Normal Human Cell Conversion to 3-D Cancer-like Growth: Genome Damage, Endopolyploidy, Senecence Escape, and Cell Polarity Change/Loss
Author(s)
Kirsten H. Walen*
ABSTRACT
In cell cultures monolayered cell growth is controlled by contact inhibition which again is controlled by the cell polarity system by always being positioned in accord with the cytoskeleton axis. Presently, cycling endopolyploid cells (tetraploidy) were shown to undergo perpendicular divisions relative to the cytoskeleton axis which disrupted to some degree contact inhibition in the near-senescent phase of human primary cells. These experiments included genome damage-induced endopolyploidization (TAS-treated) to simulate as a model system the state of in vivo accelerated cell senescence (ACS) which is induced by therapy-associated genomic damage. From ACS delayed tumor re-growth (re-lapse) occurs from “robust” cell propagation, but mechanisms for such cell escape from senescence are unknown. For TAS-treated a karyoplast bud-off process with change to limited mitotic activity occurred in young senescent cultures. In old, deep senescent (5 - 8 weeks) cultures, unexpectedly escape cell-growth showed three dimensional (3-D) tumor-like spheres from growths of morphologically different cells as compared to the fibroblastic phenotype. These cells expressed cell polarity change, and very condensed nuclei were variously perpendicularly oriented to what-ever cell polarity was present. These results were discussed in regard to in vivo relapse and, to the importance of cell polarity change in tumorigenesis. Induced senescence as an anti-tumor mechanism in therapy treatment becomes a questionable procedure from the present experimental results.
In cell cultures monolayered cell growth is controlled by contact inhibition which again is controlled by the cell polarity system by always being positioned in accord with the cytoskeleton axis. Presently, cycling endopolyploid cells (tetraploidy) were shown to undergo perpendicular divisions relative to the cytoskeleton axis which disrupted to some degree contact inhibition in the near-senescent phase of human primary cells. These experiments included genome damage-induced endopolyploidization (TAS-treated) to simulate as a model system the state of in vivo accelerated cell senescence (ACS) which is induced by therapy-associated genomic damage. From ACS delayed tumor re-growth (re-lapse) occurs from “robust” cell propagation, but mechanisms for such cell escape from senescence are unknown. For TAS-treated a karyoplast bud-off process with change to limited mitotic activity occurred in young senescent cultures. In old, deep senescent (5 - 8 weeks) cultures, unexpectedly escape cell-growth showed three dimensional (3-D) tumor-like spheres from growths of morphologically different cells as compared to the fibroblastic phenotype. These cells expressed cell polarity change, and very condensed nuclei were variously perpendicularly oriented to what-ever cell polarity was present. These results were discussed in regard to in vivo relapse and, to the importance of cell polarity change in tumorigenesis. Induced senescence as an anti-tumor mechanism in therapy treatment becomes a questionable procedure from the present experimental results.
KEYWORDS
Endo-division Perpendicularity, Contact Inhibition, Deep-senescence, Escape-route, Amorphous Flat Cells
Endo-division Perpendicularity, Contact Inhibition, Deep-senescence, Escape-route, Amorphous Flat Cells
Cite this paper
nullK. Walen, "Normal Human Cell Conversion to 3-D Cancer-like Growth: Genome Damage, Endopolyploidy, Senecence Escape, and Cell Polarity Change/Loss," Journal of Cancer Therapy, Vol. 2 No. 2, 2011, pp. 181-189. doi: 10.4236/jct.2011.22023.
nullK. Walen, "Normal Human Cell Conversion to 3-D Cancer-like Growth: Genome Damage, Endopolyploidy, Senecence Escape, and Cell Polarity Change/Loss," Journal of Cancer Therapy, Vol. 2 No. 2, 2011, pp. 181-189. doi: 10.4236/jct.2011.22023.
References
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Hayflick, “Senescent Human Diploid Cells in Culture: Survival, DNA Synthesis and Morphology,” Journal of Gerontology, Vol. 34, 1979, pp. 328-335. [43] K. H. Walen, “Mitosis is not the Only Distributor of Mutated Cells: Non-Mitotic Endopolyploid Cells produce Reproductive Genome Reduced Cells,” Cell Biology International, Vol. 34, 2010, pp. 867-872. doi:10.1042/CBI20090502 [44] K. Nishio, A. Inoue, S. Qiao, H. Kondo and A. Mimura, “Senescence and Cytoskeleton: Overproduction of Vimentin Induces Senescent-Like Morphology in Human Fibroblasts,” Histochemistry and Cell Biology, Vol. 116, No. 4, 2001, pp. 321-327. doi:10.1007/s004180100325 [45] N. E. Sharpless and R. A. DePinho, “Crime and Punishment,” Nature, Vol. 436, 2005, pp. 636-637. doi:10.1038/436636a [46] C. Michaloglou, L. C. W. Vredeveld, M. S. Soengas, C. Denotells, T. Kuilman, C. M. A. M. Van der Horst, D. M. Majoor, J. W. Shay and W. J. Mooi, “BRAF-E600-Associated Senescence-Like Cell Cycle Arrest of Human Naevi,” Nature, Vol. 436, pp. 720-724. doi:10.1038/nature03890
[1] I. B. Roninson, “Tumor Cell Senescence in Cancer Treatment,” Cancer Research, Vol. 63, 2003, pp. 2705- 2715. [2] J. Campisi, “Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens and Bad Neighbors,” Cell, Vol. 120, No. 4, 2005, pp. 513-522. doi:10.1016/j.cell.2005.02.003 [3] J. Bartkova, Z. Horejsi, K. Koed, A. Krammer, F. Tort, K. Zieger, P. Guldberg, M. Sehested, J. M. Nesland, C. Lukas, T. Orntoft, J. Lukas and J. Bartek, “DNA Damage Response as a Candidate Anti-Cancer Barrier in Early Human Tumorigenesis,” Nature, Vol. 434, No. 7035, 2005, pp. 864-870. doi:10.1038/nature03482 [4] C. A. Schmitt, “Cellular Senescence and Cancer Treatment,” Annals of Hematology, Vol. 1775, 2007, pp. 5-20. [5] D. M. Feldser and C. W. Greider, “Short Telomeres Limit Tumor Progression by Inducing Senescence,” Cancer Cell, Vol. 11, No. 5, 2007, pp. 461-469. doi:10.1016/j.ccr.2007.02.026 [6] R. S. Roberson, S. J. Kussick, E. Vallieres, S.-Y. J. Chen and D. Y. Wu, “Escape from Therapy-Induced Accelerated Cellular Senescence in P53-Null Lung Cancer Cells and in Human Lung Cancers,” Cancer Research, Vol. 65, 2005, pp. 2795-2803. doi:10.1158/0008-5472.CAN-04-1270 [7] L. W. Elmore, X. Di, C. Dumur, S. E. Holt, D. A. Gewirtz, “Evasion of a Single-Step, Chemotherapy-Induced Senescence in Breast Cancer Cells: Implications for Treatment Response,” Clinical Cancer Research, Vol. 11, No. 7, 2005, pp. 2637-2643. doi:10.1158/1078-0432.CCR-04-1462 [8] M. Sabisz and A. Skladanowski, “Cancer Stem Cells and Escape from Drug-Induced Premature Senescence in Human Lung Tumor Cells. Implications for Drug Resistance and In Vitro Drug Screening Models,” Cell Cycle, Vol. 8, No. 19, 2009, pp. 3208-3217. doi:10.4161/cc.8.19.9758 [9] C. M. Beausejour, A. Krtolica, F. Galimi, M. Narita, S. W. Lowe, P. Yaswen and J. Campisi, “Reversal of Human Senescence: Roles of P16 and P53 Pathways,” EMBO Journal, Vol. 22, No. 16, 2003, pp. 4212-4222. doi:10.1093/emboj/cdg417 [10] K. H. Walen, “Spontaneous Cell Transformation: Karyoplasts Derived from Multinucleated Cells Produce New Cell Growth in Senescent Human Epithelial Cell Cultures.” In Vitro Cellular & Developmental Biology, Vol. 40, No. 5-6, 2004, pp. 150-158. doi:10.1290/1543-706X(2004)40<150:SCTKDF>2.0.CO;2 [11] K. H. Walen, “Budded Karyoplasts from Multinucleated Fibroblast Cells Contain Centrosomes and Change Their Morphology to Mitotic Cells,” Cell Biology International, Vol. 29, No. 12, 2005, pp. 1057-1065. doi:10.1016/j.cellbi.2005.10.016 [12] K. H. Walen, “Human Diploid Fibroblast Cells in Senescence: Cycling Through Polyploidy to Mitotic Cells,” In Vitro Cellular & Developmental Biology, Vol. 42, No. 7, 2006, pp. 216-224. doi:10.1290/0603019.1 [13] K. H. Walen, “Genetic Stability of Senescence Reverted Cells: Genome Reduction Division of Polypolid Cells, Aneuploidy and Neoplasia,” Cell Cycle, Vol. 7, 2008, pp. 1623-1629. doi:10.4161/cc.7.11.5964 [14] M. Braig, S. Lee, C. Loddenkemper, C. Rudolph, A. H. Petrs, B. Schleglberger, H. Stein,B. Dorken, T. Jenuwein and C. A. Schmitt, “Oncogen-Induced Senescence as an Initial Barrier in Lymphoma Development,” Nature, Vol. 436, 2005, pp. 660-665. doi:10.1038/nature03841 [15] P.-E. Puig, M.-N. Guilly, A. Bouchot, N. Droin, D. Cathelin, F. Boyer, L. Favier, F. Ghiringhelli, G. Kroemer, E. Solari, F. Martin and B. Chauffert, “Tumor Cells can Escape DNA-Damaging Cisplatin Through DNA Endoreduplication and Reversible Polyploidy,” Cell Biology International, Vol. 32, No. 9, 2008, pp. 1031-1043. doi:10.1016/j.cellbi.2008.04.021 [16] D. N. Wheatley, “Groving Evidence of the Re-population of Regressed Tumors by the Division of Giant Cells,” Cell Biology International, Vol. 32, No. 9, 2008, pp. 1029-1030. doi:10.1016/j.cellbi.2008.06.001 [17] M. V. Blagosklonny, “Cancer Stem Cell and Cancer Stemloids.” Cancer Biology and Therapy, Vol. 6, No. 11, 2007, pp. 1684-1690. doi:10.4161/cbt.6.11.5167 [18] C. A. Schmitt, J. S. Fridman, M. Yang, S. Lee. E. Baranov, R. M. Hoffman and S. W. Lowe, “A Senescence Program Controlled by P53 and P16Ink4a Contributes to the Outcome of Cancer Therapy,” Cell, Vol. 109, No. 3, 2002, pp. 335-346. doi:10.1016/S0092-8674(02)00734-1 [19] J. H. Chen and S. E. Ozanne, “Deep Senescent Human Fibroblasts Show Diminished DNA Damage Foci but Retain Checkpoint Capacity to Oxidative Stress,” FEBS Letters, Vol. 580, No. 28, 2006, pp. 6669-6673. doi:10.1016/j.febslet.2006.11.023 [20] E. M. Munrov, “PAR Proteins and the Cytoskeleton: A Marrige of Equals,” Current Opinion in Cell Biology, Vol. 18, No. 1, 2006, pp. 86-94. doi:10.1016/j.ceb.2005.12.007 [21] S. Yoshida and D. Pellman, “Plugging the GAP between Cell Polarity and Cell Cycle,” EMBO Reports, Vol. 9, No. 1, 2008, pp. 39-41. doi:10.1038/sj.embor.7401142 [22] A. Wodarz and I. Nathke, “Cell Polarity in Development and Cancer,” Nature Cell Biology, Vol. 9, No. 9, pp. 1016-1024. doi:10.1038/ncb433 [23] P. Gonczy, “Mechanisms of Asymmetric Cell Division: Flies and Worms Pave the Way,” Nature Review, Vol. 9, No. 5, 2008, pp. 355-366. doi:10.1038/nrm2388 [24] K. G. Grell and A. Ruthmann, “Uber Die Karyologie des Radiolars Aulachantha scolymantha und die Feinstruktur Seiner Chromosomen,” Chromosoma, Vol. 15, 1964, pp. 185-211. doi:10.1007/BF00285729 [25] K. H. Walen, “Bipolar Genome Reductional Division of Human Near-Senescent, Polyploid Fibroblast Cells,” Cancer Genet Cytogenet, Vol. 173, 2007, pp.43-50. doi:10.1016/j.cancergencyto.2006.09.013 [26] K. H. Walen, “Origin of Dipochromosomal Polyploidy in Near-Senescent Fibroblast Cultures: Heterochromatin, Telomeres and Chromosomal Instability,” Cell Biology International, Vol. 31, 2007, pp. 1447-1455. doi:10.1016/j.cellbi.2007.06.015 [27] L. P. Bignold, B. L. D. Coghlan and H. P. A. Jersmann, “David von Hansemann: Contributions to Oncology: Context, Comment, and Translations,” Birkhauser Verlag, Basel, Switzerland, 2007. [28] D. J. Galgoczy and D. P. Toczyski, “Checkpoint Adaptation Precedes Spontaneous and Damage-Induced Genomic Instability in Yeast,” Molecular and Cellular Biology, Vol. 21, No. 5, 2001, pp. 1710-1718. doi:10.1128/MCB.21.5.1710-1718.2001 [29] D. Brito and C. L. Rieder, “Mitotic Slippage in Humans Occurs Via Cyclin B Destruction in the Presence of an Active Checkpoint,” Current Biology, Vol. 16, No. 12, 2006, pp. 1194-2001. doi:10.1016/j.cub.2006.04.043 [30] K. H. Walen, “Spindle Apparatus Uncoupling in Endo-Tetraploid Asymmetric Division of Stem and Non-Stem Cells,” Cell Cycle, Vol. 8, 2009, pp. 3234- 3237. doi:10.4161/cc.8.19.9570 [31] L. Hayflick and P. S. Moorhead, “The Serial Cultivation of Human Diploid Cell Strains,” Experimental Cell Research, Vol. 25, 1961, pp. 585-621. doi:10.1016/0014-4827(61)90192-6 [32] J. J. Freed and S. A. Schatz, “Chromosome Aberrations in Cultured Cells Deprived of Single Essential Amino Acid,” Experimental Cell Research, Vol. 55, 1969, pp. 393-409. doi:10.1016/0014-4827(69)90574-6 [33] R. Phillip, E. Campbell and D. N. Wheatley, “Arginine Deprivation, Growth Inhibition and Tumor Cell Death: 2. Enzymatic Degradation of Arginine in Normal and Malignant Cell Cultures,” British Journal of Cancer, Vol. 88, 2003, pp.613-623. doi:10.1038/sj.bjc.6600681 [34] B. Y. Lee, J. A. Han, J. S. Im, A. Morrone, K. Johung, E. C. Goodwin. W. Kleijer, D. DiMaio and E. S. Hwang, “Senescence-Associated Beta-Galactosidase is Lysosomal Beta-Galactosidase,” Aging Cell, Vol. 5, 2006, pp. 187-195. doi:10.1111/j.1474-9726.2006.00199.x [35] D. M. Feldser, J. A. Hackett and C. W. Greider, “Telomere Dysfunction and Initiation of genome Instability,” Nature Reviews Cancer, Vol. 53, 2003, pp. 623-627. [36] J. R. Smith and O. Pereira-Smith, “Replicative Senescence: Implications for IN Vivo Aging and Tumor Suppression.” Science, Vol. 273, No. 5271, 1996, pp. 63-67. doi:10.1126/science.273.5271.63 [37] W. S. Saunders, M. Shuster, X. Huang, B. Gharaibe, A. H. Enyenihi, I. Petersen and S. M. Gollin, “Chromosomal Instability and Cytoskeletal Defects in Oral Cancer,” Proceedings of the National Academy of Sciences, Vol. 97, No. 1, 2000, pp. 303-308. doi:10.1073/pnas.97.1.303 [38] V. Gire and D. Wynford-Thomas, “Reinitiation of DNA Synthesis and Cell Division in Senescent Human Fibroblasts by Microinjection of Anti-P53 Antibodies,” Molecular and Cellular Biology, Vol. 18, 1998, pp. 1611- 1621. [39] A. M. Dirac and R. Bernards, “Reversal of Senescence in Mouse Fibroblasts through Lentiviral Suppression of P53,” Journal of Biological Chemistry, Vol. 278, 2003, pp. 11731-11734. doi:10.1074/jbc.C300023200 [40] D. M. Baird, “Telomeres II,” Experimental Gerontology, Vol. 43, 2008, pp. 15-19. [41] V. J. Cristofalo and B. B. Sharf, “Cellular Senescence and DNA Synthesis. Thymidine Incorporation as a Measure of Population Age in Human Diploid Cells,” Experimental Cell Research, Vol. 76, 1973, pp. 419-427. doi:10.1016/0014-4827(73)90394-7 [42] T. Matsumura, Z. Zerrudo and L. Hayflick, “Senescent Human Diploid Cells in Culture: Survival, DNA Synthesis and Morphology,” Journal of Gerontology, Vol. 34, 1979, pp. 328-335. [43] K. H. Walen, “Mitosis is not the Only Distributor of Mutated Cells: Non-Mitotic Endopolyploid Cells produce Reproductive Genome Reduced Cells,” Cell Biology International, Vol. 34, 2010, pp. 867-872. doi:10.1042/CBI20090502 [44] K. Nishio, A. Inoue, S. Qiao, H. Kondo and A. Mimura, “Senescence and Cytoskeleton: Overproduction of Vimentin Induces Senescent-Like Morphology in Human Fibroblasts,” Histochemistry and Cell Biology, Vol. 116, No. 4, 2001, pp. 321-327. doi:10.1007/s004180100325 [45] N. E. Sharpless and R. A. DePinho, “Crime and Punishment,” Nature, Vol. 436, 2005, pp. 636-637. doi:10.1038/436636a [46] C. Michaloglou, L. C. W. Vredeveld, M. S. Soengas, C. Denotells, T. Kuilman, C. M. A. M. Van der Horst, D. M. Majoor, J. W. Shay and W. J. Mooi, “BRAF-E600-Associated Senescence-Like Cell Cycle Arrest of Human Naevi,” Nature, Vol. 436, pp. 720-724. doi:10.1038/nature03890