A Distinct Oncogenerative Multinucleated Cancer Cell Serves as a Source of Stemness and Tumor Heterogeneity

Abstract

The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiologic stemness of the resulting cell populations. Here, we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy-refractory ovarian tumors, which generate and gestate daughter generation Gn cells intracytoplasmically. Release of Gn cells occurred by ejection through crevices in the P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1 cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1 cells were competent to horizontally transmit offspring Gn cells into other specific proximal cells, injecting them to receptor R1 cells via cell-cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1 cells with low expression of stem cell markers despite their physiologic stemness, the first offspring generations of daughter G1 cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1 and Gn cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1 cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers. P1 oncogenerative cell entities express low levels of CSC markers, which are characteristic of their histological origin. .

Mitostemness

“…Our mitostemness proposal is consistent with a number of descriptions in which the determination of cell fate involves the asymmetric distribution of certain mitochondrial controllers into CSC-like cell entities [84][85][86][87][88][89]. Indeed, our proposal complements the view that changes in intracellular, intercellular, and extracellular mitochondrial traffic [90][91][92][93][94] appear to ensure the functional endurance of mitochondria in the tumor-initiating and drug-resistant subpopulation of CSC. New therapeutics aimed to target mitochondria not only as biochemical but also as biophysical and morpho-physiological hallmarks of CSC might certainly guide improvements to cancer treatment.…”

Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells

“…In any case, converging evidences indicated that MNGCs ultimately contribute to the generation of progeny with stem cell-like properties and may have a fundamental role in cancer recurrences and chemoresistance [22,38]. This phenotype was also observed in several studies performed on ovarian cancer models [44][45][46][47][48]. Future studies are, however, necessary to properly clarify the molecular mechanisms underlying the formation of MNGCs and how TP53 MUT contribute to this phenotype.…”

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

“…However, over 60 years ago Puck and Marcus [33] reported that PGCCs (originally called giant cells), arising in cervical carcinoma (HeLa) cell cultures following exposure to ionizing radiation, remain viable and secrete growth-promoting factors. In addition to secreting pro-survival factors, PGCCs are now known to be capable of giving rise to therapy-resistant and tumor repopulating cells through (i) nuclear budding or bursting, similar to simple organisms such as fungi [34][35][36][37][38][39][40][41][42][43][44][45][46][47]; (ii) depolyploidization, involving key mediators of meiosis, self-renewal, and mitosis [48][49][50][51][52]; and (iii) horizontal transfer of their nuclear material that contain stem-cell markers to neighboring cells [53]. Consistent with these properties, a significant number of recent reports with different biological systems (e.g., tumor-derived cell lines, animal models, and specimens from cancer patients) have underscored the key roles played by PGCCs in tumorigenesis, metastasis, and disease relapse after conventional cancer treatments.…”

“…Thus, as cancer is an extremely complex disease, its prevention has proven to be equally complex, extending far beyond modulating the DNA damage response and/or cell death pathways. It is becoming increasingly evident that, to realize the monumental goal of combating cancer, one must take into account not only the mutational basis of intrinsic/acquired therapy resistance of cancer cells, but also non-mutational events such as cancer cell dormancy, horizontal (cell-to-cell) transfer of genetic material containing cancer stem cell markers [53], an atavistic process whereby cancer cells re-express ancestral traits that includes severe stress resistance [60][61][62][63][64][65][66][67][68][69], and cancer cell fusion (e.g., cancer cell-leukocyte [28,144]) which facilitates cancer cell circulation and metastasis. Irrespective of this complexity, one must hope that a better understanding of the multifactorial nature of cancer cell resistance to therapeutic agents will finally lead to novel strategies to prevent, or at least significantly suppress, cancer recurrence.…”