destabilization (Leotlela et al., 2007; Fazakas et al., 2011; Jayagopal et al., 2011). The important components of TJ are a family of proteins called “claudins.” Twenty-four such proteins are currently known. Genes CLDN2, CLDN3, CLDN4, CLDN11CL, CLDN12, CLDN14, and CLDN15 encoding for different claudins are also located on the chromosome 7 (Paperna et al., 1998; Hillier et al., 2003; Lal-Nag and Morin, 2009). One more TJ gene on chromosome 7 is OCLN, encoding for “occludin” protein. The localization of all these genes on one chromosome indicates that these genes together with other (not yet detected) genes on the same chromosome might represent an important part of the genetic mechanism linking the development of melanoma and brain metastases. If so, then performing association study of melanoma using SNP data from chromosome 7, and investigating functions of corresponding genes, may provide important insights about biological mechanisms connecting melanoma and brain metastases.

Field of study: Biology