Short-Chain Fatty Acids and Molecular and Cellular Mechanisms of Colonic Cell Differentiation and Transformation

  • Leonard H. Augenlicht
  • Anna Velcich
  • Barbara G. Heerdt
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 354)


There has been enormous progress in defining structural alterations of genes common in colonic cancer. Accumulation of mutations and deletions in APC, p53, DCC, and Ki-ras are the sine qua non of the disease, although the roles and interactions of these genetic alterations in the biological and clinical heterogeneity of the disease are not understood. Of even greater interest from the point of view of disease prevention are inherited mutations found in the APC gene and in genes which encode mismatch repair functions, which lead to the high frequency of colonic cancer in familial polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) families, respectively1–6. However, unlike inherited childhood cancers, such as retinoblastoma and Wilm’s tumor, inherited colon cancer takes decades to develop. This can be partially understood in the context of what has been learned regarding genetic alterations in sporadic cancers. For example, one may assume that the inherited mutation supplies the first of a series of genetic alterations, and by so doing reduces the overall time and elevates the probability of accumulating the necessary number of alterations in genes such as those cited above. In the case of FAP, the inheritance of a mutant allele for APC provides one of the key events directly, since mutations in the gene occur somatically in over 70% of human colon tumors, and the mutation is sufficient to initiate development of intestinal tumors in mice7,8. In HNPCC, the situation is more complicated, in that the inherited mutations in genes responsible for DNA mismatch repair fail to repair errors which arise during DNA synthesis at tens of thousands of loci throughout the genome, and it must be presumed that among this plethora of changes there are key genes, again perhaps coincident with some of those mentioned above, which are eventual targets that lead to tumor formation.


HT29 Cell Familial Adenomatous Polyposis Colonic Mucosa Mismatch Repair Colonic Epithelial Cell 
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  1. 1.
    J. Groden, A. Thlivèris, W. Samowitz, M. Carlson, L. Gelbert, H. Albertson, G. Joslyn, J. Stevens, L. Spiro, M. Robertson, L. Sargeant, K. Krapcho, E. Wolff, R. Burt, J.P. Hughes, J. Warrington, J. McPherson, J. Wasmuth, D. Le Paslier, H. Abderrahim, D. Cohen, M. Leppert, and R. White, Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 66: 589 (1991).PubMedCrossRefGoogle Scholar
  2. 2.
    I. Nishisho, Y. Nakamura, Y. Miyoshi, Y. Miki, H. Ando, A. Horii, K. Koyama, J. Utsunomiya, S. Baba, P. Hedge, A. Markham, A.J. Krush, G. Petersen, S.R. Hamilton, M.C. Nilbert, D.B. Levy, T.M. Bryan, A.C. Preisinger, K.J. Smith, L.-K. Su, K.W. Kinzler, and B. Vogelstein, Mutations of chromosome 5g21 genes in FAP and colorectal cancer patients. Science. 253: 665 (1991).PubMedCrossRefGoogle Scholar
  3. 3.
    R. Fishel, M.K. Lescoe, M.R.S. Rao, N.G. Copeland, N.A. Jenkins, J. Garber, M. Kane, and R. Kolodner, The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 75: 1027 (1993).PubMedCrossRefGoogle Scholar
  4. 4.
    C.E. Bronner, S.M. Baker, P.T. Morrison, G. Warren, L.G. Smith, M.K. Lescoe, M. Kane, C. Earabino, J. Lipford, A. Lindblom, P. Tannergard, R.J. Bollag, A.R. Godwin, D.C. Ward, M. Nordenskjold, R. Fishel, R. Kolodner, and R.M. Liskay, Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer. Nature. 368: 258 (1994).PubMedCrossRefGoogle Scholar
  5. 5.
    F.S. Leach, N.C. Nicolaides, N. Papadopoulos, B. Liu, J. Jen, R. Parsons, P. Peltomaki, P. Sistonen, L.A. Aaltonen, M. Nystrom-Lahti, X.-Y. Guan, J. Zhang, P.S. Meltzer, J. Yu, F. Kao, D.J. Chen, K.M. Cerosaletti, R.E.K. Fournier, S. Todd, T. Lewis, R.J. Leach, S.L. Naylor, J. Weissenbach, J. Mecklin, H. Jarvinen, G.M. Petersen, S.R. Hamilton, J. Green, J. Jass, P. Watson, H.T. Lynch, J.M. Trent, A. de la Chapelle, K.W. Kinzler, and B. Vogelstein, Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell. 75: 1215 (1993).PubMedCrossRefGoogle Scholar
  6. 6.
    N. Papadopoulos, N.C. Nicolaides, Y.-F. Wei, S.M. Ruben, K.C. Carter, C.A. Rosen, W.A. Haseltine, R.D. Fleischmann, C.M. Fraser, M.D. Adams, J.C. Venter, S.R. Hamilton, G.M. Petersen, P. Watson, H.T. Lynch, P. Peltomaki, J.-P. Mecklin, A. de la Chapelle, K.W. Kinzler, and B. Vogelstein, Mutation of a mutL homolog in hereditary colon cancer. Science. 263: 1625 (1994).PubMedCrossRefGoogle Scholar
  7. 7.
    L.-K. Su, K.W. Kinzler, B. Vogelstein, A.C. Preisinger, A.P. Moser, C. Luongo, K.A. Gould, and W.F. Dove, Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 256: 668 (1992).PubMedCrossRefGoogle Scholar
  8. 8.
    R. Fodde, W. Edelmann, K. Yang, C. van Leeuwen, C. Carlson, B. Renault, C. Breukel, E. Alt, M. Lipkin, P.M. Khan, and R. Kucherlapati, A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc. Nat. Acad. Sci. USA. 91: (1994).Google Scholar
  9. 9.
    R. Parsons, G. Li, M.J. Longley, W. Fang, N. Papadopoulos, J. Jen, A. de la Chapelle, K.W. Kinzler, B. Vogelstein, and P. Modrich, Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell. 75: 1227 (1993).PubMedCrossRefGoogle Scholar
  10. 10.
    B. Vogelstein, E.R. Fearon, S.E. Kern, S.R. Hamilton, A.C. Preisinger, Y. Nakamura, and R. White, Allelotype of colorectal carcinomas. Science. 244: 207 (1989).PubMedCrossRefGoogle Scholar
  11. 11.
    A. Kallioniemi, 0.-P. Kallioniemi, D. Sudar, D. Rutovitz, J.W. Gray, F. Waldman, and D. Pinkel, Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 258: 818 (1992).PubMedCrossRefGoogle Scholar
  12. 12.
    A. Kallioniemi, 0.-P. Kallioniemi, J. Piper, M. Tanner, T. Stokke, L. Chen, H.S. Smith, D. Pinkel, J.W. Gray, and F.M. Waldman, Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc. Nat. Acad. Sci. USA. 91: 2156 (1994).PubMedCrossRefGoogle Scholar
  13. 13.
    T. Ried, I. Petersen, H. Holtgreve-Grez, M.R. Speicher, E. Schrock, S.d Manoir, and T. Cremer, Mapping of multiple DNA gains and losses in primary small cell lung carcinomas by compararative genomic hybridization. Cancer Res. 54: 1801 (1994).Google Scholar
  14. 14.
    B.G. Heerdt, S. Molinas, D. Deitch, and L.H. Augenlicht, Aggressive subtypes of human colorectal tumors frequently exhibit amplification of the c-myc gene. Oncogene. 6: 125 (1991).PubMedGoogle Scholar
  15. 15.
    M. Groudine and H. Weintraub, Activation of cellular genes by avian RNA tumor viruses. Proc.Natl.Acad.Sci.USA. 77: 5351 (1980).PubMedCrossRefGoogle Scholar
  16. 16.
    L.H. Augenlicht, M.Z. Wahrman, H. Halsey, L. Anderson, J. Taylor, and M. Lipkin, Expression of cloned sequences in biopsies of human colonic tissue and in colonic carcinoma cells induced to differentiate in vitro. Cancer Res. 47: 6017 (1987).PubMedGoogle Scholar
  17. 17.
    L.H. Augenlicht, J. Taylor, L. Anderson, and M. Lipkin, Patterns of gene expression that characterize the colonic mucosa in patients at genetic risk for colonic cancer. Proc.Natl.Acad.Sci.USA. 88: 3286 (1991).PubMedCrossRefGoogle Scholar
  18. 18.
    L.H. Augenlicht, B. Heerdt, S. Molinas, and M. Lipkin,Patterns of gene expression that characterize the mucosa at risk for development of colorectal cancer,Calcium, vitamin D, and prevention of colon cancer„eds.,M. Lipkin, H.L. Newmark, and G. Kelloff,1991,CRC Press,Boca Raton,pp. 283–300Google Scholar
  19. 19.
    L.H. Augenlicht and B.G. Heerdt, Modulation of gene expression as a biomarker in colon. Journal of Cellular Biochemistry. 16G: 151 (1992).CrossRefGoogle Scholar
  20. 20.
    L.H. Augenlicht, G. Corner, S. Molinas, and B.G. Heerdt,Genetic biomarkers,Cancer Chemoprevention„eds.,L. Wattenberg, M. Lipkin, C.W. Boone, and G.J. Kelloff,1992,CRC Press,Boca Raton,Fla,pp. 559–569Google Scholar
  21. 21.
    L.H. Augenlicht and B.G. Heerdt,Colonic Carcinoma: a common tumor with multiple genomic abnormalities,Biochemical and Molecular Aspects of Selected Cancers, vol 2„eds.,T. Pretlow and T. Pretlow, 1994, Academic Press, NY, pp. 47–91Google Scholar
  22. 22.
    L.H. Augenlicht,Gene structure and expression in colon cancer,Cell and Molecular Biology of Colon Cancer„eds., L.H. Augenlicht, 1989, CRC Press, Boca Raton, Florida,pp. 165–186Google Scholar
  23. 23.
    B.J. Barrow, M.A. O’Riordan, T.A. Stellato, B.M. Calkins, and T.P. Pretlow, Enzyme-altered foci in colons of carcinogen-treated rats. Cancer Res. 50: 1911 (1990).PubMedGoogle Scholar
  24. 24.
    N.R. Hughes, R.S. Walls, R.C. Newland, and J.E. Payne, Gland to gland heterogeneity in histologically normal mucosa of colon cancer patients demonstrated by monoclonal antibodies:o tissue-specific antigens. Cancer Res. 46: 5993 (1986).PubMedGoogle Scholar
  25. 25.
    B.G. Heerdt, H.K. Halsey, M. Lipkin, and L.H. Augenlicht, Expression of mitochondrial cytochrome c oxidase in human colonic cell differentiation, transformation, and risk for colonic cancer. Cancer Res. 50: 1596 (1990).PubMedGoogle Scholar
  26. 26.
    J.S. Chen and L.H. Augenlicht. Sequence analysis of clones altered in expression in risk for colonic cancer. in preparation (1994).Google Scholar
  27. 27.
    D.A. Clayton, Nuclear gadgets in mitochondrial DNA replication and transcription. Trends Biochem. Sci. 16: 107 (1991).Google Scholar
  28. 28.
    B.G. Heerdt, J.S. Chen, L.R. Stewart, and L.H. Augenlicht, Polymorphisms, but lack of mutations or instability, in the promotor region of the mitochondrial genome in human colonic tumors. Cancer Res. 54: 3912 (1994).PubMedGoogle Scholar
  29. 29.
    J.S. Chen, B.G. Heerdt, and L.H. Augenlicht, Presence and instability of repetitive elements in sequences the altered expression of which characterizes risk for colonic cancer. Cancer Res. 55, 174 (1995).PubMedGoogle Scholar
  30. 30.
    B.G. Heerdt and L.H. Augenlicht, Effects of fatty acids on expression of genes encoding subunits of cytochrome c oxidase and cytochrome c oxidase activity in HT29 human colonic adenocarcinoma cells. J.Biol.Chem. 266: 19120 (1991).PubMedGoogle Scholar
  31. 31.
    B.G. Heerdt, M.A. Houston, and L.H. Augenlicht, Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines. Cancer Res. 54: 3288 (1994).PubMedGoogle Scholar
  32. 32.
    J.R. Wong and L.B. Chen,Recent advances in the study of mitochondria in living cells,Advances in Cell Biology, 2, 1988, JAI Press, Inc., pp. 263–290Google Scholar
  33. 33.
    I.C. Summerhayes, T.J. Lampidis, S.D. Bernal, J.J. Nadakavukaren, K.K. Nadakavukaren, E.L. Shepherd, and L.B. Chen, Unusual retention of rhodamine 123 by mitochondria in muscle and carcinoma cells. Proc. Nat. Acad. Sci. USA. 79: 5292 (1982).PubMedCrossRefGoogle Scholar
  34. 34.
    J.S. Modica-Napolitano, G.D. Steele, and L.B. Chen, Aberrant mitochondria in two human colon carcinoma cell lines. Cancer Res. 49: 3369 (1989).PubMedGoogle Scholar
  35. 35.
    B.G. Heerdt and L.H. Augenlicht, Absence of detectable deletions in the mitochondrial genome of human colon tumors. Cancer Commun. 2: 109 (1990).PubMedGoogle Scholar
  36. 36.
    W. Bursch, S. Paffe, B. Putz, G. Barthel, and R. Schulte-Hermann, Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats. Carcinogenesis. 11: 847 (1990).PubMedCrossRefGoogle Scholar
  37. 37.
    G. Yander, H. Halsey, M. Kenna, and L.H. Augenlicht, Amplification and elevated expression of c-myc in a chemically induced mouse colon tumor. Cancer Res. 45: 4433 (1985).PubMedGoogle Scholar
  38. 38.
    M.D. Erisman, J.K. Scott, R.A. Watt, and S.M. Astrin, The c-myc protein is constitutively expressed at elevated levels in colorectal carcinoma cell lines. Oncogene. 2: 367 (1988).PubMedGoogle Scholar
  39. 39.
    M.D. Erisman, P.G. Rothberg, R.E. Diehl, C.C. Morse, J.M. Spandorfer, and S.M. Astrin, Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol. Cell. Biol. 5: 1969 (1985).PubMedGoogle Scholar
  40. 40.
    G.I. Evan, A.H. Wyllie, C.S. Gilbert, T.D. Littlewood, H. Land, M. Brooks, C.M. Waters, L.Z. Penn, and D.C. Hancock, Induction of apoptosis in fibroblasts by c-myc protein. Cell. 69: 119 (1992).PubMedCrossRefGoogle Scholar
  41. 41.
    M.D. Erisman, J.K. Scott, and S.M. Astrin, Evidence that the familial adenomatous polyposis gene is involved in a subset of colon cancers with a complementable defect in c-myc regulation. Proc. Nat. Acad. Sci. USA. 86: 4264 (1989).PubMedCrossRefGoogle Scholar
  42. 42.
    P.G. Rothberg, J.M. Spandorfer, M.D. Erisman, R.N. Staroscik, H.F. Sears, R.O. Petersen, and S.M. Astrin, Evidence that c-myc expression defines two genetically distinct forms of colorectal adenocarcinoma. Br. J. Cancer. 52: 629 (1985).PubMedCrossRefGoogle Scholar
  43. 43.
    C. Rodriguez-Alfageme, E.J. Stanbridge, and S.M. Astrin, Suppression of deregulated c-MYC expression in human colon carcinoma cells by chromosome 5 transfer. Proc. Nat. Acad. Sci. USA. 89: 1482 (1992).PubMedCrossRefGoogle Scholar
  44. 44.
    B. Rubinfeld, B. Souza, I. Albert, O. Muller, S.H. Chamberlain, F.R. Masiarz, S. Munemitsu, and R. Polakis, Association of the APC gene product with b-catenin. Science. 262: 1731 (1993).PubMedCrossRefGoogle Scholar
  45. 45.
    L.-K. Su, B. Vogelstein, and K. Kinzler, Association of the APC tumor suppressor protein with catenins. Science. 262: 1734 (1993).PubMedCrossRefGoogle Scholar
  46. 46.
    Peifer, Cancer, catenins, and cuticle pattern: a complex connection. Science. 262: 1667 (1993).PubMedCrossRefGoogle Scholar
  47. 47.
    K.J. Smith, D.B. Levy, R. Maupin, T.D. Pollard, B. Vogelstein, and K.W. Kinzler, Wild-type but not mutant APC associates with the microtubule cytoskeleton. Cancer Res. 54: 3672 (1994).PubMedGoogle Scholar
  48. 48.
    S. Munemitsu, B. Souza, O. Muller, I. Albert, B. Rubinfeld, and P. Polakis, The APC gene product associates witht microtubules in vivo and promotes their assemby in vitro. Cancer Res. 54: 3676 (1994).PubMedGoogle Scholar
  49. 49.
    L. Hedrick, K.R. Cho, E.R. Fearon, T.-C. Wu, K.W. Kinzler, and B. Vogelstein, The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 8: 1174 (1994).PubMedCrossRefGoogle Scholar
  50. 50.
    E.R. Fearon, K.R. Cho, J.M. Nigro, S.E. Kern, J.W. Simons, J.M. Ruppert, S.R. Hamilton, A.C. Preisinger, G. Thomas, K.W. Kinzler, and B. Vogelstein, Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 247: 49 (1990).PubMedCrossRefGoogle Scholar
  51. 51.
    A. Velcich and L.H. Augenlicht, Regulated expression of an intestinal mucin gene in HT29 colonic carcinoma cells. J.Biol.Chem. 268: 13956 (1993).PubMedGoogle Scholar
  52. 52.
    A. Velcich, L. Palumbo, A. Jarry, C. Laboisse, J. Rachevskis, and L. Augenlicht, Patterns of expression of lineage specific markers during the in vitro differentiation of HT29 colon carcinoma cells. submitted (1994).Google Scholar
  53. 53.
    B.G. Heerdt, M.A. Houston, J.J. Rediske, and L.H. Augenlicht. Relationships among differentiation enhanced mitochondrial activity and apoptosis in human colonic carcinoma cells.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Leonard H. Augenlicht
    • 1
  • Anna Velcich
    • 1
  • Barbara G. Heerdt
    • 1
  1. 1.Department of OncologyAlbert Einstein Cancer CenterBronxUSA

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