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Page 2 of 11 Kaufman et al. J Cancer Metastasis Treat 2019;5:73 I http://dx.doi.org/10.20517/2394-4722.2019.19

Keywords: High risk human papillomavirus, microbiota, Fusobacterium nucleatum , epithelial-mesenchymal
transition, anogenital cancer, head & neck squamous cell carcinoma, colorectal cancer, transepithelial electrical
resistance

INTRODUCTION
[1]
As referred in the last human papillomavirus (HPV) cancer report of the HPV Information Centre ,
unremitting HPV infection, mainly promoted by high-risk HPV (HR-HPV) 16 and 18 E6 and E7
oncoproteins, is the main microbial etiological factor till now recognized that is necessary, yet not
sufficient, for the development of anogenital and of head & neck cancers (namely of the tonsil, tongue and
oropharynx).

[2,3]
Despite the progresses in vaccination and screening prevention led to the reduction of cases number ,
these tumors are still diffuse among the general population, with the highest mortality rate in countries
[3]
with a low socio-economic level .
Cervical cancer is the 3rd most frequent female tumor in the world (2nd in the age range 15-44) with about
[4,5]
600,000 new cases/year and a 50% mortality rate .
In the last three decades oropharyngeal tumors, which include some 450,000 new cases/year (mostly
affecting older tobacco and alcohol users worldwide), have increased also in young people, due to sexual
[6]
habits changes predisposing to HR-HPV infection .
It has been reported that oncogenic HPV-related oropharyngeal tumors have a better prognosis than
[7,8]
those HPV negative . On the other hand, it is known that HR-HPV-mediated cervical oncogenesis
generally develops after a long latency (about 10-30 years from infection). Thus, it remains a conundrum
the fact that tumor latency and prognosis differ in the two populations of patients, regardless of the
[9]
treatment and of the fact that both types of cancer share a common infective cause . Seemingly, HR-HPV
infection is not per se enough to cause these cancers, though viruses are classified as Class 1 carcinogens
[4]
by the International Agency for Research on Cancer . Recent evidences suggest that the microbiota of
the cervical and oropharyngeal niches (that includes bacteria, protozoa, viruses and fungi, although
sometimes the term specifically refers only to bacterial communities) can have both a harmful and a
protective role. Further, the microbiota can influence persistent HPV-mediated inflammation, epithelial
mesenchymal transition (EMT) and tumorigenesis, although the mechanisms involved are still largely
[10]
unknown and controversial . In fact, just as a balanced bacteriota may be constituted by both pathogens
and commensals, the human virota can include, among the others, both low risk and HR-HPVs, without
inducing morbidity for its host if the immune surveillance and the whole microbiota itself are able to
[11]
control its load and persistence .

Therefore, an open question is if commensal HPV types, belonging to the human virota, play a protective
role against the oncogenic ones or not [12-15] . What is sure is that cancer often arises from a metabolic
imbalance. Given this assumption, the metabolic profile of the microenvironment, in which host cells
directly cooperate with viruses and bacteria, could reveal a snapshot of their functional and complex
interactions that are at the basis of HPV infection, persistence susceptibility, inflammation, EMT,
uncontrolled cell proliferation and cancer progression.

To learn more about it, researchers have developed several in vitro co-culture systems that could mimic the
[16]
physiological appearance of the tumoral microenvironment .