Chromatin streaming from giant polyploid nuclei in Ishikawa endometrial hollow spheroids results in the amitotic proliferation of nuclei that fill the spheroid envelope

Abstract

This paper describes the amitotic proliferation of nuclei that fill the envelope of Ishikawa hollow spheroids. The presence of hollow spheroids in malignant ascites fluid has intrigued cancer researchers, but little is understood about how they form. Observations in Ishikawa endometrial cell cultures demonstrate that nuclei filling the spheroid envelope are generated amitotically by the same mechanism responsible for cell formation in domes. Transient structures of aggregated chromatin surrounded by fused giant mitochondria, the initiating structure for dome formation, are also the starting point for the differentiation of unicellular polyploid hollow spheroids. Nuclei from monolayer cells are aggregated in a single enlarged cell where they become surrounding by giant fused mitochondria. A gaseous vacuole forms inside the mitonucleon extending it so that all of the cell material, including nuclei is pressed against the cell membrane. The resulting unicellular hollow spheroid detaches from the colony, capable of migration from the site of its formation. Ultimately, pressure on the aggregated chromatin results in the release of streams of chromatin granules that initially travel as if guided by microtubules through the shell of the hollow spheroid. Granules dissolve into filaments and, as initially described in dome formation, this material self-assembles into clusters of nuclei. Nuclei move out of these clusters into a regular array within the spheroid envelope, with formation of cell membranes as the final step in the creation of multicellular hollow spheroids. The curved membrane characteristic of domes and spheroids, as well as colonies of nuclei produced by amitosis have been identified in tumor tissue that survives chemotherapy, suggesting that amitotic cell proliferation may at least partially explain the population of cancer tumor cells in humans that are resistant to chemotherapy.