Amitotic Cell Division, Malignancy, and Resistance to Anticancer Agents: A Tribute to Drs. Walen and Rajaraman
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Amitotic Cell Division in Polyploid Mammalian Cells
1.2. Objectives
2. Polyploidy, Amitosis, and In Vitro Cell Transformation
3. Fate of Cancer Cells with Genome Instability
3.1. Amitosis in Solid Tumors/Tumor-Derived Cell Lines
3.2. Amitosis and System-Level Information Alteration
4. Targeting PGCCs in Cancer Therapy
- The formation of PGCCs and their tumor repopulating progeny (via neosis) can be blocked by the contraceptive drug mifepristone [70].
- PGCCs developed following cisplatin treatment have a high content of mitochondria and a distinct metabolic profile, which includes high levels of lipid droplets and cholesterol. These PGCCs could be targeted using zoledronic acid, a potent inhibitor of osteoclasts (multinucleated bone cells) [71], which is commonly used to treat osteoporosis and bone metastases [72,73].
- Treatment with LCL521 or simvastatin disrupts cholesterol signaling and interferes with PGCC progeny formation [74].
- The ESCRT (endosomal complexes required for transport) proteins are involved in the budding of PGCCs [78]. Treatment of PGCCs with interferon, a modulator of ESCRT, prevented PGCC budding [78]. In that study, PGCCs were created following exposure to ionizing radiation and were referred to as “radiation-tolerant persister” cells.
5. The Role of PGCCs in Minimal Residual Disease and Tumor Repopulation Post-Therapy
- i.
- Treatment Phase. This first phase involves conventional therapeutic strategies (such as surgery, chemotherapy, and radiation therapy) to inhibit tumor growth and hopefully to prevent or at least mitigate metastasis. The majority (perhaps >95%) of anticancer studies have focused on this vital phase of cancer therapy.
- ii.
- Response. A proportion of cancer cells within a solid tumor responds to genotoxic insult (incurred from the treatment phase) by entering a state of dormancy (active sleep). This group includes PGCCs. In tissue culture studies, it may take ~10 days after treatment for PGCCs to be fully manifested (see, e.g., [78]). It is worth noting that ubiquitously used preclinical anticancer end-points (e.g., multiwell plate cell “viability” and tumor growth delay assays in live animals) are performed within this time frame, and thus they often overlook the impact of PGCCs or score them as “dead” (see, e.g., [22,26]).
- iii.
- Dormancy. Senescence-like dormancy [84] (also referred to as MRD [85]) is an extended latency period during which PGCCs undergo depolyploidization through a meiosis-like process as well as through amitosis-neosis. PGCCs are also known to have the ability to transfer a small portion of their nuclear material containing stem cell markers to neighboring cells via cytoplasmic tunnels [86].
- iv.
- Recurrence. Rapidly proliferating progenitor cells emerging from PGCCs repopulate the tumor. Such cells have stem cell characteristics and can show resistance to conventional therapies (used in the “treatment phase”). Whether cells subjected to horizontal gene transfer also exhibit these properties is not known.
6. Amitotic Cell Division Contributes to Intratumor Heterogeneity
7. Human Genetic Disorders Associated with Genome Instability and Cancer Predisposition: Does Amitosis-Neosis Play a Role?
8. Conclusions
Funding
Conflicts of Interest
Appendix A
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Disorder | Mode of Transmission | Defective Protein | Defective Function |
---|---|---|---|
Xeroderma pigmentosum | Autosomal recessive | XPA through XPG, DNA polymerase η | Nucleotide excision repair (XPA through XPG), postreplication repair (XPV) |
Ataxia telangiectasia | Autosomal recessive | ATM | ATM signaling |
Li-Fraumeni syndrome | Autosomal dominant | p53; Chk2 | p53/Chk2 signaling |
Nijmegen breakage syndrome | Autosomal recessive | NBS1 | DSB repair |
Werner syndrome | Autosomal recessive | WRN | DNA helicase |
Bloom syndrome | Autosomal recessive | BS | DNA helicase |
Rothmund-Thompson syndrome | Autosomal recessive | RTS | DNA helicase |
Fanconi anemia | Autosomal recessive | FANCA, B, C, D1, D2, E, F, G, I, J, L and M | DNA helicase, DNA cross-link repair |
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Mirzayans, R.; Murray, D. Amitotic Cell Division, Malignancy, and Resistance to Anticancer Agents: A Tribute to Drs. Walen and Rajaraman. Cancers 2024, 16, 3106. https://doi.org/10.3390/cancers16173106
Mirzayans R, Murray D. Amitotic Cell Division, Malignancy, and Resistance to Anticancer Agents: A Tribute to Drs. Walen and Rajaraman. Cancers. 2024; 16(17):3106. https://doi.org/10.3390/cancers16173106
Chicago/Turabian StyleMirzayans, Razmik, and David Murray. 2024. "Amitotic Cell Division, Malignancy, and Resistance to Anticancer Agents: A Tribute to Drs. Walen and Rajaraman" Cancers 16, no. 17: 3106. https://doi.org/10.3390/cancers16173106