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

injury site. NFκB is an established pathway in the mediation of inflammation. NFκB is a heterodimer of
p65 and p50 subunits who are both bound to IkB, an inhibitory protein. Toll-like receptors, tumor necrosis
[60]
factor (TNF) receptors, and RTK can all cause NFκB activation by activating IkB via phosphorylation .
This process removes the inhibition of NFκB, allowing the protein to move into the nucleus and promote
the transcription of pro-inflammatory genes such as TNF-α, IL-1 IL-6, IL-8, and various other cytokines
[61]
and interferons . Furthermore, p65-dependent NFκB signaling nurtures a pro-inflammatory environment
inducing SCC tumor initiation and promotion [60,61] .

STAT3 pathway
Pro-inflammatory growth factors and cytokines induce the expression of the STAT family of transcription
factor. STAT3 enhances the transcription of factors related to inflammation, tumor promotion, cell survival,
and metastasis . In mice exposed to UVB, the overexpression of STAT3 results in accelerated skin
[62]
[63]
tumorigenesis whereas the removal of STAT3 genes confers a resistance to skin tumor formation .
Once thought of as independent determinants of tumorigenesis, the four hallmarks of cancer form an
interdependent network of signals that promote successful tumor growth. The study of skin cancer occurs
under various conditions and laboratory settings. The high degree of variability in models, UV dosage,
dimensions (2D vs. 3D), and methodologies creates potential confounds in the comparison of cancer
signaling pathway.

GENETICS OF SQUAMOUS CELL CARCINOMA
Cutaneous squamous cell carcinoma (cSCC) is one of the most common forms of skin cancer worldwide.
cSCCs most commonly present on the head and neck, particularly on the forehead, face, ears, and cheeks.
Although melanoma is categorically perceived as a higher threat in society, more than 15,000 patients die
from metastatic cSCC each year in the United States; this figure exceeds the total mortalities attributed
[65]
[64]
annually to melanoma . In addition, the mortality rate of metastatic cSCC is over 70% . While multiple
treatment modalities have been developed for advanced melanoma, advanced cSCC continues to have poor
[66]
prognosis and limit options for treatment besides a newer immune checkpoint inhibitor, Cemplimab .
The factors evoking the carcinogenesis of cSCC are multiple and varied; the primary contributor is
exposure to solar UV radiation. cSCC may also be initiated by industrial and inorganic exposures to tar,
crude paraffin oil, fuel oil, creosote, lubricating oil, nitrosoureas, and arsenic in medications, foods, and
drinking water . Organ transplant recipients and other immunosuppressed patients have increased risk
[67]
for cSCC, especially locally advanced cSCC (lacSCC) and metastatic cSCC. Additionally, cSCC can develop
in the setting of chronic inflammation. For example, cSCCs may develop from chronic ulcers, psoriasis,
cutaneous lupus erythematosus, radiation dermatitis, porokeratosis, and lichen sclerosus. Understanding
the various genetic pathways in which cSCC emerges will provide insight into improved and individualized
treatments of cSCCs. The underlying genetic processes involved in the initiation, promotion, maintenance,
and establishment of aggressive growth patterns resemble the pathophysiology hallmarks common to all
cancers: cell growth, prevention of apoptosis, development of supportive stroma and vascularization, and
modulation of the immune response.

Thus, each of the carcinogenic pathways for cSCC will follow complex genetic crosstalk between pathways
for each of these hallmark systems as well as between these components. These signaling pathways may
be unique to a hallmark component of the genetic pathway or be present in multiple parts of the genetic
pathway. These genetic pathways include primary, well recognized, genetic mutations of signaling pathways,
initiation of alternative genetic pathways, or modulation to and between alternative genetic pathways.
Each of these signaling pathways may vary in how it affects the overall status of cSCC through one or more
hallmarks systems.