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Page 14 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

arsenic exposure leads to hypersecretion of MMPs, which degrade type IV collagen in the basement
membrane. This promotes the diapedesis of immune cells and the release of inflammatory markers
and chemokines, causing further cell growth and increased malignant potential. In addition to arsenic,
UV also affects the stroma of underlying keratinocytes. UV radiation leads to genetic changes within
the cell affecting dermal fibroblasts and the underlying basement membranes. The structure of the
microenvironment, including the epidermal basement membrane and dermal extracellular matrix, can be
altered by precancerous lesions. These precancerous lesions cause a release of chemokines, leading to an
invasion of inflammatory cells and encourage the growth of cSCCs. These AKs and cSCCs have been found
to have increases in MMPs, disintegrin-like metalloproteinases domain (ADAMs), tissue inhibitors of
metalloproteinases, and other extracellular matrix degrading enzymes. Furthermore, tumor cells change the
molecular function of cell-cell adhesion and prevent the integrins of damaged basement membrane from
binding to extracellular matrix and binding to tumor cells. Tumor cells upregulate complement factor H
and factor H-like protein 1, leading to further insult and invasion. The upregulation of these inflammatory
signals by tumor cells directly affects the microenvironments of keratinocytes, causing further insult to the
[92]
stroma .

Trauma and chronic inflammatory conditions
Chronic inflammation and trauma can change the epigenetics of the composition of the underlying stroma
on which the epithelial cells lie, allowing these cells to have greater metastatic potential. The upregulation
of STAT3, p63, FGFR2, and other genes coding for and upregulating chemokines can be the change
[92]
necessary for conferring invasive potential . The chemokine SDF-1 and its endothelial cell receptor
C-X-C chemokine receptor type 4 (CXCR4), both involved in angiogenesis, are upregulated in chronic
inflammatory states. Once premalignant lesions are formed, SDF-1 and CXCR4 may affect chemotaxis,
upregulation of metalloproteins, and activation of stromal fibroblasts, leading to loss of collagen types in
[93]
the basement membrane . Marjolijn ulcers (seen in burn patients), chronic decubitus ulcers, and diabetic
ulcers can all undergo processes that lead to stromal changes and subsequent keratinocyte differentiation.
The signaling pathways associated with chronic inflammatory ulcer transformation can appear from a
spontaneously new pathway that is also associated with the epithelial cell growth. One signaling pathway
is linked with inhibiting the cdk, PDGF, and SHH pathway modulations. However, an additional pathway
deals with the suppression of the proapoptotic WNT/β catenin pathway. Both pathways downregulate
the extracellular matrix genes and upregulate MMP gene activation, affecting many of the same pathways
affected by UV radiation. Nevertheless, Marjolijn ulcers trigger a fibrotic change in the basement
[94]
membrane causing a transformation in the function of adhesion molecules between keratinocytes .
Marjolijn ulcers display decreased expression of IL-18, suggesting that overexpression and utilization of the
immune system in chronic inflammation can eventually cause suppression of the immune response towards
infections and cancerous cells . This information can guide further research into chronic inflammatory
[83]
conditions and trauma causing cutaneous malignancies.

Not all cSCCs are preceded by precancerous lesions. Some cSCCs can appear de novo. This is especially true
in the cSCCs developed by transplant patients. Transplant patients often have weakened immune systems
due to both immunosuppressive therapy and the underlying conditions that necessitated the transplant.
Post-transplant patients with cSCC have been found to have de novo T lymphocyte mutations in ZNF577
coding for zinc finger proteins and FLOT gene coding for T-cell migration, dampening the immune
response against tumor cells and subsequent overgrowth . These types of genetic mutation pathways
[95]
that lead to cSCC can be investigated as innovative treatment approaches for patients with more advanced
forms of cSCC.

The tumorigenesis of cSCC is complex. UV exposure, exposure to carcinogenic substances, alteration
of the stromal environment of keratinocytes, and chronic inflammatory states may all be implicated in