Polyploid Giant Cancer Cells, a Hallmark of Oncoviruses and a New Therapeutic Challenge

Abstract

Tumors are renowned as intricate systems that harbor heterogeneous cancer cells with distinctly diverse molecular signatures, sizes and genomic contents. Among those various genomic clonal populations within the complex tumoral architecture are the polyploid giant cancer cells (PGCC). Although described for over a century, PGCC are increasingly being recognized for their prominent role in tumorigenesis, metastasis, therapy resistance and tumor repopulation after therapy. A shared characteristic among all tumors triggered by oncoviruses is the presence of polyploidy. Those include Human Papillomaviruses (HPV), Epstein Barr Virus (EBV), Hepatitis B and C viruses (HBV and HCV, respectively), Human T-cell lymphotropic virus-1 (HTLV-1), Kaposi's sarcoma herpesvirus (KSHV) and Merkel polyomavirus (MCPyV). Distinct viral proteins, for instance Tax for HTLV-1 or HBx for HBV have demonstrated their etiologic role in favoring the appearance of PGCC. Different intriguing biological mechanisms employed by oncogenic viruses, in addition to viruses with high oncogenic potential such as human cytomegalovirus, could support the generation of PGCC, including induction of endoreplication, inactivation of tumor suppressors, development of hypoxia, activation of cellular senescence and others. Interestingly, chemoresistance and radioresistance have been reported in the context of oncovirus-induced cancers, for example KSHV and EBV-associated lymphomas and high-risk HPV-related cervical cancer. This points toward a potential linkage between the previously mentioned players and highlights PGCC as keystone cancer cells in virally-induced tumors. Subsequently, although new therapeutic approaches are actively needed to fight PGCC, attention should also be drawn to reveal the relationship between PGCC and oncoviruses, with the ultimate goal of establishing effective therapeutic platforms for treatment of virus-associated cancers. This review discusses the presence of PGCCs in tumors induced by oncoviruses, biological mechanisms potentially favoring their appearance, as well as their consequent implication at the clinical and therapeutic level.

IR-Surviving NSCLC Cells Exhibit Different Patterns of Molecular and Cellular Reactions Relating to the Multifraction Irradiation Regimen and p53-Family Proteins Expression

“…Polyploid giant cancer cells are another hallmark of cancer, and the polyploidy is associated with instability of chromosomes and cancer progression. Although described for over a century, PGCCs are now being widely recognized for their prominent role in tumorigenesis, metastasis, therapy resistance, and cancer recurrence after therapy [ 35 , 36 ].…”

Identification of UL69 Gene and Protein in Cytomegalovirus-Transformed Human Mammary Epithelial Cells

“…p53, Rb) and the properties of virus regulatory proteins such as pUL69 (38). Although we did not yet decipher the molecular mechanism(s) involved in HCMV transformation and the role played by pUL69 (alone or in conjunction with other viral proteins) in this phenomenon, pUL69 favors sustained proliferation of CTH cells in parallel with low sustained viral growth in culture which have been reported as key elements for the transforming capabilities of the two oncogenic herpesviruses EBV and KSHV (25).…”

“…pUL69 is a multifunctional regulatory protein belonging to the ICP27 herpesvirus family (23) which contains the ICP27 homology domain (IHD) (24). pUL69 could participate in the transformation of CTH cells via two distinct mechanisms: low viral replication levels in parallel to viral latency as already reported for the two oncoviruses (EBV and KSHV), and/or through a direct oncogenic potential of the viral protein (9)(10)(11)25). Those two mechanisms might not be exclusive to each other.…”

“…In addition, a virally-encoded deSUMOylase activity is required for HCMV reactivation from latency (48). In line with the fact that SUMOylation is involved in HCMV latency, it is often considered as a prerequisite for cellular transformation by herpes oncoviruses (7,25). It should be pointed out that the binding of pUL69 to PRMT6 could be another mechanism elucidating its role in cancer development.…”

Therapy Induced Genome Chaos: A Novel Mechanism of Rapid Cancer Drug Resistance

“…Finally, following the characterization of “the giant cell cycle,” and the comparison of PGCCs with blastomeres, the relationship between PGCCs, different types of cancers, and developmental stages/hierarchy were synthesized, which laid out the strong basis for PGCC studies (Niu et al, 2017 ; Liu, 2018 , 2020 ). Meanwhile, an exciting frontier of using PGCCs to study drug resistance has emerged, involving diverse molecular mechanisms (Mirzayans et al, 2018 ; Lin et al, 2019 ; Herbein and Nehme, 2020 ; Mannan et al, 2020 ; Pienta et al, 2020b ; Tagal and Roth, 2020 ; White-Gilbertson and Voelkel-Johnson, 2020 ).…”