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Squarzanti et al. J Cancer Metastasis Treat 2019;5:73 I http://dx.doi.org/10.20517/2394-4722.2019.19 Page 3 of 11

On this basis, the purpose of this study was to show the state of the art on epithelial carcinogenesis and on
the most suitable in vitro 3D models till now developed for the study of host-pathogens interactions.

By using MEDLINE, terms such as “microbiota”, “virota”, “virus”, “epitheliotropic virus”, “HPV”,
“bacteriota”, “bacteria”, “Fusobacterium nucleatum”, “Porphyromonas gingivalis”, “EMT”, “eukaryotic cells”,
“keratinocytes”, “epithelial cells” “epithelial infection”, “epithelial cancer”, “anogenital cancer”, “head and
neck squamous cell carcinoma (HNSCC)”, “epithelial models”, “2D”, “3D”, “3D epithelial cultures”, “rafts”,
“spheroids”, “reconstructed tissues”, both in single and mutually combined, were searched in titles and
abstracts in order to find PubMed indexed most pertinent articles; only original research articles published
in peer review journal were considered. Papers including EBV or other epitheliotropic viruses other than
HPV were excluded.

The literature search was limited to the most recent scientific publications (10 years); six thousand and five
hundred nine appropriate abstracts and full papers were carefully read and reviewed; those relevant (216)
were reconsidered based on the above described inclusion and exclusion criteria and then 70 were reported
in detail and included in the text.

Overall, our findings highlight the most recent advances in the field of host-pathogens interactions. We
focused on the in vitro 3D modeling for the study of the microbial induced epithelial carcinogenesis
and emphasized its ability in mimicking at best the role of bacteria and viruses within an in vivo
microenvironment.

mICRObIOTa, ImmUNe RespONse aND epITHeLIaL CaNCeR
[10]
Several studies, among which that conducted by Kyrgiou et al. , underlined that vaginal microbiota
may drastically influence host innate immune response, infection susceptibility and cervical cancer
development, but without proving causality and thus making necessary further longitudinal studies. In
[17]
this direction, Ilhan et al. , through a triple approach based on liquid chromatography mass spectrometry,
16S rRNA gene sequencing and immunoassay, evaluated and integrated the metabolic signature of the
vaginal microbiota and the inflammatory status changes of 78 women, including HPV-negative/positive
controls, low-/high-grade cervical-dysplasia or -cancer affected females. These authors found that
unique cervicovaginal metabolites and microbes allow to discriminate clearly the affected patients from
healthy subjects, thus providing novel cancer hallmarks. For example, the lipidic three-hydroxy-butyrate,
eicosenoate, and oleate/vaccenate are distinctive of cancer patients, while sphingolipids, plasmalogens and
linoleate positively correlate with cervicovaginal inflammation.

Regarding this niche, the absence of dysbiosis and a dominance of peculiar gram-positive bacteria belonging
to the Lactobacillus genus may inhibit several pathogens, preserve aminoacidic and nucleotide metabolisms
and avoid the inflammatory state. Conversely, Fusobacterium spp., F. nucleatum in primis, promotes cell
survival, proliferation, dysregulated carcinogenesis and cervical cancer through the induction of the WNT/
Beta catenin signaling pathway, as emerged by research in colorectal cancer (CRC) [12,18,19] .

Since it has been demonstrated a significant correlation between bacteria belonging to the Fusobacteria
genus, mainly Sneathia sanguinegens, and high-grade squamous intraepithelial lesions, they could be hired
[10]
as microbiological markers of clinically significant cervical diseases .
[12]
This evidence has also been observed in another study by Mitra et al. , who found that a relative
abundance of Fusobacterium spp. associates with higher levels of cytokines such as IL-4 and TGF-1β, which
have been shown to generate local immunosuppression, HPV immune evasion and cancer development.