Do papillomaviruses cause feline cutaneous squamous cell carcinoma?

Feline cutaneous squamous cell carcinomas (SCC) are considered to be the most common malignant skin neoplasms of cats, representing approximately 15 percent of all feline skin neoplasms (Miller et al., 1991; Munday et al., 2009; O’Neill et al., 2011; Murphy, 2013).

Some recent research has found evidence to suggest that feline papillomaviruses (PV), in particular Felis catus papillomavirus type 2 (FcaPV-2), are oncogenic, actively contributing to the development of feline SCC, similar to human papillomaviruses (HPV) and cervical cancer (Munday et al., 2008; O’Neill et al., 2011; Munday and Aberdein, 2012; Murphy, 2013; Altamura et al., 2016b; Geisseler et al., 2016; Oh et al., 2018; Munday et al., 2019).

Given the high prevalence of SCC in the feline population and the suspected oncogenic link between FcaPV-2 and the development of SCC, it is worth considering whether prevention of papillomaviral infections in cats can become a novel method to reduce the risk and prevalence of SCC (Thomson et al., 2019).

You decide to explore the evidence supporting FcaPV-2 involvement in SCC oncogenesis. This may open a new pathway to reduce the incidence of the SCC cases by preventing PV infections, such as through vaccination (Thomson et al., 2019).

The evidence

Eleven papers were critically appraised; nine were case-control studies and two were experimental in vitro studies.

Earlier studies mainly focused on demonstrating an association between the presence of PV and SCC lesions, primarily through PCR amplification of PV DNA (including FcaPV-2) from SCC lesions (Nespeca et al., 2006; Munday et al., 2007; Munday et al., 2008; O’Neill et al., 2011). While the studies demonstrated a significant association between the presence of FcaPV-2 within SCC lesions, a causal relationship cannot be established. PCR alone cannot differentiate whether the presence of FcaPV-2 in SCC lesions is a contaminant, a transient infection or an active carcinogen (Hoggard et al., 2018).

PCR alone cannot differentiate whether the presence of FcaPV-2 in SCC lesions is a contaminant, a transient infection or an active carcinogen

Three studies investigated the roles of host cell tumour suppressor genes and proteins p16, p53 and retinoblastoma (pRb) using immunohistochemistry (Munday et al., 2011a; Munday et al., 2011b; Munday and Aberdein, 2012). All demonstrated that increased p16 levels were significantly associated with the presence of PV DNA in SCC lesions. Elevated p16 levels were significantly associated with reductions in pRb in PV-infected cutaneous neoplastic lesions (including SCC), and decreases in pRb were significantly associated with presence of PV DNA in cutaneous lesions (Munday and Aberdein, 2012). Interestingly, p53 levels were unaffected in PV-infected cutaneous neoplastic lesions (Munday and Aberdein, 2012). These studies provided evidence that FcaPV-2 shares a similar transformative pathway to HPV, by disrupting the pRb/p16 cell regulation pathway, with the exception of p53 degradation.

If FcaPV-2 was actively involved in the oncogenesis of SCC, then it would be expected that the virus would be present in the lesion at high viral loads and with active transcription, especially of E6 and E7 genes, because their products can influence neoplastic transformation and cell proliferation (Wilczynski et al., 1998; Thomson et al., 2016). Overexpression of PV E6/E7 oncogenes in the basal cells results in abnormal cell proliferation and the acquisition of new mutations which can ultimately progress to cancer (Isaacson Wechsler et al., 2012).

Overexpression of PV E6/E7 oncogenes in the basal cells results in abnormal cell proliferation and the acquisition of new mutations which can ultimately progress to cancer

Thomson et al. (2016) demonstrated that transcriptionally active FcaPV-2 expressing E6/E7 oncogenes was present in one-third of the study’s formalin-fixed paraffin-embedded (FFPE) SCC sample size which was also significantly associated with increased p16 levels. Continuing from those findings, Altamura et al. (2016b) showed in vivo that biologically active FcaPV-2 can express the oncogenic viral genes E2, E6 and E7 in FFPE SCC lesions, as well as the transformative effects of E6/E7 oncogenes in disrupting p53 and pRb pathways in vitro. This seemingly conflicts with a 2012 study which found that FcaPV-2 does not degrade p53 (Munday and Aberdein, 2012).

A completely in vitro study by Altamura et al. (2016a) revealed a difference between the pathogenesis of FcaPV-2 and the HPV model of pathogenesis. FcaPV-2 E6 oncogene enhances the activation of mitogen-activated protein kinases (MAPK) and protein kinase B (Akt) pathways independently of EGFR expression, which contrasts with the HPV model of pathogenesis which is EGFR-dependent (Altamura et al., 2016a). MAPK is a key regulator of the Ras-MAPK signalling route, which is involved in cellular proliferation, and Akt is involved in the inhibition of apoptosis (Ranieri et al., 2013). Hoggard et al. (2018) demonstrated the presence of E6/E7 mRNA and unregulated E6/E7 transcription in SCC lesions.

The molecular pathways examined in these studies may not accurately represent the molecular pathways in skin epithelial cells and thus provide a moderate level of evidence to support the clinical query

These studies provided evidence to support the carcinogenic properties of FcaPV-2. Altamura et al. (2016a) and Altamura et al. (2016b) used in vitro models in their studies (specifically cultured feline kidney epithelial cells) which may mean that the results are somewhat challenging to extrapolate to living cats. Furthermore, while the studies used feline epithelial cells, these cells are independent of the tissue environment that skin epithelial cells would be. Therefore, the molecular pathways examined in these studies may not accurately represent the molecular pathways in skin epithelial cells and thus provide a moderate level of evidence to support the clinical query.

In conclusion

There is evidence to say with moderate confidence that FcaPV-2 is actively involved in carcinogenesis and the development of SCC. The pathogenesis of FcaPV-2 and neoplastic transformation processes share many similar characteristics with the HPV model of pathogenesis; however, they are not identical. Therefore, prevention of infection with FcaPV-2 should prevent some cancers.