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P1 oncogenerative cell division as a whole cell entity is shown here.

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.Significance: P1 oncogenerative cell entities express low levels of CSC markers, which are characteristic of their histological origin. Cancer Res; 78(9); 2318–31. ©2018 AACR.

P1 cells seem to undergo divisions in to similar oncogenerative cells by cytoplasm separation. The process is in par orchestrated with the participation of mitochondria which delimitate boundaries of cytoplasms to be separated. After this, it is possible to observe a directional cytokinesis like separation of multinucleated cells.

Expression of CSC markers and morphology of P1 oncogenerative and G1-Gn cells as detected by ICC and IHC.

P1 reconstruction in 3D horizontal projection from TEM sections superposed. The inner structure of G1-containing cells is shown.

Replicative elements found in P1 and G1 cells and the expression of HERV envelope proteins in small G1-G2 cells can be visualised here.

P1 oncogenerative cells undergo long quiescent phases in which they do not appear to generate and eject G1 cells.

Resistance profile and spherogenicity of SKOV3 ovarian carcinoma models.

Oncogenerative P1 cells are giant cells with a syncytium-like morphology. This distinctive cell type complete cell life cycles which resemble lysogenic viral cycles. The mode of cellularization of the intracytoplasmically generated G1 cells (generation 1) is unique and takes place in different ways: a) in a lateral form which means that the G1 cells abandon the maternal P1 cells by trans cytoplasmic budding, b) through crevices formed with the participation of mitochondria around G1s until expulsion. After cellularization, the resulted aperture is filled by fusogenic HERV proteins, c) using a kind of funiculus or bridge connected to P1 maternal cells. An interesting process conducted by P1 cells is the horizontal transmission of G1 inoculating these cells into proximal receptor cells.

The lateral separation of G1 from P1 cells is observed in this clip.

The formation of the crevices is observed with the subsequent detachment of G1-Gn cells from mother cytoplasm.

P1 reconstruction in 3D vertical projection from TEM sections superposed. The inner structure of G1-containing cells is shown.

Occurrence and morphology of multinucleated cells in different tumors.

Oncogenerative P1 cells are giant cells with a syncytium-like morphology. This distinctive cell type complete cell life cycles which resemble lysogenic viral cycles. The mode of cellularization of the intracytoplasmically generated G1 cells (generation 1) is unique and takes place in different ways: a) in a lateral form which means that the G1 cells abandon the maternal P1 cells by trans cytoplasmic budding, b) through crevices formed with the participation of mitochondria around G1s until expulsion. After cellularization, the resulted aperture is filled by fusogenic HERV proteins, c) using a kind of funiculus or bridge connected to P1 maternal cells. An interesting process conducted by P1 cells is the horizontal transmission of G1 inoculating these cells into proximal receptor cells.

Expression of CSC markers in multinucleated cells at protein and RNA levels.