Official (NIH) cancer investigation is on identification of inherited cancer genes in you and me for early interventions, and for use of such knowledge in therapy. In this review the emphasis is on the unknown cancer initiation, and on the question of a mechanism for inherited CIN (chromosomal instability). Evidence for fitness increased cells from the mitotic slippage process ( in vivo/in vitro ) originated from genome damaged diploid cells in G2/M, skipping mitosis to G1, which illegitimately permitted S-phase re-replication of the chromatid cohesed-2n cells to 4n-tetraploidy. During which, down-load of genome-wide cohesin occurred, producing 4-chromatid diplochromosomes, evolutionary conserved in repair of DNA. This type of 4n cells divided 2-step meiotic-like, leading to diploid aneuploid cells with increased fitness, and expression of gross chromosomal anomalies in proliferation. The diploid cohesed chromatids during re-replication would hinder replication of sticky heterochromatic regions, resulting in their under-replication, and known from Drosophila. The human chromosomes are longitudinally differentiated into satellite DNA regions, folic acid sensitive sites and the primary constriction (centromere); they are breakage sensitive regions and being heterochromatic. This strongly suggests, multiple, chromosomal regional under-replication-cites, translated to origin of slippage, S-CIN, a genome inherited destabilization mechanism. Logically, S-CIN would affect genes differentially depending on chromosome location, for example, the high frequency in cancers of mutated p53 on the small 17p-arm, which with centromere breakage would be preferentially lost in mitosis. This likely S-CIN mechanism in cancer evolution can be studied in vivo for APC mutated crypt cells with demonstrated mitotic slippage process.
Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: the Next Generation. Cell, 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
Sioud, M. (2007) An Overview of the Immune System and Technical Advances in Tumor Antigen Discovery and Validation. Method in Molecular Biology, 360, 277-318.
Liu, J.K. (2014) Anti-Cancer Vaccines—A One Hit Wonder? The Yale Journal of Biology and Medicine, 87, 481-489.
Kleponis, J., Skelton, R. and Zheng, L. (2015) Fueling the Engine and Releasing the Break: Combinational Therapy of Cancer Vaccines and Immune Checkpoint Inhibitors. Cancer Biology and Medicine, 12, 201-208.
Blagosklonny, M.V. (2007) Cancer Stem Cell and Cancer Stemloids. Cancer Biology & Therapy, 6, 1684-1690. https://doi.org/10.4161/cbt.6.11.5167
Cleveland, D.A. (2016) Prioritizing Good Diets. Science, 354, 1385. https://doi.org/10.1126/science.aak9923
Teicholz, N. (2014) The Big FAT Surprise: Why Butter, Meat & Cheese Belong in a Healthy Diet. Simon & Schuster, New York.
Lengauer, C., Kinzler, K.W. and Vogelstein, B. (1998) Genetic Instability in Human Cancers. Nature, 396, 643-649. https://doi.org/10.1038/25292
Kinzler, K.W., Nowak, M.A., Komarova, N.L., Sengupta, A., Jallepalli, P.V., Shih, M. and Vogelstein, B. (2002) The Role of Chromosomal Instability in Tumor Initiation. Proceedings of the National Academy of Sciences of the United States of America, 99, 16226-16231. https://doi.org/10.1073/pnas.202617399
Barber, T.D., McManus, K., Yuen, K.W.Y., Teis, M., Parmigiani, G., Shen, D., et al. (2008) Chromatid Cohesion Defects May Underlie Chromosome Instability in Human Colorectal Cancers. Proceedings of the National Academy of Sciences of the United States of America, 105, 3443-3448. https://doi.org/10.1073/pnas.0712384105
Vincent, M.D. (2010) The Animal within: Carcinogenesis and Clonal Evolution of Cancer Cells are Speciation Events Sensu Stricto. Evolution, 64, 1173-1183. https://doi.org/10.1111/j.1558-5646.2009.00942.x
Tomasetti, C., Marchionni, L., Nowak, M.A., Parmigiani, G. and Vogelstein, B. (2015) Only Three Driver Gene Mutations Are Required for the Development of Lung and Colorectal Cancers. Proceedings of the National Academy of Sciences of the United States of America, 112, 118-123. https://doi.org/10.1073/pnas.1421839112
Kaiser, J. (2012) Cancer Genetics with an Edge. Science, 337, 282-284. https://doi.org/10.1126/science.337.6092.282
DNA Damage/Repair
Aneuploid Diploidy
Walen, K.H. (2016) Cancer Prevention: Fundamental Genomic Alterations Are Present in Preneoplasia Including Function of High Frequency Selected Mutations (HFSM). Journal of Cancer Therapy, 7, 416-426. https://doi.org/10.4236/jct.2016.76044
Beroukhlim, R., Mermel, C.H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J.S., Bobson, J., et al. (2010) The Landscape of Somatic Copy Number Alterations across Human Cancers. Nature, 463, 899-905. https://doi.org/10.1038/nature08822
Davoli, T., Uno, H., Wooten, E.C. and Elledge, S.J. (2017) Tumor Aneuploidy Correlates with Markers of Immune Evasion and with Reduced Response to Immunotherapy. Science, 355, 261. https://doi.org/10.1126/science.aaf8399
Walen, K.H. (2006) Human Diploid Fibroblast Cells in Senescence: Cycling from Polyploidy to Mitotic Cells. In Vitro Cellular & Developmental Biology—Animal, 42, 216-224. https://doi.org/10.1290/0603019.1
Walen, K.H. (2007) Bipolar Genome Reductional Division of Human Near-Senescent, Polyploid Fibroblast Cells. Cancer Genetics and Cytogenetics, 173, 43-50.
Walen, K.H. (2010) Mitosis Is Not the Only Distributor of Mutated Cells: Non-Mitotic Endopolyploid Cells Produce Reproductive Genome-Reduced Cells. Cell Biology International, 34, 867-872. https://doi.org/10.1042/CBI20090502
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. https://doi.org/10.4236/jct.2011.22023
Walen, K.H. (2012) Genome Reversion Process of Endopolyploidy Confers Chromosome Instability on the Descendent Diploid Cells. Cell Biology International, 36, 1-9. https://doi.org/10.1042/CBI20110052
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, 19-33. https://doi.org/10.5539/cco.v2n2p19
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, Vol. 1, 215-226. https://doi.org/10.1007/978-94-007-5958-9_18
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. https://doi.org/10.4236/jct.2014.59094
Walen, K.H. (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. https://doi.org/10.4236/jct.2015.610099
Walen, K.H. (2015) Cancers in Children Ages 8 to 12 Are Injury-Related. Journal of Cancer Therapy, 6, 177-181. https://doi.org/10.4236/jct.2015.62020
Wood, L.D., Parsons, D.W., Jones, S., Lin, J., Sjoblom, T., Leary, R.J., et al. (2007) The Genomic Landscape of Human Breast and Colorectal Cancer. Science, 318, 1108-1113. https://doi.org/10.1126/science.1145720
Weinberg, R.A. (2014) Coming Full Circle—From Endless Complexity to Simplicity and Back Again. Cell, 157, 267-271.
Collins, F.S. and Varmus, H. (2015) A New Initiative on Precision Medicine. The New England Journal of Medicine, 372, 793-795. https://doi.org/10.1056/NEJMp1500523
Malkin, D., Garber, J.E., Strong, L.C. and Friend, S.H. (2016) The Cancer Predisposition Revolution: How Was the Inherited Basis of Cancer Foreshadowed? Science, 352, 1052-1053. https://doi.org/10.1126/science.aag0832
Kinzler, K.W. and Vogelstein, B. (1996) Lessons from Hereditary Colorectal Cancer. Cell, 87, 159-170.
Watson, I.R., Takahashi, K., Futreal, P.A. and Chin, L. (2013) Emerging Patterns of Somatic Mutations in Cancer. Nature Reviews Genetics, 14, 703-718. https://doi.org/10.1038/nrg3539
Garraway, L.A. and Lander, E.S. (2013) Lessons from Cancer Genome. Cell, 153, 17-37.
Boeke, J.D., Church, G., Hessel, A., Kelley, N.J., Arkin, A., Cai, Y., Carlson, R., et al. (2016) The Genome Project-Write: We Need Technology and an Ethical Framework for Genome-Scale Engineering. Science, 353, 126-127. https://doi.org/10.1126/science.aaf6850
Hey, S.P. and Kesselheim, A.S. (2016) Countering Imprecisions in Precision Medicine: Better Coordination Is Needed to Study Complex Interventions. Science, 353, 448-449. https://doi.org/10.1126/science.aaf5101
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, 2031-2043.
Wang, Q., Wu, P.C., Dong, D.Z., Ivanova, I., Chu, E., Zeliadt, S., et al. (2013) Polyploid Road to Therapy-Induced Cellular Senescence and Escape. International Journal of Cancer, 132, 1505-1515. https://doi.org/10.1002/ijc.27810
Zhang, S., Mercado-Uribe, I., Xing, Z., Sun, B., Kuang, J. and Liu, J. (2014) Generation of Cancer-Stem-Like Cells through the Formation of Polyploid Giant Cells. Oncogene, 33, 116-125.
Einstein, J.M. and Yeo, G.W. (2016) Making the Cut in the Dark Genome. Science, 354, 705-706. https://doi.org/10.1126/science.aak9849
Sanjana, N.E., Wright, J., Zheng, K., Shalem, O., Fontanillas, P., Joung, J., et al. (2016) High-Resolution Interrogation of Functional Elements in the Noncoding Genome. Science, 353, 1545-1548. https://doi.org/10.1126/science.aaf7613
Heng, H.H. (2015) Debating Cancer: The Paradox in Cancer Research. World Scientific, Singapore.
Loewenstein, W.R. (1999) The Touchstone of LIFE. Oxford University Press, New York.
Kondrashov, A.S. (1994) The Asexual Ploidy Cycle and the Origin of Sex. Nature, 370, 213-216. https://doi.org/10.1038/370213a0
Haig, D. (1993) Alternatives to Meiosis: The Unusual Genetics of Red Algae, Mirosporidia and Others. Journal of Theoretical Biology, 163, 15-31. https://doi.org/10.1006/jtbi.1993.1104
Hurst, L.D. and Nurse, P. (1991) A Note on the Evolution of Meiosis. Journal of Theoretical Biology, 150, 561-563.
Wilkins, A.S. and Holliday, R. (2009) The Evolution of Meiosis from Mitosis. Genetics, 181, 3-12. https://doi.org/10.1534/genetics.108.099762
Enzien, M., McKhann, H.I. and Margulis, L. (1989) Ecology and Life History of an Amoebo-Mastigote, Paratetramitus jugosus, from a Microbial Mat: New Evidence for Multiple Fission. The Biological Bulletin, 177, 110-129. https://doi.org/10.2307/1541839
Margulis, L., Enzien, M. and McKhann, H.I. (1990) Revival of Dobell’s “Chromidia” Hypothesis: Chromatin Bodies in Amoebomastigote Paratetramitus jugosus. The Biological Bulletin, 178, 300-304. https://doi.org/10.2307/1541832
Ye, C.J., Liu, G., Bremer, S.W. and Heng, H.H.Q. (2007) The Dynamics of Cancer Chromosomes and Genomes. Cytogenetic and Genome Research, 118, 237-246. https://doi.org/10.1159/000108306
Duesberg, P. and MCCormack, A. (2013) Immortality of Cancer: A Consequence of Inherent Karyotypic Variation and Selections for Autonomy. Cell Cycle, 12, 783-802. https://doi.org/10.4161/cc.23720
Stepanenko, A.A. and Kavasan, V.M. (2012) Evolutionary Karyotypic Theory of Cancer versus Conventional Cancer Gene Mutation Theory. Biopolymers and Cell, 28, 267-280. https://doi.org/10.7124/bc.000059
Duesberg, P., Madrioli, D., MCCormack, A. and Nicholson, J.M. (2011) Is Carcinogenesis a Form of Speciation? Cell Cycle, 10, 2100-2114. https://doi.org/10.4161/cc.10.13.16352
Bloomfield, M. and Duesberg, P. (2015) Karyotype Alteration Generates the Neoplastic Phenotypes of SV40-Infected Human and Rodent Cells. Molecular Cytogenetics, 8, 79-109. https://doi.org/10.1186/s13039-015-0183-y
Mitelman, F. (1988) Catalog of Chromosome Aberrations in Cancer. Alan Liss, Inc., New York.
Heim, S. and Mitelman, F. (1995) Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells. 2nd Edition, Wiley-Liss, Inc., New York.
Pikor, L., Thu, K. and Lam, W. (2013) The Detection and Implication of Genome Instability in Cancer. Cancer and Metastasis Reviews, 32, 341-352. https://doi.org/10.1007/s10555-013-9429-5
Prasetyani, P.R., Zimberlin, C.D., Bots, M., Vermulen, L., Melo, F., De Sousa, E. and Medema, J.P. (2013) Regulation of Stem Cell Self-Renewal and Differentiation by Wnt and Notch Are Conserved throughout the Adenoma-Carcinoma Sequence in the Colon. Molecular Cancer, 12, 126-133. https://doi.org/10.1186/1476-4598-12-126
Wang, T., Birsoy, K., Hughes, N.W., Krupezak, K.M., Post, Y., Wei, J.J., Lander, E.S. and Sabatini, D.M. (2015) Identification and Characterization of Essential Genes in the Human Genome. Science, 350, 1096-1079. https://doi.org/10.1126/science.aac7041
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.
Gorgoulis, V.G., Vassillou, L.-V.F., Karakaldos, 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. https://doi.org/10.1038/nature03485
White, E. and DiPaola, R.S. (2009) The Double-Edged Sword of Autophagy Modulation in Cancer. Clinical Cancer Research, 15, 5308-5316. https://doi.org/10.1158/1078-0432.CCR-07-5023
Deem, A., Keszthelyl, A., Blackgrove, T., Vayl, A., Coffey, B., Mathur, R. and Chabes, A. (2011) Break-Induced Replication Is Highly Inaccurate. PLOS Biology, 9, e1000594. https://doi.org/10.1371/journal.pbio.1000594
Tomasetti, C., Vogelstein, B. and Parmigiani, G. (2013) Half or More of the Somatic Mutations in Cancers of Self-Renewing Tissues Originate Prior to Tumor Initiation. Proceedings of the National Academy of Sciences of the United States, 110, 1999-2004. https://doi.org/10.1073/pnas.1221068110
Fernholm, A. (2015) DNA Repair—Providing Chemical Stability for Life. The Royal Swedish Academy of Sciences.
Mirzayans, R., Andrais, B., Kumar, P. and Murrey, D. (2016) The Growing Complexity of Cancer Cell Response to DNA-Damaging Agents: Caspase 3 Mediates Cell Death or Survival. International Journal of Molecular Sciences, 17, 708-725. https://doi.org/10.3390/ijms17050708
Ermis, A., Oberringer, M., Wirbel, R., Kochnick, M., Mutschler, W. and Hanselmann, R.G. (1998) Tetra-Ploidization Is a Physiological Enhancer of Wound Healing. European Surgical Research, 30, 385-392. https://doi.org/10.1159/000008603
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.
Steinbeck, R.G. (2004) Dysplasia in View of the Cell Cycle. European Journal of Histochemistry, 48, 203-211.
Ohno, S. (1970) Evolution by Gene Duplication. Georg Allen and Unwin. London. https://doi.org/10.1007/978-3-642-86659-3
Wolfe, K.H. (2001) Yesterday’s Polyploids and the Mystery of Diploidization. Nature Reviews Genetics, 2, 333-341. https://doi.org/10.1038/35072009
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, 194-200.
Restall, I.J., Parolin, D.F.E., Daneshmand, M., Hanson, J.E.L., Simard, M.A., Fitzpatrick, M.E., et al. (2015) PKCι Depletion Initiates Mitotic Slippage-Induced Senescence in Glioblastoma. Cell Cycle, 14, 2938-2948. https://doi.org/10.1080/15384101.2015.1071744
Davoli, T., Denchi, E.L. and de Lange, T. (2010) Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy. Cell, 141, 81-93.
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.
Uhlmann, F. (2009) A Matter of Choice: The Establishment of Sister Chromatid Cohesion. EMBO Reports, 10, 1095-1102. https://doi.org/10.1038/embor.2009.207
Erenpreisa, J., Cragg, M.S., Salima, K., Hausmann, M. and Scherthan, H. (2009) The Role of Meiotic Cohesin REC8 in Chromosome Segregation in Irradiation-Induced Endopolyploid Tumor Cells. Experimental Cell Research, 315, 2593-2603.
Taylor, J.H. and Taylor, S.H. (1953) The Autoradiograph—The Tool for Cytogenetics. Journal of Heredity, 44, 129-132. https://doi.org/10.1093/oxfordjournals.jhered.a106375
Walen, K.H. and Brown, S.W. (1962) Chromosomes in a Marsupial (Potororous tridactylis) Tissue Culture. Nature, 194, 406. https://doi.org/10.1038/194406a0
Brenner, S., Branch, A., Meredith, S. and Berns, M.W. (1977) The Absence of Centrioles from Spindle Poles of Rat Kangaroo PtK1 Cells Undergoing Meiotic-Like Reduction Division in Vitro. The Journal of Cell Biology, 72, 368-379. https://doi.org/10.1083/jcb.72.2.368
Watrin, E. and Peters, J.-M. (2007) How and When the Genome Sticks Together. Science, 317, 209. https://doi.org/10.1126/science.1146072
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. https://doi.org/10.1126/science.1140637
Walen, K.H. (1965) Spatial Relationships in the Replication of Chromosomal DNA. Genetics, 51, 915-929.
Schwarzacher, H.G. and Schnedl, W. (1966) Position of Labelled Chromatids in Diplochromosomes of Endo-Reduplicated Cells after Uptake of Tritiated Thymidine. Nature, 209, 107-108. https://doi.org/10.1038/209107a0
Kuhn, E.M. and Therman, E. (1988) The Behavior of Heterochromatin in Mouse and Human Nuclei. Cancer Genetics and Cytogenetics, 34, 143-151.
Therman, E. and Susman, M. (1993) Human Chromosomes—Structural, Behavior, and Effects. 3rd Edition, Springer-Verlag, New York.
Benn, P.A. (1976) Specific Chromosome Aberrations in Senescent Fibroblast Cell Lines Derived from Human Embryos. The American Journal of Human Genetics, 28, 465-473.
Fearon, E.R. and Vogelstein, B. (1990) A Genetic Model of Colorectal Tumorigenesis. Cell, 61, 759-767.
Coldwell, C.M., Green, R.A. and Kapland, K.B. (2007) APC Mutation Lead to Cytokinetic Failures in Vitro and Tetraploid Genotypes in MIN Mice. The Journal of Cell Biology, 178, 1109-1120. https://doi.org/10.1083/jcb.200703186
Dikovskaya, D., Schiffmann, D., Newton, I.P., Oakley, A., Kroboth, K., Sansom, O., et al. (2007) Loss of APC Induces Polyploidy as a Result of a Combination of Defects in Mitosis and Apoptosis. The Journal of Cell Biology, 176, 183-193. https://doi.org/10.1083/jcb.200610099
Saunders, W.S., Shuster, M., Huang, X., Gharaibe, B., Enyenihi, A.H., Petersen, J. and Gollin, S.M. (2000) Chromosomal Instability and Cytoskeleton Defects in Oral Cancer. Proceedings of the National Academy of Sciences of the United States, 97, 303-308. https://doi.org/10.1073/pnas.97.1.303
Royer, C. and Lu, X. (2011) Epithelial Cell Polarity: A Major Gatekeeper against Cancer? Cell Death and Differentiation, 18, 1470-1477. https://doi.org/10.1038/cdd.2011.60
Wodarz, A. and Nathke, I. (2007) Cell Polarity in Development and Cancer. Nature Cell Biology, 9, 1016-1024. https://doi.org/10.1038/ncb433
Gonczy, P. (2008) Mechanisms of Asymmetric Cell Division: Flies and Worms Pave the Way. Nature Review, 9, 355-366. https://doi.org/10.1038/nrm2388
Llorente, B., Smith, C.E. and Symington, L.S. (2008) Break-Induced Replication: What Is It and What Is It for? Cell Cycle, 7, 859-864. https://doi.org/10.4161/cc.7.7.5613
Stephens, P.J., Greenman, C.D., Fu, B., Yang, F., Bignell, G.R., Mudie, L.J., Pleasance, E.D., Lau, K.W., et al. (2011) Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development. Cell, 144, 27-40.
Przybytkowski, E., Lenkiewicz, E., Barrett, M.T., Klein, K., Nabavi, S., Greenwood, C.M.T. and Basik, M. (2014) Chromosome-Breakage Genomic Instability and Chromothripsis in Breast Cancer. BMC Genomics, 15, 579-592. https://doi.org/10.1186/1471-2164-15-579
Tomacetti, C., Li, L. and Vogelstein, B. (2017) Stem Cell Divisions, Somatic Mutations, Cancer Etiology, and Cancer Prevention. Science, 355, 1330-1334. https://doi.org/10.1126/science.aaf9011
Bayani, J., Paderova, J., Murphy, J., Rosen, B., Zielenska, M. and Squire, J.A. (2008) Distinct Patterns of Structural and Numerical Chromosomal Instability Characterize Sporadic Ovarian Cancer. Neoplasia, 10, 1057-1065. https://doi.org/10.1593/neo.08584
Heng, H.H., Bremer, S.W., Stevens, J.B., Horne, S.D., Liu, G., Abdallah, B.Y., et al. (2013) Chromosomal Instability (CIN): What It Is and Why It Is Crucial to Cancer Evolution. Cancer and Metastasis Reviews, 32, 325-340. https://doi.org/10.1007/s10555-013-9427-7