https://biblio.ugent.be/publication/8670131/file/8672512.pdf

Polyploidy: A Biological Force From Cells to Ecosystems

The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay detects DNA breakage by labeling the free 3'-hydroxyl termini. Given that genomic DNA breaks arise during early and late stages of apoptosis, TUNEL staining continues to be widely used as a measure of apoptotic cell death. The advantages of the assay include its relative ease of performance and the broad availability of TUNEL assay kits for various applications, such as single-cell analysis of apoptosis in cell cultures and tissue samples. However, as briefly discussed herein, aside from some concerns relating to the specificity of the TUNEL assay itself, it was demonstrated some twenty years ago that the early stages of apoptosis, detected by TUNEL, can be reversed. More recently, compelling evidence from different biological systems has revealed that cells can recover from even late stage apoptosis through a process called anastasis. Specifically, such recovery has been observed in cells exhibiting caspase activation, genomic DNA breakage, phosphatidylserine externalization, and formation of apoptotic bodies. Furthermore, there is solid evidence demonstrating that apoptotic cells can promote neighboring tumor cell repopulation (e.g., through caspase-3-mediated secretion of prostaglandin E2) and confer resistance to anticancer therapy. Accordingly, caution should be exercised in the interpretation of results obtained by the TUNEL and other apoptosis assays (e.g., caspase activation) in terms of apoptotic cell demise.

Do TUNEL and Other Apoptosis Assays Detect Cell Death in Preclinical Studies

The "life code": A theory that unifies the human life cycle and the origin of human tumors.

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

https://www.pnas.org/content/pnas/118/7/e2020838118.full.pdf

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Cancer cells utilize the forces of natural selection to evolve evolvability allowing a constant supply of heritable variation that permits a cancer species to evolutionary track changing hazards and opportunities. Over time, the dynamic tumor ecosystem is exposed to extreme, catastrophic changes in the conditions of the tumor-natural (e.g., loss of blood supply) or imposed (therapeutic). While the nature of these catastrophes may be varied or unique, their common property may be to doom the current cancer phenotype unless it evolves rapidly. Poly-aneuploid cancer cells (PACCs) may serve as efficient sources of heritable variation that allows cancer cells to evolve rapidly, speciate, evolutionarily track their environment, and most critically for patient outcome and survival, permit evolutionary rescue, therapy resistance, and metastasis. As a conditional evolutionary strategy, they permit the cancer cells to accelerate evolution under stress and slow down the generation of heritable variation when conditions are more favorable or when the cancer cells are closer to an evolutionary optimum. We hypothesize that they play a critical and outsized role in lethality by their increased capacity for invasion and motility, for enduring novel and stressful environments, and for generating heritable variation that can be dispensed to their 2N+ aneuploid progeny that make up the bulk of cancer cells within a tumor, providing population rescue in response to therapeutic stress. Targeting PACCs is essential to cancer therapy and patient cure-without the eradication of the resilient PACCs, cancer will recur in treated patients.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/eva.12929

Poly-aneuploid cancer cells promote evolvability, generating lethal cancer.

Polyploidy is associated with increased cell size and is commonly found in a subset of adult organs and blastomere stage of the human embryo. The polyploidy is formed through endoreplication or cell fusion to support the specific need of development including earliest embryogenesis. Recent data demonstrated that Polyploid Giant Cancer Cells (PGCCs) may have acquired an activated early embryonic-like program in response to oncogenic and therapeutic stress to generate reprogrammed cancer cells for drug resistance and metastasis. Targeting PGCCs may open up new opportunities for cancer therapy.

Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer.

Expression of B7-H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas.

GATA6: a new predictor for prognosis in ovarian cancer.

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Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer.

Expression of B7-H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas.

GATA6: a new predictor for prognosis in ovarian cancer.