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Page 22 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

stroma is associated with dense inflammation which attributes to stroma-derived factors that recruit
additional inflammatory cells or inflammatory cell secreting factors that change stromal characteristics [147] .
Inflammatory cell/secreting factor recruitment of collagenolytic enzymes that cause destruction of
the surrounding collagen and matrix metalloproteinases that cause proteolysis of extracellular matrix
components are implicated in SCC and likely BSC to cause desmoplastic stroma, facilitating tumor growth
and metastasis [148] . Further research needs to be done to identify the types and functions of immune cells
in peritumoral inflammation in order to understand the interactions between peritumoral inflammation
and stroma specifically in BSC. Additionally, activated fibroblasts and inflammatory cells of peritumoral
stroma secrete extracellular matrix proteins and growth factors in a paracrine fashion which can change the
expression of genes affecting angiogenesis, tumor growth, and metastasis. Though the precise mechanisms
underlying the complex interactions between the stroma and tumor in BSC is unknown, the crosstalk
communication between various genetic signaling pathways indicates the flux state amongst signaling
pathways and keratinocyte homeostasis.

Modulating immune response
Dense peritumoral/perivascular inflammation in BSC is a marker of host immune response and may be
associated with recruitment of protumor immune cells. For LR BCC, 83.3% of the lesions exhibit only
mild peritumoral inflammation whereas of the HR BCC, 76% of the lesions exhibit dense peritumoral
inflammation. Of the BSCs, 51.4% demonstrate dense peritumoral inflammation and 37.1% demonstrate
moderate peritumoral inflammation, frequencies that most closely approximated those of the HR BCC
group [147] . Similarly, perivascular inflammation in adjacent dermis was observed in 91.4% of BSC group
lesions, 97.5% of HR BCC group lesions, and 55% of LR BSC group lesions. Only the BSC and HR BCC
group lesions were found to have dense perivascular inflammation [147] .

The host immune response between BSC and HR BCC shows some similarities based on peritumoral
and perivascular inflammation density, both in contrast to LR BCC. Firstly, differences in inflammation
density between BSC and LR BCC may be attributed to an increased number of regulatory T-cells in BSC
that suppress anti-tumor T-cell response and are associated with a worse prognosis compared to LR BCC
that do not have increased regulatory T-cells [147] . Secondly, immature dendritic cells (IDCs) are involved in
attenuating the immune response in BCC and perhaps also in BSC. Attenuation of the immune response
occurs through the induction of peripheral T-cell tolerance by IDCs and through regulatory DC secretion
of IL-10 that suppresses T-cell proliferation. IDCs are also believed to contribute directly to tumor
proliferation through unknown mechanisms. Lastly, an increase in expression of Th2 cytokines, specifically
IL-4 and IL-10 contribute to an immunosuppressive tumor environment that favors proliferation in BCC
and perhaps also BSC [149] . It should be noted that the tumor permissive mechanisms described above likely
occur concurrently with immune responses directed towards tumor eradication. Anti-tumor immune
+
responses include: CD8 T-cells for a specific adaptive antitumor response, IL-23 for enhanced proliferation
of memory T-cells, IL-12 for activation of mature DCs and Th1 antitumor immunity [149] . Overall, BSC
modulation of immune response appears to occur dynamically with a protumor, attenuated immune
state only partially compensated for by the host antitumor response. This dynamic state shows myriad
fluctuations and crosstalk signaling between genetic signaling pathways, which can further personalized
BSC treatment for advanced or metastatic BSCs.

GENETICS OF MELANOMA
Although NMSC are the most common type of skin cancer, cutaneous melanoma is the most aggressive,
accounting for greater than 80% of skin cancer deaths largely due to its susceptibility to metastasize to other
organs [150] . Close to 200,000 cases of melanoma will be diagnosed in the United States in 2020 with a rate
of one American dying from melanoma every hour [151] . There are 4 main types of melanoma: superficial
spreading melanoma (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), and acral