ABSTRACT
Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.
Subject(s)
Neoplasms , Polyploidy , Cell Nucleus , Chromatin/genetics , Genome , Humans , Neoplasms/genetics , Neoplasms/therapyABSTRACT
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.
