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Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60 Page 5 of 40

Stroma vascularization effects
RTK activation
[36]
RTKs are a group of receptors activated in response to UV exposure . Some of the more well-known RTKs
[37]
include the IGF1-R, EGFR, FGFR, and VEGFR . RTK activation and RTK downstream pathways are
[38]
targets for drug development . In NMSC, cetuximab (an EGFR inhibitor) is available as a pharmaceutical
[39]
therapy . There are two main RTK activation pathways in NMSC, PI3K/mTOR signaling and RAF/MEK/
[37]
ERK signaling [Figure 2].
PI3K/mTOR signaling
There are two forms of mTOR, mTORC1 and mTORC2, and both forms are involved in the development
[40]
of NMSC secondary to sun exposure . PI3K and tensin homolog (PTEN) mutations are common in
NMSC [41,42] . To activate mTORC1, PI3K is recruited to the receptor which then leads to the phosphorylation
of the p85 subunit. This allows PI3K to phosphorylate PIP2, converting it to PIP3. PIP3 then recruits
phosphoinositide-dependent kinase 1 and AKT to the receptor to activate AKT. AKT then phosphorylates
the MTORC1 negative regulator which leads to the activation of mTORC1, signaling for cell growth and
proliferation [43,44] [Figure 3].

Activation of mTORC2 occurs once PI3K phosphorylates PIP2 to PIP3 . Part of the SIN1 protein
[45]
is recruited to the cell membrane where it binds to PIP3, resulting in a conformational change in
mTORC2 that reveals an active kinase site . PIP3 then recruits AKT to mTORC2 which results in the
[24]
[46]
phosphorylation of AKT at the active kinase site .
FOXO3 signaling
The FOX”O” family of proteins are transcription factors known to regulate tumor longevity and
suppression [47,48] . FOXO3a transcriptionally targets apoptotic genes such as FasL, TNF-related apoptosis-
inducing ligand gene (TRAIL), BIM, and PUMA, all of which are involved in UV-induced apoptosis [49-51] .
AKT is a negative regulator of FOKO3a that acts by translocating into the cell nucleus with a chaperone
[52]
protein, 14-3-3 . Together, AKT and its chaperone reduce FOXO3a activity, sensitizing keratinocytes to
UVB-induced apoptosis [49-51,53] .

Raf/MEK/ERK signaling
The Raf/MEK/ERK pathway can be activated secondary to UV exposure. Raf binds MEK1 and MEK2,
[54]
phosphorylating them. MEK1 and MEK2 then phosphorylate ERK . ERK1 is involved in the regulation
[55]
of cell growth, malignant transformation, and drug resistance . A study found that cells treated with SMO
inhibitors (a hedgehog pathway BCC treatment) have a tendency to increase RAS/MEK/ERK signaling,
[56]
leading to the development of SCC . Thus, therapies should consider targeting the mTORC2/AKT and
[57]
RAF/MEK/ERK pathways to simultaneously suppress BCC and SCC malignancies .
Isoelectric signaling
There appears to be a relationship between the isoelectric signaling and gene modulation. One study
[58]
+
showed that IFN-γ can lead to the loss of EGF’s inhibition of basolateral K channel activity . IFN-γ levels
are often elevated during periods of inflammation which leads to the shift in signaling to favor the EGF-
[59]
stimulated pathways (such as Raf/MEK/ERK and PI3K/mTOR described above) .
Modifying immune response
NF-κB pathway
Aside from the direct effects of sunlight, skin injury resulting in inflammatory response may also
lead to tumorigenesis in NMSC. When the skin is damaged, such as in UV-induced sunburns, the
microenvironment of the damaged area changes to allow for the extravasation of leukocytes to the tissue