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in glycolysis by phosphorylating glucose to produce genetic analysis are instrumental for prognosis and targeted
glucose-6-phosphate. A microarray study, comparing gene therapy; [102] for example, mutations of BRAF, particularly
expression profiles of BM and primary breast tumors, found the V600E and V600K mutations, have been identified both
an overexpression of HK2 in BM. HK2 is overexpressed in benign melanocytic proliferations and in all stages of
[93]
in several cancer types, compared to normal tissues, and its metastatic melanoma, with the frequency of 36-45% BRAF
overexpression is generally related to a poor prognosis; its mutations in primary melanomas and 42-55% in metastatic
[94]
upregulation in BM suggests that it could be instrumental for melanomas. The presence of a BRAF mutation in patients
cell growth under conditions of limited nutrient availability. with primary melanoma appears to be related to the OS and
to a worse prognosis compared to patients who lack the
Also, in a recent work 86 matched BM and primary tumors mutation. [103] Nearly 50% of melanoma BM display V600
were analyzed by whole-exome sequencing and the authors BRAF mutation [104] and the analysis of BRAF alterations in
found that metastatic samples, though showing common melanoma BM is of critical in the selection of patients for
features with the primary counterpart, display alterations targeted therapy with specific inhibitors.
particularly related to PI3K/AKT/mTOR, CDK, and
HER2/EGFR cascade. [95] In a very recent and extensive study the Cancer Genome
Atlas program performed a systematic characterization of
Another gene that appears to have a role in the metastatic 333 cutaneous melanomas at the DNA, RNA and protein
behaviour of breast cancer is the Forkhead-box levels with the specifi c goal to create a catalog of somatic
transcription factor C1 (FOXC1), essential for mesoderm alterations with important and potential implications for
tissue development and highly expressed in the basal- prognosis and therapy. [105]
like (BLBC) and in the triple-negative breast cancer.
Overexpression of FOXC1 in BLBC cells and in MCF-7 The first step of metastasis formation, before detachment
cell line increases cell proliferation, migration, invasion from the primary tumor, is supposed to be represented by
and anchorage-independent growth of MCF-7 cells in EMT. During this step cancer melanocytes change their
soft agar. The mechanism underlying FOXC1-mediated adhesion properties and modify their gene expression
[96]
invasive behaviour is the induction of MMP7 expression profiles that results in changes in the amount of integrins
in breast cancer cells and interestingly, both FOXC1 and and cadherins at protein levels, [106] associated to an increased
MMP7 are overexpressed in BLBC samples, suggesting a expression of EMT markers such as SNA1 (Snail and
possible new molecular target for BLBC therapy. [97] twist), Wnt, Notch, SPARC and Hedgehog. [107] Early-stage
melanocytes express CDH5/non-epithelial cadherin [107,108]
Finally, an analysis of circulating tumor cells (CTCs) from that leads to the loss of epithelial adhesion properties and
breast cancer patients demonstrated that CTCs, circulating to gain of mesenchimal progenitor cells features.
as single cells or as clusters bound to platelets, express EMT
markers such as TGF-β and FOXC1, thus supporting the Melanoma metastatic cells are driven to lymph or
role of EMT in metastasic cells and indicating FOXC1 as a blood vessels by concentration gradients of cytokines,
reliable peripheral marker of breast cancer dissemination. [98] chemokines, and growth factors. [109] Like in other metastatic
tumors, in the bloodstream most cancer cells undergo
MELANOMA anoikis but a sub-set acquires some genetic modifications
that confer survival advantages such as anoikis resistance.
Malignant melanoma is a frequently lethal malignant Deregulated activation of the PI3K/Akt pathway, in
tumor that accounts for 4% of all skin cancers but it is particular the increased phosphorylation of Akt3, confers
responsible for 80% of skin-cancer deaths. BM are a resistance to anoikis to melanoma cancer cells and like in
[99]
frequent complication in melanoma patients, and unlike in other metastatic tumors, loss of phosphatase and tensin
other solid tumors, arise independently from other visceral homologue contributes to the Akt pathway deregulation
metastasis. Many melanoma patients are cured after related to the tumor malignancy. [110,111]
excision of the primary tumor but, in some cases, a disease
recurrence appears in different sites as metastatic lesions [100] The circulating melanoma cancer cells that have acquired
suggesting that melanoma cells had already spread before the ability to survive in the circulatory system may also
excision of the primary tumor. form microaggregates with platelets or leucocytes and
travel protected in bloodstream. These microemboli,
[15]
Melanomas are classified into four major sub-types once finding a niche in very small size capillaries, promote
according to their histological features: lentigo maligna extra-vasation in tissues displaying the appropriate feature
melanoma, superficial spreading melanoma, acral such as brain parenchyma.
lentiginous melanoma and nodular melanoma. [101] A series
of parameters are usually taken into account for patient It has been found that extra-vasation of melanoma
prognosis: tumor thickness, tumor location, histological circulating cells is prompted by interleukin-8 (IL-8)
sub-type and ulceration. Melanoma classifi cation based on secretion by melanoma cells and IL-8 summons neutrophils

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦