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Page 30 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

Other mutations in tumor suppressor genes, CDKN2A, TNF-α Induced Protein 3 (TNFAIP3), zinc finger
E-box binding homeobox 1 (ZEB1) and FAS, have been identified in CTCL [199] . TNFAIP3 protein works to
inactivate IKK when the NF-κB pathway is overactivated by TCR [213] . ZEB1 is a zinc finger transcription
repressor protein, and the loss of ZEB1 in CTCL is linked to the overexpression of cytokines like IL-2.
Mutations in ZEB1 also increases the expression of GATA3, which binds to the promoter site of the gene
encoding for thymocyte selection-associated HMG box protein (TOX) [199,214] . TOX is a mediator of T-cell
+
+
maturation from CD4 and CD8 to CD4 +[214] . The loss of FAS in CTCL cell lines most likely also contributes
to apoptosis resistance [199] .
As mentioned previously, the pathogenesis and progression of CTCL are believed to be influenced by
alterations to the local cytokine milieu. These changes are thought to occur in part due to disfunction in
CXCR4 [215] . CXCR4 mediates downstream effects of various receptor tyrosine kinases, one of which is TCR.
When TCR is activated, CXCR4 is able to ligate with TCR, triggering a process that enhances the stability
of mRNA transcripts for IL-2, IL-4, and IL-10. This process occurs in the presence and in the absence of
CXCL12, the sole endogenous ligand for CXCR4. Furthermore, blocking the association between CXCR4
and TCR decreases mRNA transcript stability for both TCR-dependent and TCR-independent cytokine
production in SS cell lines, without altering other downstream effects of TCR [215] .

Supporting stroma and vascularization
More recently, CTCL progression via angiogenesis is being studied. Angiogenesis via the VEGF pathway
results in the congregation of tumor cells [216] . The stromal involvement of CTCL involves a CXCL12 [216] .
The stromal factor and its adjacent receptor work to create a signaling network for bone marrow stem cells,
which is found in earlier disease states [216] .

Summary
Though there is a need for further research on CTCL, there are many treatment options available.
Historically, first line treatment for CTCL has been psoralen and UVA (PUVA) therapy [217] . When used in
conjunction with interferon-α, efficacy has been shown to increase due to elevated levels of apoptosis [217] .
PUVA upregulates p53 allowing increased apoptosis within the tumor cells [217] . With the addition of
interferon-α, apoptosis is increasingly regulated via the JAK1 signaling pathway [217] .

[218]
Brentuximab vedotin is also a potential treatment for CTCL . This monoclonal antibody has been shown
[218]
to have efficacy against refractory cases of CTCL, as well as peripheral T-cell lymphoma . During the
studies performed using this medication, it was found that success is greatest in those CTCL cases where
+
+
CD30 positive cells are present. CD30 falls within the TNF receptor class, which is involved in cell
+
proliferation . Thus, explaining the mechanism of this monoclonal antibody to inhibit specifically CD30
[218]
expression [218] . Another monoclonal antibody used in the treatment of MF and SS is Alemtuzumab [219] .
Thus, research of immunomodulatory treatments is on the rise for CTCL leading to personalized
treatments targeted to the genetic signaling pathways, which are dependent on the person’s specific flux
state.

CONCLUSION
Melanoma and non-melanoma skin cancer are some of the most prevalent cancers that can lead to death
if not properly managed. However, knowing the genetic signaling pathways of these conditions can further
help researchers and providers give more options to patients suffering from these conditions. With this
information, the provoking genetic factors can be blocked with the use of pharmaco- and immunotherapy
allowing for patients with treatment resistant, locally advanced and even metastatic lesions to be treated
due to the different options of therapy blocking multiple signaling pathways. Though some information is
known about the genetic pathways of cutaneous malignancies, there is still a demand for research that can
be done to improve treatment options to decrease mortality rate and recurrence.