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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 17 of 40

suppressor, and is involved in tumor proliferation, metastasis, apoptosis, and angiogenesis. miR-195 exerts
its effects through various target genes, one of which is cdk6. cdk6 is activated in the G1 phase of the cell-
cycle and plays a role in the development of various cancers; cdk6 is found to be significantly upregulated
in OVC [110] . This negative correlation between the expression of cdk6 and miR-195 in OVC serves as
confirmation of the interaction between the two. However, the specific role of miR-195 and cdk6 in OVC
pathogenesis is an area requiring further investigation.

Apoptosis evasion
The diagnostic value of expression of the apoptosis-related regulatory proteins p16, p53, p21, and RBGP
(retinoblastoma gene product) in cases of oral, penile, and cutaneous VC has been studied. The variation in
expression of these proteins may be helpful in differentiating VC from classic SCC [111] .

P16 is a cyclin D-dependent kinase inhibitor that is inactivated in a variety of cancers. This protein blocks
the progression of the cell from the G to S phase [112] . Interestingly, p16 additionally plays a role in the
1
[113]
regulation of UV-induced apoptosis of cells . In cases of VC, some level of p16 expression is found in 79%
of cases [111] . p21, a mediator of p53 function, is upregulated by p53 in response to DNA damage. Similar to
the actions of p16, p21 upregulation leads to the inhibition of cdk2 and CD4 complexes, causing cell cycle
arrest in the G phase [111] . In 58% of VC cases, p21 expression is seen in the lower third of the epithelium,
1
while the remaining 42% of cases show full-thickness expression [111] .

While p53 mutations are one of the most frequently reported tumor suppressor mutations in human
cancers, p53 expression is significantly different in VC vs. SCC. All cases of SCC showed p53 expression
throughout the entire thickness of the epithelium, yet cases of VC showed p53 expression exclusively in the
lower third of the epithelium [111] . Interestingly, the Ki67 protein showed a very similar pattern of expression
in VC vs. SCC, with the former showing expression only in the lower third of the epithelium. The exact
function of Ki67 is yet to be understood; it is thought to play a role in regulation of the G1, S, G2, and M
phases of the cell cycle [114] . Both p53 and Ki67 showed a statistically significant difference in expression
between VC and SCC and may play a role in differentiating these tumors.

Supporting stroma and vascularization
The differences in angiogenesis between SCC and VC have been studied using measures such as
microvascular density (MVD) and endothelial proliferative index (EPI). MVD is measured by scanning
CD34 immunostained sections to find areas with a high density of microvascularization. EPI is estimated
using MIB-1 stained slides to locate MIB-1 positive endothelial cells. Both MVD and EPI were found
to be significantly lower in VC vs. SCC; it is hypothesized that the less aggressive nature of VC may be
attributable to these lower values [115] .

The release of chemokines due to chronic inflammation also plays a role in angiogenesis. Members of
the CXC chemokine family that are glutamate-leucine-arginine motif positive (ELR+) exert their pro-
angiogenic effects by activating the CXCR2 receptor. This activation leads to increased levels of VEGF
and decreased levels of thrombospondin-1, an antiangiogenic glycoprotein [116] . Stromal cell derived
factor known as SCDF1 or CXCL12 plays a role in increasing endothelial VEGF expression, as well as the
chemotaxis of cancer cells [117] .

Modulating immunity
Chronic inflammation correlates with a lack of tumor immune surveillance. The cytokine IL-23 is
upregulated in many human tumors. While IL-23 increases angiogenesis and upregulates matrix
metalloproteases, one of its functions is to inhibit CD8 T-cells, which are an essential component of
+
tumor surveillance. Deletion of IL-23 was shown to restrict tumor growth, leading to protection against
carcinogenesis [118] .