Skip to main content
SpringerLink
Log in

Heterogeneity of human colon carcinoma

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Summary

In order to better understand colon cancer, a model system reflecting the heterogenous nature of this disease was developed and used in the development of new cytotoxic and non-cytotoxic therapeutic approaches. A large bank of colon carcinoma cell lines was established from primary human colon carcinomas and grouped based on their tumorigenicity in athymic mice, their growth rates in soft agarose and in tissue culture, and their secreted levels of carcinoembryonic antigen. These cell lines were later characterized based on cell surface proteins and antigens detected with antisera raised against a differentiated colon carcinoma cell line. Although these biochemical markers correlated with the biological classification of these cell lines, there was still extensive heterogeneity within each group in all properties examined. This colon carcinoma cell system was used to study natural vs. selected resistance to the anticancer drug mitomycin C (MMC). The differing IC50 values in vitro were reflected in the inhibition by MMC of xenograft growth in athymic mice. A new, more readily bioactivatable analogue of MMC was tried and shown to be more active in vitro and in vivo, suggesting that rapid efflux of the drug before activation may be important in examining causes of resistance to MMC. Another approach to the treatment of colon cancer is the use of non-cytotoxic agents such as growth factors and differentiation agents to restore normal growth to the malignant cells. We have isolated and characterized two types of polypeptides from colon carcinoma cells and conditioned medium from these cells. The first, transforming growth factors (TGF's) confer a transformed phenotype on non-transformed fibroblasts while the second, tumor inhibitory factors (TIF's), inhibits the anchorage independent growth of transformed cells. The fact that extracts of colon carcinoma cells contain both activities suggests that the heterogeneity of the cell lines could be due to different levels of TGF's and TIF's produced. The effectiveness of differentiation agents to restore normal growth control using a transformed mouse embryo cell line was examined. Treatment of these cells with differentiation agents restored normal growth control to these cells. An increased synthesis of TGF's resulted from these treatments. Therefore, differentiation agents may be useful in non-cytotoxic treatment. The use of this model system for human colon carcinoma will hopefully lead to more effective drugs for the treatment of colon cancer in man.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Chapter © 2017

References

  1. Brattain MG, Kimball PM, Pretlow TG, Pitts AM: Partial purification of human colonic carcinoma cells by sedimentation. Br J Cancer 35: 850–857, 1977a.

    Google Scholar 

  2. Brattain MG, Pretlow TP, Pretlow TG: Cell fractionation of large bowel cancer. Cancer 40: 2476–2486, 1977b.

    Google Scholar 

  3. Brattain MG, Brattain DE, Fine WD, Khaled FM, Marks ME, Arcolano LA, Danbury BH: Initiation of cultures of human colonic carcinoma with different biological characteristics utilizing feeder layers of confluent fibroblasts. Oncodevel Biol and Med 2: 355–366, 1981a.

    Google Scholar 

  4. Brattain MG, Fine WD, Khaled FM, Thompson J, Brattain DE: Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res 41: 1751–1756, 1981b.

    Google Scholar 

  5. Brattain MG, Marks ME, McCombs J, Finely W, Brattain DE: Characterization of human colon carcinoma cell lines isolated from a single primary tumor. Br J Cancer 47: 373–381, 1983.

    Google Scholar 

  6. Dexter DL, Barbosa JA, Calabresi P: N,N-dimethyl-formamide-induced alteration of cell culture characteristics and loss of tumorigenicity in cultured human colon carcinoma cells. Cancer Res 39: 1020–1025, 1979.

    Google Scholar 

  7. Clark RL: The Large Bowel Cancer Project: Its achievement and future directions of investigation. Cancer Bull 33: 119–120, 1981.

    Google Scholar 

  8. Minna JD, Carney DN, Alvarez R, Bunn PA, Cuttitta F, Ihde DC, Mathews MJ, Die H, Rosen S, Whang-Peng J, Gazdar AF: Heterogeneity and homogeneity of human small cell lung cancer. In: Owens AH, Coffey DS, Baylin SB (eds) Tumor cell heterogeneity: Origins and implications. Academic Press, New York, 1982, pp 30–52.

    Google Scholar 

  9. Smith HS, Lan S, Ceriani R, Hackett AJ, Stampfer MR: Clonal proliferation of cultured nonmalignant and malignant human breast epithelia. Cancer Res 41: 4637–4643, 1981.

    Google Scholar 

  10. Gallie BL, Holmes W, Phillips RA: Reproducible growth in tissue culture of retinoblastoma tumor specimens. Cancer Res 42: 301–305, 1982.

    Google Scholar 

  11. Brattain MG, Brattain DE, Sarrif AM, McRae LJ, Fine WD, Hawkins JG: Enhancement of growth of human colon tumor cell lines by feeder alyers of murine fibroblasts. JNCI 69: 767–771, 1982.

    Google Scholar 

  12. Long BH, Wilson JKV, Brattain DE, Musial S, Brattain MG: The effects of motimycin C on human colon carcinoma cells. JNCI, in press.

  13. Wolman SR, Mastromarino AJ, Markers of colonic cell differentiation. JNCI 72: 497–500, 1984.

    Google Scholar 

  14. Nicolson GL, Birdwell CR, Brunson KW, Robbins JC, Beattie G, Fidler IJ: Cell interactions in the metastatic process. Some cell surface properties associated with successful blood-borne tumor spread. In: Lash JW, Burger MM (eds) Cell and tissue interactions. Raven Press, New York, 1977, pp 225–241.

    Google Scholar 

  15. Fidler IJ, Gersten DM, Hart IR: The biology of cancer invasion and metastasis. Adv Cancer Res 28: 149–250, 1978.

    Google Scholar 

  16. Yogeeswaran G, Stein BS, Sebastian H: Altered cell surface organization of gangliosides and sialylglycoproteins of mouse metastatic melanoma variant lines selected in vivo for enhanced lung implantation. Cancer Res 38: 1336–1344, 1978.

    Google Scholar 

  17. Gahmberg CG, Hakomori S: Altered growth behavior of malignant cells associated with changes in externally labeled glycoprotein and glycolipid. Proc Nat'l Acad Sci USA 70: 3329–3333, 1973.

    Google Scholar 

  18. Marks ME, Danbury BH, Miller CA, Brattain MG: Plasma membrane proteins and glycoproteins from colonic carcinoma cell lines with different bioloical properties. JNCI 71: 663–671, 1983.

    Google Scholar 

  19. Chakrabarty S, Taylor CW, Yeoman LC: Comparison of immunoelectrophoretic techniques for the analysis of cytosol antigens. J Immunol Methods 43: 301–311, 1981.

    Google Scholar 

  20. Taylor CW, Brattain MG, Yeoman LC: Rate of growth and extent of differentiation reflected by cytoplasmic proteins and antigens of human colon tumor cell lines. Cancer Res 44: 1200–1205, 1984.

    Google Scholar 

  21. Chakrabarty S, McRae LJ, Levine AE and Brattain MG: Restoration of normal growth control and membrane antigen composition in malignant cells by N,N-dimethylformamide. Cancer Res 44: 000–000, 1984.

    Google Scholar 

  22. Fidler IJ, Poste G: The heterogeneity of metastatic properties in malignant tumor cells and regulation of the metastatic phenotype. In: Owens AH, Coffey DS, Baylin SB (eds) Tumor cell heterogeneity: Origin and Implications. Academic Press, New York, 1982, pp 127–146.

    Google Scholar 

  23. Curt GA, Clendeninn NJ, Chabner BA: Drug resistance in cancer. Cancer Treatment Repts 68: 87–99, 1984.

    Google Scholar 

  24. Bradner WT, Claridge CA: Screening systems. In: Remers WA (ed) Antineoplastic agents. John Wiley and Sons, New York, 1984, pp 41–82.

    Google Scholar 

  25. Staquet MJ, Byar DP, Green SB, Rozencweig M: Clinical predictivity of transplantable tumor systems in the selection of new drugs for solid tumors: Rationale for a three-stage strategy. Cancer Treatment Repts 67: 753–765, 1983.

    Google Scholar 

  26. Venditti JM: Preclinical drug development: Rationale and methods. Semin Oncology 8: 349–361, 1981.

    Google Scholar 

  27. Dolnick BJ, Bertino JR: Gene amplification in human tumor systems. In: Owens AH, Coffey DA, Baylin SB (eds) Tumor cell heterogeneity: Origins and implications. Academic Press, New York, 1982, pp 169–179.

    Google Scholar 

  28. McBain J, Weese J, Meisner L, Wolberg WH, Willson JKV: Establishment and characterization of human colorectal cancer cell lines. Proc Amer Assoc Cancer Res 24: 000, 1983.

    Google Scholar 

  29. Brattain D, Brattain M, Willson J, Long B, Marks M, Chakrabarty S, Miller C: Selection of a non-pleiotropic mitomycin C resistant subpopulation of human colon carcinoma cells. Proc Amer Assoc Cancer Res 25: 332, 1984.

    Google Scholar 

  30. Remers WA: Mitomycin C and analogue development. In: Carter SK, Crooke ST (eds) Mitomycin C: Current status and new developments. Academic Press, New York, 1978, pp 27–32.

    Google Scholar 

  31. Meyn RE, Jenkins SF, Thompson CH: Defective removal of DNA cross-links in a repair deficient mutant of Chinese hamster cells. Cancer Res 42: 3106–3110, 1982.

    Google Scholar 

  32. Fujiwara Y, Tatsumi M, Sasaki MS: Crosslink repair in human cells and its possible defect in Fanconi's anemia cells. J Mol Biol 113: 635–649, 1977.

    Google Scholar 

  33. Kaufman RJ, Schimke RT: Amplification and loss of dihydrofolate reductase genes in a Chinese hamster ovary cell line. Mol Cell Biol 1: 1069–1076, 1981.

    Google Scholar 

  34. Kartner N, Riordan JR, Ling V: P-glycoprotein. Science 221: 1285–1287, 1983.

    Google Scholar 

  35. Bertino JR, Dolnick BJ, Berenson RJ, Scheer DI, Kamen BA: Cellular mechanisms of resistance to methotrexate. In: Sartorelli A, Lazo J, Bertino J (eds) Molecular actions and targets for cancer chemotherapy. Academic Press, New York, 1981, pp 385–400.

    Google Scholar 

  36. Marks ME, Brattain MG: Induction of plasma membrane alterations in AKR-2B mouse embryo fibroblasts by endogenous growth factors from malignant human cells. Int J Cancer 33: 139–146, 1984.

    Google Scholar 

  37. Doolittle RF, Hunkapillar MW, Hood LE, Devare SG, Robbins KC, Aaronson SA, Antoniades HN: Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221: 275–276, 1983.

    Google Scholar 

  38. Waterfield MD, Scrace GT, Whittle N, Stroobant P, Johnsson A, Wateson A, Westermark B, Heldin C-H, Huang JS, Deuel TF: Platelet derived growth factor is structurally related to the putative transforming protein p28 sis of Simian Sarcoma Virus. Nature (Lond) 304: 35–39, 1983.

    Google Scholar 

  39. Hunter T, Sefton BM: The transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Nat'l Acad Sci USA 77: 1311–1315, 1980.

    Google Scholar 

  40. Pike LJ, Marquardt H, Todaro GJ, Gallis B, Casneille JE, Bornstein P, Krebs EG: Transforming growth factor and epidermal growth factor stimulate the phosphorylation of a synthetic, tyrosine-containing peptide in a similar manner. J Biol Chem 257: 14628–14631, 1982.

    Google Scholar 

  41. Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD: Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307: 521–527, 1984.

    Google Scholar 

  42. Halper J, Moses HL: Epithelial tissue derived growth factor-like polypeptides. Cancer Res 43: 1972–1979, 1983.

    Google Scholar 

  43. Tucker RF, Volkenant ME, Branum EL, Moses HL: Comparison of intra-and extracellular transforming growth factors from non-transformed and chemically transformed mouse embryo cells. Cancer Res 43: 1581–1586, 1983.

    Google Scholar 

  44. DeLarco JE, Todaro GJ: Growth factors from murine sarcoma virus-transformed cells. Proc Nat'l Acad Sci USA 75: 4001–4005, 1978.

    Google Scholar 

  45. Sporn MB, Roberts AB, Shull JH, Smith JM, Ward JM, Sodek J: Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science 219: 1329–1331, 1983.

    Google Scholar 

  46. Nicola NA, Metcalf D, Matsumoto M, Johnson GR: Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. J Biol Chem 258: 9017–9023, 1983.

    Google Scholar 

  47. Lotem J, Sachs L: Mechanisms that uncouple growth and differentiation in myeloid leukemia cells: Restoration of requirement for normal growth inducing protein without restoring induction of differentiation inducing protein. Proc Nat'l Acad Sci USA 79: 4347–4351, 1982.

    Google Scholar 

  48. Lotem J, Sachs L: Coupling of growth and differentiation in normal meyloid precursors and the breakdown of this coupling in leukemia. Int J Cancer 32: 127–134, 1983.

    Google Scholar 

  49. Kimball PM, Brattain MG, Pitts AM: A soft agar procedure for measuring the growth of human colonic carcinomas. Br J Cancer 37: 1015–1019, 1978.

    Google Scholar 

  50. Todaro GJ, Fryling C, DeLarco JE: Transforming growth factors produced by certain human tumor cells: polypeptides that interact with epidermal growth factor receptors. Proc Nat'l Acad Sci USA 77: 5258–5262, 1980.

    Google Scholar 

  51. Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB: New class of transforming growth factors potentiated by epidermal growth factor: Isolation from non-neoplastic tissus. Proc Nat'l Acad Sci USA 78: 5339–5343, 1981.

    Google Scholar 

  52. Moses HL, Branum EL, Proper JA, Robinson RA: Transforming growth factor production by chemically transformed cells. Cancer Res 41: 2842–2848, 1981.

    Google Scholar 

  53. Brattain MG, Levine AE: Tumor inhibitory factor. In: Salmon SE, Trent JM (eds) Tumor cloning, Grune and Stratton, New York, 1984, in press.

    Google Scholar 

  54. Levine AE, Hamilton DA, Yeoman LC, Busch H, Brattain MG: Identification of a tumor inhibitory factor in rat ascites fluid. Biochem Biophys Res Commun 119: 76–82, 1984.

    Google Scholar 

  55. Moses HL, Proper JA, Volkenant ME, Wells DJ, Getz MJ: Mechanism of growth arrest of chemically transformed cells in culture. Cancer Res 38: 2807–2812, 1978.

    Google Scholar 

  56. Robinson RA, Volkenant ME, Ryan RJ, Moses HL: Decreased epidermal growth factor biding in cells growth arrested in G by nutrient deficiency. J Cell Phys 109: 517–524, 1981.

    Google Scholar 

  57. Benz EW, Getz MJ, Wells DJ, Moses HL: Nuclear RNA polymerase activities and poly-A containing m-RNA accumulation in cultured AKR mouse embryo cells stimulated to proliferate. Exp Cell Res 108: 157–165, 1977.

    Google Scholar 

  58. Chakrabarty S, McRae LJ, Levine AE, Brattain MG: Restoration of normal growth control and membrane antigens in malignant cells by N,N-dimethylformamide. Cancer Res 44: in press, 1984.

  59. Levine AE, McRae LJ, Hamilton DA, Brattain MG: Effects of dimethylformamide on growth of a transformed cell line. J Cell Biol 97: 70a, 1983.

  60. Butwell T, Hamilton D, McRae LJ, Miller C: Effects of retinoids on transformed AKR-MCA cells. Fed Proc 43: 778, 1984.

    Google Scholar 

  61. Levine AE, Hamilton DA, McRae LJ, Brattain MG: Elevated growth factor levels in transformed cells treated with N,N-dimethylformamide. Cancer Res, in press, 1984.

Download references

Author information

Authors and Affiliations

  1. Bristol-Baylor Laboratory, Dept. of Pharmacology, Baylor College of Medicine, 77030, Houston, TX, USA

    M. G. Brattain, A. E. Levine, S. Chakrabarty & B. Long

  2. Dept. of Pharmacology, Baylor College of Medicine, 77030, Houston, TX, USA

    L. C. Yeoman

  3. Veteran's Administration Hospital, Dept. of Human Oncology, University of Wisconsin, 53705, Madison, WI, USA

    J. K. V. Willson

Authors
  1. M. G. Brattain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. E. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Chakrabarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. C. Yeoman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. K. V. Willson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B. Long
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by NIH Grant 34432 and ACS Grant PDT-109.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brattain, M.G., Levine, A.E., Chakrabarty, S. et al. Heterogeneity of human colon carcinoma. Cancer Metast Rev 3, 177–191 (1984). https://doi.org/10.1007/BF00048384

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00048384

Keywords

Search

Navigation