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Page 26 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

Sustained ERK phosphorylation inhibits MITF keeping its levels low leading to proliferation. High MITF
levels along with transient ERK phosphorylation triggers melanocyte differentiation [178] . cAMP signaling
activates HIF-1α and increases MITF levels [179] . HIF-1α and VEGF promotion triggers microenvironment
changes that promote melanoma progression [Figure 11]. Cellular crosstalk in signaling pathways also
plays a driving role. MITF activates anti-apoptotic gene BCL2, promoting melanocyte survival [180] . Cell
cycle inhibitors p21 has been implicated along with p16INK4A and p14ARF [Figure 10] in the senescence
of melanocytes [181] . As the fate regulator of the melanocyte lineage, MITF activity fluctuates through
modification of signaling pathways and microenvironmental dynamics.

Modulating immune response
Melanoma utilizes co-inhibitory pathways to avoid surveillance by the immune system and its ability to
respond and possibly eradicate the tumor cells. Two well-characterized co-inhibitory pathways involve
the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death-1 (PD-1) T-cell
co-receptor [182] . CTLA-4 outcompetes CD28 for B7 binding on antigen presenting cells, limiting IL-2
production and lowered survivability of the T-cell [183] . PD-1 is induced later during T-cell activation and
ligation with PDL1 and PDL2 promote tumor growth [184] . Immunotherapy for melanoma blocks PD-1
and CTLA-4 checkpoints and elicits a therapeutic response [183] . The role of mechanical trauma in the
development of melanoma remains unclear. One retrospective analysis on acral melanoma accounting
for the majority of melanoma in the Chinese population provided epidemiological evidence for potential
association between trauma and acral melanoma [185] . For dark-skinned and East-Asian populations, patients
have reported direct trauma related to subungual melanoma [186] . However, there is not enough literature to
support an established correlation.

Future directions
Many patients with good prognosis indicated by early stage through traditional clinicopathologic histology
staging methods still decline from metastases [187] . Recent advances in personalized medicine could be
instrumental in capturing a more accurate and detailed micro-staging of melanoma through next-
generation sequencing and genetic profiling. Validation studies of the 31-GEP, which categorizes risk as
low or high by class, has indicated the 31-GEP test as an accurate predictor of metastasis of cutaneous
melanoma [188-190] . Systematic meta-analysis demonstrated the 31-GEP test consistently identifies melanoma
patients at increased risk of metastasis independent of clinicopathologic factors and improves on current
staging [191] . The identification of early stage low-risk patients vs. late stage high-risk stage patients would
significantly help in determining life-saving adjuvant therapies or avoiding unnecessary treatments and
costs. Analysis of profiles of gene expression modification induced by different signaling pathways in
melanoma cells has considerable potential in understanding clinically relevant molecular mechanisms and
biomarkers for non-melanoma skin cancers to create personalized treatment plans for each patient with
melanoma. Unfortunately, the use of 31-GEP testing on thin melanomas is controversial. A recent article
believes that the testing should not be done on people with thin melanomas if there is no evidence on
change of outcome and treatment plan. Once further studies on 31-GEP testing are done, the evidence of
[192]
effectiveness in thin melanomas will be apparent .

Summary
Recent endeavors into understanding the pathways involved in the development and metastasis of skin
cancer into melanoma has led to some degree of hope in therapy against this historically difficult to treat
cancer. It is clear melanoma is not homogenous, but a complex multifactorial disease characterized by
crosstalk of several different pathways and elucidation of mechanisms that contribute to tumor growth and
chemoresistance. Hence, understanding these complex mechanisms is crucial and will lead to more optimal
treatments for each patient.