Murali Rajaraman

Neosis: A Novel Type of Cell Division in Cancer

Using computerized video time-lapse microscope, we studied early cellular events during carcinogen-induced transformation of C3H10T1/2 cells. Multinucleate / polyploid giant cells (MN/PGs) formed due to DNA damage is thought to die via mitotic catastrophe. Before they die, some MN/PGs undergo a novel type of cell division, termed neosis, characterized by karyokinesis via nuclear budding followed by asymmetric, intracellular cytokinesis, producing several small mononuclear cells, termed the Raju cells, with extended mitotic life span (MLS). Mitotic derivatives of Raju cells give rise to transformed cell lines, inherit genomic instability, display a phenotype and transcriptome different from the neosis mother cell, and display anchorage-independent growth. Neosis of MN/PGs also precedes spontaneous transformation of p53-/- mouse cells. Rodent neotic clones, and primary and metastatic human tumor cells undergo spontaneous or induced secondary/tertiary neosis. Neosis seems to extend the MLS of cells under conditions of genetic duress not favoring mitosis. It precedes tumorigenesis, occurs several times during tumor progression, yielding tumor-initiating Raju cells and introducing tumor cell heterogeneity subject to natural selection during tumor progression. Events during neosis, and its relevance to origin of established cell lines, multistep carcinogenesis, cancer stem cells, and therapeutic advantages of anti-neotic agents (neosicides) are discussed.

Tumor proliferation and apoptosis in human uterine cervix carcinoma I: correlations between variables

PURPOSE Parameters for tumor proliferation and apoptosis were studied prospectively in 84 previously untreated patients with a diagnosis of carcinoma of the uterine cervix. MATERIALS AND METHODS Tumor proliferation was assessed by in vivo labeling with bromodeoxyuridine (BrdU), followed by a biopsy of the tumor 4-10 h thereafter during an examination under anesthesia. The potential doubling time (Tpot) was obtained by deriving the BrdU labeling index (LI) and S-phase duration (Ts) using flow cytometry. The LI for BrdU and its staining pattern were also determined immunohistochemically. Apoptosis was assessed histologically using morphological criteria. RESULTS Seven patients were excluded and the FIGO stages of the remaining 77 patients were as follows: IB and IIA, 20 patients; IIB, 29 patients; IIIB and IV, 28 patients. The median tumor diameter was 6 cm. There were 61 squamous cell, 11 adeno- and five adenosquamous carcinomas. Of the 63 patients in whom the tumor grade could be determined, 37 were well or moderately well differentiated and the remaining 26 were poorly differentiated. The median mitotic index (MI) was 0.7%. There were 43 diploid and 34 aneuploid tumors. Median values for Ts and S-phase fraction (SPF) were 9.9 h and 16%, respectively. The median BrdU LI by flow cytometry (LI-fc) was 6.7%. There was a significant correlation between LI-fc and LI by histology, although values for the latter (median 11.1%) were consistently higher than those determined by flow cytometry by a factor of 1.5. The median Tpot value was 5.0 days. The median apoptotic index (AI) was 1.0% and AI correlated positively with LI-fc. Median values for LI-fc increased with increasing tumor size and were 5.1%, 6.4%, 7.5% and 11.0% for tumors measuring < or = 4 cm, 4-6 cm, 6-8 cm and > 8 cm, respectively. The remaining proliferation parameters, however, showed no correlation with tumor size, stage, grade or histologic type. CONCLUSIONS In carcinomas of the cervix, tumor proliferation is positively associated with apoptosis and tumor size. These findings suggest that parameters for tumor proliferation and apoptosis are associated with tumor progression and may thus be predictive of clinical outcome.

Neosis - A Parasexual Somatic Reduction Division in Cancer

Abstract We have recently reported a novel type of cell division involved in the origin and growth of cancers. Termed neosis, as opposed to mitosis and meiosis, this type of cell division occurs only in senescent polyploid giant cells and not in normal diploid cells. Up to ~10% of tumor cells in vitro and in vivo, are polyploid giant cells and so far there is no explanation for their role in cancer. These resemble senescent cells, which are thought to play a tumor suppressor role. We have shown that such cells have the potential to undergo neosis, a parasexual, somatic reduction division characterized by karyokinesis via nuclear budding, followed by asymmetric cytokinesis, (often) giving rise to aneuploid daughter cells termed Raju cells, which are the progenitors of tumor cells. These Tumor Initiating Raju Cells (TIRCs) are unique in that they transiently display stem cell properties, have inherited genomic instability, differentiate into tumor cells and have extended, but, limited mitotic life span (*MLS). At the end of their extended MLS (EMLS), the tumor cells repeat the cycle of senescence, neosis and production of Tumor Rejuvenating Raju Cells (TRRCs), which repeat the same cycle of events several times through the life of tumor in a progressively non-synchronous fashion. When tumor cells are subjected to chemotherapy or radiotherapy, they undergo premature senescence; but, some cells escape senescence via S/T-neosis and yield TRRCs, whose mitotic progenies may be resistant to genotoxins. Although neosis-like events have appeared in the literature sporadically for more than a century under different names, they were neglected since the significance of such events was not known till now. The data on neosis questions the basic tenets of the current concepts of cancer, i.e., (1) Cancer arises via mitosis, (2) Cancer cells are immortal and (3) Cancer cell continuity is due to the unlimited asymmetric mitotic potential of mutant stem cells or Cancer Stem Cells (CSCs). Neosis paradigm supports the concept that (1) Cancer arises via neosis, (2) cancer cells are not immortal, but undergo repeated senescent phases and that (3) tumor cell lineage continuity is due to escape from senescent phase via neosis, since tumor cells carry mutant or epimutant genes in the senescent checkpoint pathway. Thus, genesis and regenesis of Raju cells via repetitive neotic divisions is responsible for the origin and continuous growth of different tumor types. This concept accommodates epigenetic expression of telomerase, meiotic genes, multidrug resistance genes and stem cell-specific genes in tumor cells and also explains the role of senescent cells found in tumor tissues. Thus, neosis appears to involve global epigenetic modulation (EM), in order to fine-tune the chromatin with DNA damage important for producing reproductively viable genomes from the non-viable polyploid genome, before being discarded by post-neotic death of neosis mother cells (NMCs).

Use of radioiodine-131 scan to measure influence of surgical discipline, practice, and volume on residual thyroid tissue after total thyroidectomy for differentiated thyroid carcinoma

Our studys purpose is to determine the influence of surgical discipline, surgeon site, and volume on remnant thyroid tissue visualized on radioactive iodine‐131 (I‐131) scans after total thyroidectomy and I‐131 ablation in patients with well‐differentiated thyroid carcinomas.