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Activation of Meiosis-Specific Genes Is Associated with Depolyploidization of Human Tumor Cells following Radiation-Induced Mitotic Catastrophe

Departments of ¹ Pathology and ² Radiation Oncology, University of Iowa, ³ Department of Biomedical Engineering, Seamans Center, University of Iowa, Iowa City, Iowa; and ⁴ Latvia Biomedical Research and Study Centre, Riga, Latvia

Requests for reprints: Fiorenza Ianzini, Department of Pathology, 1026 ML, University of Iowa, 500 Newton Road, Iowa City, IA 52242. Phone: 319-335-6637; Fax: 319-335-8453; E-mail: fiorenza-ianzini{at}uiowa.edu.

Key Words: radiation • mitotic catastrophe • polyploidy • depolyploidization • Large-scale digital cell analysis system (LSDCAS) • meiosis-specific genes • tumor cells • tumor progression • tumor resistance to treatment

Cancer is frequently characterized histologically by the appearance of large cells that are either aneuploid or polyploid. Aneuploidy and polyploidy are hallmarks of radiation-induced mitotic catastrophe (MC), a common phenomenon occurring in tumor cells with impaired p53 function following exposure to various cytotoxic and genotoxic agents. MC is characterized by altered expression of mitotic regulators, untimely and abnormal cell division, delayed DNA damage, and changes in morphology. We report here that cells undergoing radiation-induced MC are more plastic with regards to ploidy and that this plasticity allows them to reorganize their genetic material through reduction division to produce smaller cells which are morphologically indistinguishable from control cells. Experiments conducted with the large-scale digital cell analysis system are discussed and show that a small fraction of polyploid cancer cells formed via radiation-induced MC can survive and start a process of depolyploidization that yields various outcomes. Although most multipolar divisions failed and cell fusion occurred, some of these divisions were successful and originated a variety of cell progeny characterized by different ploidy. Among these ploidy phenotypes, a progeny of small mononucleated cells, indistinguishable from the untreated control cells, is often seen. We report here evidence that meiosis-specific genes are expressed in the polyploid cells during depolyploidization. Tumor cells might take advantage of the temporary change from a promitotic to a promeiotic division regimen to facilitate depolyploidization and restore the proliferative state of the tumor cell population. These events might be mechanisms by which tumor progression and resistance to treatment occur in vivo. [Cancer Res 2009;69(6):2296–304]

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