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Wound Healing Is a First Response in a Cancerous Pathway: Hyperplasia Developments to 4n Cell Cycling in Dysplasia Linked to Rb-Inactivation

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DOI: 10.4236/jct.2015.610099    2,143 Downloads   2,408 Views   Citations


In a series of publications, the hypothesis of a special-type of endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the initiation of tumorigenesis has been presented from in vitro experiments. This review uses cellular happenings in benign pre-neoplasia to substantiate this idea, which appears to be linked to the wound-healing process of injured tissue. Rarer association between a wound healing process and a cancer occurrence has long been known. The wound healing multi-program-system involved a phase of tetraploidy that showed diplochromosomes. The hypothesis is that the inflammatory phase may not always be sufficient in getting rid of dead and damaged cells (by apoptosis and autophagy), such that cells with genomic damage (DNA breakage) may survive by genomic repair associated with change to diplochromosomal tetraploidy. In vitro data have shown division of these cells to be an orderly, mechanistic two-step, meiotic-like system, resulting in only two types of progeny cells: 4n/4C/G1 and 2n/2C/G1 pseudo-diploid cells with hyperplastic-like growth-morphology. In vivo damage to tissues can be from many sources for example, physical, toxic environment or from a disease as in Barrett’s esophagus (BE) with acid reflux into the esophagus. For this condition, it is acknowledged that damage of the esophagus lining is a pre-condition to hyperplastic lesions of pre-neoplasia. These initial lesions were from “diploid” propagating cells and, 4n cells with G2 genomic content (no mitosis) accumulated in these lesions before a change to dysplasia. Cell cycle kinetics put these 4n cells in G1, which with S-phase entry would lead to asymmetric tetraploid mitoses, characteristic for dysplastic lesions. This change in hyperplasia to dysplasia is the root-essential condition for a potential progression of pre-neoplasia to cancer. In BE the hyperplastic lesion showed increasing gains of cells with inactivated p53 and p16[ink4a] genes, which destroyed the retinoblastoma (Rb) protein-control over S-phase entry from G1. Rb-protein is a key controller of cycling advancement from G1 (also for normal cells), and is frequently inactivated in tumor cells. Thus in BE, 4n/4C/G1 cells with mutated p53 and p16[ink4a] genes gained cycling ability to tetraploid aneuploid cell cycles, which constituted the change from hyperplasia to dysplastic lesions. In general, such lesions have high predictive value for a cancerous change. Proliferation rates of pre-neoplasia and progression have been shown to be increased by a component of the wound healing program.

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The authors declare no conflicts of interest.

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Walen, K. (2015) Wound Healing Is a First Response in a Cancerous Pathway: Hyperplasia Developments to 4n Cell Cycling in Dysplasia Linked to Rb-Inactivation. Journal of Cancer Therapy, 6, 906-916. doi: 10.4236/jct.2015.610099.


[1] Bozic, I., Antal, T., Obtsuki, H., Carter, H., Kim, D., Chen, S., Karchin, R., Kinzler, K.W., Vogelstein, B. and Nowak, M.A. (2010) Accumulation of Driver and Passenger Mutations during Tumor Progression. Proceedings of the National Academy of Sciences, 107, 18545-18550.
[2] Nowak, M.A., Komarova, N.L., Sengupta, A., Jallepalli, P.V., Shih, L.-M. and Vogelstein, B. (2002) The Role of Chromosomal Instability in Tumor Initiation. Proceedings of the National Academy of Sciences, 99, 16226-16231.
[3] Vogelstein, B. and Kinzler, K.W. (1993) The Multistep Nature of Cancer. TIG, 9, 138-141.
[4] Shabad, L.M. (1973) Precancerous Morphologic Lesions. JNCI, 50, 1421-1428.
[5] Albertson, D.G., Collins, C., McCormick, F. and Gray, J.W. (2003) Chromosome Aberrations in Solid Tumors. Nature Genetics, 14, 369-376.
[6] Mitelman, F. (1988) Catalog of Chromosome Aberrations in Cancer. Alan Liss, Inc., New York.
[7] Heim, S. and Mitelman, F. (1995) Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells. 2nd Edition, Wiley-Liss, Inc., New York.
[8] Bignold, L.P., Coghlan, B.L.D. and Jersmann, H.P.A. (2007) David von Hansemann: Contributions to Oncology Context Comments and Translations. Birkhauser Verlag, Basel.
[9] Ermis, A., Oberringer, M., Wirbel, R., Koschnick, M., Mutschler, W. and Hanselmann, R.G. (1998) Tetraploidization Is a Physiological Enhancer of Wound Healing. European Surgical Research, 30, 385-392.
[10] Oberring, M., Lothschutz, D., Jennewein, M., Koschnick, M., Mutschler, W. and Hanselmann, R.G. (1999) Centrosome Multiplication Accompanies a Transient Clustering of Polyploidy Cell during Repair. Molecular Cell Biology Research Communications, 2, 190-196.
[11] Erenpreisa, J. (2014) Cancer Is Ontogenetically Pre-Programmed. MEDIC, 22, 24-27.
[12] Vinnitsky, V. (2014) The Development of a Malignant Tumor Is Due to a Desperate Asexual Self-Cloning Process in Which Cancer Stem Cells Develop the Ability to Mimic the Genetic Program of Germline Cells. Intrinsically Disordered Proteins, 2, Article ID: e29997.
[13] Walen, K.H. (2013) Normal Human Cells Acquiring Proliferative Advantage to Hyperplasia-Like Growth-Morphology: Aberrant Progeny Cells Associated with Endopolyploid and Haploid Divisions. Cancer and Clinical Oncology, 2, 1-15.
[14] Walen, K.H. (2014) Neoplastic-Like Cell Changes of Normal Fibroblast Cells Associated with Evolutionary Conserved Maternal and Paternal Genomic Autonomous Behavior (Gonomery). Journal of Cancer Therapy, 5, 860-877.
[15] Hurst, L.D. and Nurse, P. (1991) A Note on the Evolution of Meiosis. Journal of Theoretical Biology, 150, 561-563.
[16] Weinberg, R.A. (2014) Coming Full Circle—From Endless Complexity to Simplicity and Back Again. Cell, 157, 267-271.
[17] Walen, K.H. (2006) Human Diploid Fibroblast Cells in Senescence: Cycling through Polyploidy to Mitotic Cells. In Vitro Cellular & Developmental Biology—Animal, 42, 216-224.
[18] Davoli, T., Denchi, E.L. and de Lange, T. (2010) Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy. Cell, 141, 81-93.
[19] Davoli, T. and de Lange, T. (2012) Telomere-Driven Tetraploidization Occurs in Human Cells Undergoing Crisis and Promotes Transformation of Mouse Cells. Cancer Cell, 21, 765-776.
[20] Walen, K.H. (2007) Bipolar Genome Reductional Division of Human Near-Senescent, Polyploid Fibroblast Cells. Cancer Genetics and Cytogenetics, 173, 43-50.
[21] Walen, K.H. (2008) Genetic Stability of Senescence Reverted Cells: Genome Reduction Division of Polyploid Cells, Aneuploidy and Neoplasia. Cell Cycle, 7, 1623-1629.
[22] Walen, K.H. (2009) Spindle Apparatus Uncoupling in Endo-Tetraploid Asymmetric Division of Stem and Non-Stem Cells. Cell Cycle, 8, 3234-3237.
[23] Brand, K.G. (1982) Cancer Associated with Asbestos, Schitosomiasis, Foreign Bodies, and Scars. In: Becker, F.F., Ed., Cancer: A Comprehensive Treatise, Plenum Press, New York, 661-692.
[24] Walen, K.H. (2015) Cancers in Children Ages 8 to 12 Are Injury-Related. Journal of Cancer Therapy, 6, 177-181.
[25] Bibbo, M., Dytch, H.E., Alenghat, E., Bartels, P.H. and Wied, G.L. (1989) DNA Ploidy Profiles as Prognostic Indicators in CIN Lesions. American Journal of Clinical Pathology, 92, 261-265.
[26] Bibbo, M. and Wilbur, D. (2014) Comprehensive Cytopathology. 4th Edition, Elsevier Health, Philadelphia.
[27] Brito, D. and Rieder, C.L. (2006) Mitotic Slippage in Humans Occurs via Cyclin B Destruction in the Presence of an Active Checkpoint. Current Biology, 16, 1194-2000.
[28] Strom, L., Karlsson, C., Lindroos, H.B., Wedahl, S., Katou, Y., et al. (2007) Postreplicative Formation of Cohesion Is Required for Repair and Induced by a Single DNA Break. Science, 317, 242-248.
[29] Watrin, E. and Peters, J.M. (2006) Cohesin and DNA Damage Repair. Experimental Cell Research, 312, 2687-2693.
[30] Unal, E., Heidinger-Pauli, J.M. and Koshland, D. (2007) DNA Double-Strand Breaks Trigger Genome-Wide Sister-Chromatid Cohesion through Eco1 (Ctf7). Science, 317, 245-248.
[31] Uhlmann, F. (2009) A Matter of Choice: The Establishment of Sister Chromatid Cohesion. EMBO Reports, 10, 1095-1102.
[32] Walen, K.H. (1965) Spatial Relationships in the Replication of Chromosomal DNA. Genetics, 51, 915-929.
[33] Walen, K.H. (2012) Genome Reversion Process of Endopolyploidy Confers Chromosome Instability on Descendent Diploid Cells. Cell Biology International, 36, 137-145.
[34] Puig, P.E., Guilly, M.N., Bouchot, A., Droin, N., Cathelin, D., Bouyer, F., et al. (2008) Tumor Cell Can Escape DNA-Damaging Sisplatin through DNA Endoreduplication and Reversible Polyploidy. Cell Biology International, 32, 1031-1043.
[35] Martin, F., Puig, P.-E., Ghiringhelli, F. and Chauffert, B. (2009) DNA-Damaged Popyploid Cancer Cells Reverse to Diploidy: An Ordered, but Little Understood, Process of Genomic Reduction [With Reference to the Previous Comments of Forer (2008) and Wheatley (2008a and b)]. Cell Biology International, 33, 702-703.
[36] Forer, A. (2008) Ploidy and Division in Cancer and Mosquito Hind Gut Cells. Cell Biology International, 33, 247-252.
[37] Levan, A. and Hauschka, T.S. (1953) Endomitotic Reduplication Mechanisms in Ascites Tumors of the Mouse. Journal of the National Cancer Institute, 14, 1-43.
[38] Kuhn, E.M. (1981) A High Incidence of Mitotic Chiasma in Endoreduplicated Bloom’s Syndrome. Human Genetics, 58, 417-421.
[39] Kuhn, E.M. and Therman, E. (1986) Cytogenetics of Bloom’s Syndrome. Cancer Genetics and Cytogenetics, 22, 1-18.
[40] Zybina, E.V., Zybina, T.G., Bogdanova, M.S. and Stein, G.I. (2005) whole-Genome Chromosome Distribution during Nuclear Fragmentation of Giant Cells of Microtus rossiae-meridonalis Studies by Use of Gonosomal Chromatin Arrangement. Cell Biology International, 29, 1066-1070.
[41] Haig, D. (1993) Alternatives to Meiosis: The Unusual Genetics of Red Algae, Microsporidia and Others. Journal of Theoretical Biology, 163, 15-31.
[42] Stern, C. (1936) Somatic Crossing-Over and Segregation in Drosophila melanogaster. Genetics, 21, 625-730.
[43] Walen, K.H. (2011) Normal Human Cell Conversion to 3-D Cancer-Like Growth: Genome Damage, Endopolyploidy, Senescence Escape, and Cell Polarity Change/Loss. Journal of Cancer Therapy, 2, 181-189.
[44] Freed, J.J. and Schatz, S.A. (1969) Chromosome Aberrations in Cultured Cells Deprived of Single Essential Amino Acids. Experimental Cell Research, 55, 393-409.
[45] Cantor, J.R. and Sabatini, D.M. (2012) Cancer Cell Metabolism: One Hallmark, Many Faces. Cancer Discovery, 2, 881-898.
[46] Deberardinis, R.J. and Cheng, T. (2010) Q’s Next: The Diverse Function of Glutamine in Metabolism, Cell Biology and Cancer. Oncogene, 29, 313-324.
[47] Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Hiroaki, I., Paolino, M., Sigl, V., Hanada, T., Hanada, R., et al. (2012) ACE2 Links Amino Acid Malnutrition to Microbial Ecology and Intestinal Inflammation. Nature, 487, 477-481.
[48] Rohstein, R., Michel, B. and Gangloff, S. (2000) Replication Fork Pausing and Recombination or “Gimme a Break”. Genes & Development, 14, 1-10
[49] Weinert, T. (2007) What a Cell Should Know (But May Not). Science, 315, 1374-1375.
[50] Walen, K.H. (2013) Senescence Arrest of Endopolyploid Cells Renders Senescence into One Mechanism for Positive Tumorigenesis. In: Hayat, M.A., Ed., Tumor Dormancy and Cellular Quiescence and Senescence, Springer, Berlin, 215-226.
[51] Belge, G., Roque, L., Soares, J., Bruckmann, S., Thode, B., Fonseca, E., Clode, A., Bartnitzke, S., et al. (1998) Cytogenetic Investigation of 340 Thyroid Hyperplasias and Adenoma Revealing Correlations between Cytogenetic Findings and Histology. Cancer Genetics and Cytogenetics, 101, 42-48.
[52] Bignold, L.P. (2003) Initiation of Genetic Instability and Tumor Formation: A Review and Hypothesis of a Nongenotoxic Mechanism. Cellular and Molecular Life Sciences, 60, 1107-1117.
[53] Steinbeck, R.G. (2004) Dysplasia in View of the Cell Cycle. European Journal of Histochemistry, 48, 203-211.
[54] Bhardwaj, A., Stairs, D.B., Mani, H. and McGarrity, T.J. (2012) Barrett’s Esophagus: Emerging Knowledge and Strategies. Pathology Research International, 2012, 1-20.
[55] Chang, H.Y., Sneddon, J.B., Alizadeh, A.A., Sood, R., West, R.B., Montgomery, K. and Chi, J.-T. (2004) Gene Expression Signature of Fibroblast Serum Response Predicts Cancer Progression: Similarities between Tumors and Wounds. PLoS Biology, 2, e7.
[56] Orimo, A., Gupta, P.B., Sgroi, D.C., Arenzana-Seisdedos, F., Delanuay, T., Naeem, R., et al. (2005) Stromal Fibroblasts Present in Invasive Human Breast Carcinoma Promote Tumor Growth and Angiogenesis through Elevated SDF-1/ CXCL 12 Secretion. Cell, 121, 335-348.
[57] Gallipeau, C., Cowan, D.S., Sanchez, C.A., Barrett, M.T., Emond, M.J., Levine, D., Rabinovitch, P.S. and Reid, B.J. (1996) 17p (p53) Allelic Losses, 4n (G2/Tetraploid) Populations, and Progression to Aneuploidy in Barrett’s Esophagus. Proceedings of the National Academy of Sciences of the United States of America, 93, 7081-7084.
[58] Barrett, M.T., Pritchard, D., Palanca-Wessels, C., Anderson, J., Reid, B.J. and Rabinovitch, P.S (2003) Molecular Phenotype of Spontaneously Arising 4N (G2-Tetraploid) Intermediates of Neoplastic Progression in Barrett’s Esophagus. Cancer Research, 63, 4211-4217.
[59] Reid, B.J., Sanches, C.A., Blount, P.L. and Levine, D.S. (1993) Barrett’s Esophagus Cell Cycle Abnormalities in Advancing Stages of Neoplastic Progression. Gastroenterology, 105, 119-129.
[60] Reid, B.J., Prevo, L.J., Galipeau, P.C., Sanchez, A., Longton, G., et al. (2001) Predictors of Progression in Barrett’s Esophagus II: Baseline 17p (p53) Loss of Heterozygosity Identifies a Patient Subset with Increased Risk for Neoplastic Progression. American Journal of Gastroenterology, 96, 2839-2848.
[61] Rabinovitch, P.S., Longton, G., Blount, P.L., Levine, D.S. and Reid, B.J. (2001) Predictors of Progression in Barrett’s Esophagus III: Baseline Flow Cytometric Variables. American Journal of Gastroenterology, 96, 3071-3083.
[62] Maley, C.C., Galipeau, P.C., Finley, J.C., Wongsurawat, J., Li, X., Sanchez, C.A., Paulson, T.G., Blout, P.L., et al. (2006) Genetic Clonal Diversity Predicts Progression to Esophageal Adenocarcinoma. Nature, 38, 468-473.
[63] Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger, K., et al. (2005) DNA Damage Response as a Candidate Anti-Cancer Barrier in Early Human Tumorigenesis. Nature, 434, 864-870.
[64] Palanca-Wessels, M.C. (1999) In Vitro Analysis of Cultured Barrett’s Esophagus Cells: Insights into Mechanisms of Genomic Instability and Possible Therapeutic Strategies. PhD Thesis, University of Washington, Seattle.
[65] Sherwood, S.W., Rush, D., Ellsworth, J.L. and Schimke, R. (1988) Defining Cellular Senescence in IMR-90 Cells: A Flow Cytometric Analysis. Proceedings of the National Academy of Sciences of the United States of America, 85, 9086-9090.
[66] Wood, L.D., Parsons, D.W., Jones, S., Lin, J., Sjoblom, T., Leary, R.J., et al. (2007) The Genomic Landscapes of Human Breast and Colorectal Cancer. Science, 318, 1108-1113.
[67] Hartman, A., Moser, K., Kriegmair, M., Hofstetter, A., Hofstaedter, F. and Knuechel, R. (1999) Frequent Genetic Alterations in Simple Urothelial Hyperplasias of the Bladder in Patients with Papillary Urothelial Carcinoma. American Journal of Pathology, 154, 721-727.
[68] Wong, D.J., Paulson, T.G., Prevo, L.J., Galipeau, P.C., Longton, G., et al. (2001) p16[Ink4a] Lesions Are Common, Early Abnormalities That Undergo Clonal Expansion in Barrett’s Metaplastic Epithelium. Cancer Research, 61, 8284-8289.
[69] Rabinovitch, P.S., Dzisdon, S., Brentnail, T.A., Emond, M.J., Crispin, D.A., et al. (1999) Pancolonic Chromosomal Instability Precedes Dysplasia and Cancer in Ulcerative Colitis. Cancer Research, 59, 5148-5153.
[70] Morales, C.P., Souza, R.F. and Spechler, S.J. (2002) Hallmarks of Cancer Progression in Barrett’s Oesophagus. The Lancet, 360, 1587-1589.
[71] Gorgoulis, V.G., Vassiliou, L.V.F., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., et al. (2005) Activation of the DNA Damage Checkpoint and Genomic Instability in Human Precancerous Lesions. Nature, 434, 907-912.
[72] Van Dekken, H., Vissers, C.J., Tilanus, H.W., Tanke, H.J. and Rosenberg, C. (1999) Clonal Analysis of a Case of Multifocal Oesophageal (Barrett’s) Adenocarcinoma by Comparative Genomic Hybridization. Journal of Pathology, 188, 263-266.<263::AID-PATH374>3.0.CO;2-Y
[73] Fox, D.T. and Duronio, R.J. (2013) Endoreplication and Polyploidy: Insight into Development and Disease. Development, 140, 3-12.
[74] Heng, H.H., Liu, G., Stevens, J.B., Abdallah, Y., Horne, S.D., Ye, K.J., Bremer, S.W., Chowdhury, S.K. and Ye, C.J. (2013) Karyotype Heterogeneity and Unclassified Chromosomal Abnormalities. Cytogenetic and Genome Research, 139, 144-157.
[75] Van Harn, T., Foijer, F., Van Vugt, M., Banerjee, R., Yang, F., et al. (2010) Loss of Rb Proteins Causes Genomic Instability in the Absence of Mitogenic Signaling. Genes & Development, 24, 1377-1388.
[76] Manning, A.L., Longworth, M.S. and Dyson, N.J. (2010) Loss of RB Causes Centromere Dysfunction and Chromosomal Instability. Genes & Development, 24, 1364-1376.
[77] Sage, J., Miller, A.L., Perez-Mancera, P.A., Wysocki, J.M. and Jacks, T. (2003) Acute Mutation of Retinoblastoma Gene Function Is Sufficient for Cell Cycle Re-Entry. Nature, 424, 223-228.
[78] Antonio, N., Bonnelykke-Behrndtz, M.L., Ward, L.C., Collin, J., Christensen, I.J., Steiniche, T., et al. (2015) The Wound Inflammatory Response Exacerbates Growth of Pre-Neoplastic Cells and Progression. The EMBO Journal, 34, 2219-2236.
[79] Agrawal, N., Jiao, Y., Bettegowda, C., Hutfless, S.M., Wang, Y., David, S., et al. (2012) Comparative Genomic Analysis of Esophageal Adenocarcinoma and Squamous Cell Carcinoma. Cancer Discovery, 2, 899-905.
[80] Collisson, E.A. and Cho, R.J. (2012) Histology, Anatomy, or Geography? Exome Sequencing Begins to Delineate Somatic Mutational Differences in Esophageal Cancer. Cancer Discovery, 2, 870-871.

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