Changing Stem Cell Dynamics during Papillomavirus Infection: Potential Roles for Cellular Plasticity in the Viral Lifecycle and Disease

Strati, Katerina

doi:10.3390/v9080221

Cited by 14 publications

(11 citation statements)

References 68 publications

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“…Recent studies also support a potential role for stem cells in viral persistence and oncogenesis [ 10 ]. Infection of a stem cell is much more likely to give rise to long-term infection than that of a transit amplifying cell [ 11 ].…”

Section: Natural History Of Hpv Infectionmentioning

confidence: 99%

Persistent Human Papillomavirus Infection

Fera

Warburton

Coursey

et al. 2021

Viruses

108

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Persistent infection with oncogenic human papillomavirus (HPV) types is responsible for ~5% of human cancers. The HPV infectious cycle can sustain long-term infection in stratified epithelia because viral DNA is maintained as low copy number extrachromosomal plasmids in the dividing basal cells of a lesion, while progeny viral genomes are amplified to large numbers in differentiated superficial cells. The viral E1 and E2 proteins initiate viral DNA replication and maintain and partition viral genomes, in concert with the cellular replication machinery. Additionally, the E5, E6, and E7 proteins are required to evade host immune responses and to produce a cellular environment that supports viral DNA replication. An unfortunate consequence of the manipulation of cellular proliferation and differentiation is that cells become at high risk for carcinogenesis.

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Section: Natural History Of Hpv Infectionmentioning

confidence: 99%

Persistent Human Papillomavirus Infection

Fera

Warburton

Coursey

et al. 2021

Viruses

108

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“…Notably, we identified the reservoir of HPV in non-neoplastic epithelial cells within the crypts of colonic normal mucosa adjacent to the neoplastic mucosa and we demonstrated that these cells were stem-cells, which are known to be susceptible to transformation by HPV 16 (39, 40). It can be argued that following inflammatory response to a number of stimuli (also including dysbiosis) (41), non-cancer stem cells may be activated into cancer stem cells, sustaining a feed-forward circuit of self-renewal, proliferation, differentiation and neoplastic transformation in a condition of immune evasion, as previously demonstrated (40, 42–44). Due to the pluripotency of stem-cells, a squamous cell carcinoma may arise also in colorectal mucosa in the absence of any metaplastic changes, as in our case.…”

Section: Discussionmentioning

confidence: 79%

Putative Role of Circulating Human Papillomavirus DNA in the Development of Primary Squamous Cell Carcinoma of the Middle Rectum: A Case Report

et al. 2019

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Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by in vitro studies, we confirmed the capability of HPV DNA-positive exosomes, isolated from the supernatant of a HPV DNA positive cell line (CaSki), to transfer its DNA to human colon cancer and normal cell lines. In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least in vitro , to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA in situ hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites.

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“…Hence, hepatitis B virus (HBV) harms liver progenitor cells and elicits hepatocellular carcinoma (HCC) [ 9 , 10 ]. HPV disturbs progenitor cells in the epidermal tissues and causes squamous cell carcinoma in the cervix and penis [ 11 ]. Epstein–Barr virus (EBV) disrupts progenitor cells in the head and neck and causes nasopharyngeal carcinoma (NPC) [ 12 ].…”

Section: Virally Induced Malignanciesmentioning

confidence: 99%

“…Hence, when HPV infects a progeny differentiated cervical cell, the affected cell dies and disappears along with the viruses (similar to HAV). However, when HPV infects a progenitor cervical cell with stem-like properties, the infection may perpetuate and malignancy eventuate (similar to HBV) [ 11 ].…”

Section: Hpv and Cervical Cancermentioning

confidence: 99%

Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies

2021

Cancers

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In 1911, Peyton Rous (Nobel Prize winner in 1966) demonstrated that a virus (i.e., RSV) caused cancer in chickens. In 1976, Bishop and Varmus (Nobel Prize winners in 1989) showed that the cellular origin of retroviral oncogenes was actually normal cellular genes (i.e., proto-oncogenes). In this article, we revisit the role viruses play in the genetic origin of cancer. We review a link between viruses or cancer and autoimmunity in an alternative stem cell origin of cancer. We propose that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We postulate that both known (e.g., HBV and HPV) and novel viruses (e.g., SARS-CoV-2) pose an imminent threat in the emergence of chronic viral diseases as well as virally induced malignancies. Knowing the origin of cancer has profound implications on our current conception and perception of cancer. It affects our conduct in cancer research and our delivery of cancer care. It would be ironic if viruses turn out to be a useful tool and an ideal means in our quest to verify a genetic versus stem cell origin of cancer. When it pertains, oncology recapitulates ontology; viral (or genetic) content may be king, but cellular (or stem-like) context is key.

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Changing Stem Cell Dynamics during Papillomavirus Infection: Potential Roles for Cellular Plasticity in the Viral Lifecycle and Disease

Cited by 14 publications

References 68 publications

Persistent Human Papillomavirus Infection

Persistent Human Papillomavirus Infection

Putative Role of Circulating Human Papillomavirus DNA in the Development of Primary Squamous Cell Carcinoma of the Middle Rectum: A Case Report

Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies

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