Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. 1992 Mar; 12(3): 1387–1395.
PMCID: PMC369572

Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer.


Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. [PubMed]
  • Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990 Aug 24;249(4971):912–915. [PubMed]
  • Bischoff JR, Friedman PN, Marshak DR, Prives C, Beach D. Human p53 is phosphorylated by p60-cdc2 and cyclin B-cdc2. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4766–4770. [PMC free article] [PubMed]
  • Bodmer WF, Bailey CJ, Bodmer J, Bussey HJ, Ellis A, Gorman P, Lucibello FC, Murday VA, Rider SH, Scambler P, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. [PubMed]
  • Capon DJ, Seeburg PH, McGrath JP, Hayflick JS, Edman U, Levinson AD, Goeddel DV. Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations. Nature. 1983 Aug 11;304(5926):507–513. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Deppert W, Haug M. Evidence for free and metabolically stable p53 protein in nuclear subfractions of simian virus 40-transformed cells. Mol Cell Biol. 1986 Jun;6(6):2233–2240. [PMC free article] [PubMed]
  • Farr CJ, Marshall CJ, Easty DJ, Wright NA, Powell SC, Paraskeva C. A study of ras gene mutations in colonic adenomas from familial polyposis coli patients. Oncogene. 1988 Dec;3(6):673–678. [PubMed]
  • Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. [PubMed]
  • Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. [PubMed]
  • Fields S, Jang SK. Presence of a potent transcription activating sequence in the p53 protein. Science. 1990 Aug 31;249(4972):1046–1049. [PubMed]
  • Geiser AG, Anderson MJ, Stanbridge EJ. Suppression of tumorigenicity in human cell hybrids derived from cell lines expressing different activated ras oncogenes. Cancer Res. 1989 Mar 15;49(6):1572–1577. [PubMed]
  • Graham FL, van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. [PubMed]
  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991 Aug 9;66(3):589–600. [PubMed]
  • Harris H, Miller OJ, Klein G, Worst P, Tachibana T. Suppression of malignancy by cell fusion. Nature. 1969 Jul 26;223(5204):363–368. [PubMed]
  • Ignotz RA, Massagué J. Cell adhesion protein receptors as targets for transforming growth factor-beta action. Cell. 1987 Oct 23;51(2):189–197. [PubMed]
  • Joslyn G, Carlson M, Thliveris A, Albertsen H, Gelbert L, Samowitz W, Groden J, Stevens J, Spirio L, Robertson M, et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell. 1991 Aug 9;66(3):601–613. [PubMed]
  • Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991 Jun 21;252(5013):1708–1711. [PubMed]
  • Kimchi A, Wang XF, Weinberg RA, Cheifetz S, Massagué J. Absence of TGF-beta receptors and growth inhibitory responses in retinoblastoma cells. Science. 1988 Apr 8;240(4849):196–199. [PubMed]
  • Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, et al. Identification of FAP locus genes from chromosome 5q21. Science. 1991 Aug 9;253(5020):661–665. [PubMed]
  • Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hamilton SR, Hedge P, Markham A, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991 Mar 15;251(4999):1366–1370. [PubMed]
  • Knudson AG., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. [PMC free article] [PubMed]
  • Knudson AG., Jr Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985 Apr;45(4):1437–1443. [PubMed]
  • Leibovitz A, Stinson JC, McCombs WB, 3rd, McCoy CE, Mazur KC, Mabry ND. Classification of human colorectal adenocarcinoma cell lines. Cancer Res. 1976 Dec;36(12):4562–4569. [PubMed]
  • Leppert M, Dobbs M, Scambler P, O'Connell P, Nakamura Y, Stauffer D, Woodward S, Burt R, Hughes J, Gardner E, et al. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science. 1987 Dec 4;238(4832):1411–1413. [PubMed]
  • Levine AJ, Momand J. Tumor suppressor genes: the p53 and retinoblastoma sensitivity genes and gene products. Biochim Biophys Acta. 1990 Jun 1;1032(1):119–136. [PubMed]
  • Smith IE. LHRH analogues in breast cancer: clever, but do we need them? Br J Cancer. 1991 Jan;63(1):15–16. [PMC free article] [PubMed]
  • Manning AM, Williams AC, Game SM, Paraskeva C. Differential sensitivity of human colonic adenoma and carcinoma cells to transforming growth factor beta (TGF-beta): conversion of an adenoma cell line to a tumorigenic phenotype is accompanied by a reduced response to the inhibitory effects of TGF-beta. Oncogene. 1991 Aug;6(8):1471–1476. [PubMed]
  • McCoy MS, Bargmann CI, Weinberg RA. Human colon carcinoma Ki-ras2 oncogene and its corresponding proto-oncogene. Mol Cell Biol. 1984 Aug;4(8):1577–1582. [PMC free article] [PubMed]
  • Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. [PubMed]
  • Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991 Aug 9;253(5020):665–669. [PubMed]
  • Noonan KE, Roninson IB. mRNA phenotyping by enzymatic amplification of randomly primed cDNA. Nucleic Acids Res. 1988 Nov 11;16(21):10366–10366. [PMC free article] [PubMed]
  • Paraskeva C, Harvey A, Finerty S, Powell S. Possible involvement of chromosome 1 in in vitro immortalization: evidence from progression of a human adenoma-derived cell line in vitro. Int J Cancer. 1989 Apr 15;43(4):743–746. [PubMed]
  • Pignatelli M, Bodmer WF. Integrin-receptor-mediated differentiation and growth inhibition are enhanced by transforming growth factor-beta in colorectal tumour cells grown in collagen gel. Int J Cancer. 1989 Sep 15;44(3):518–523. [PubMed]
  • Raycroft L, Wu HY, Lozano G. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science. 1990 Aug 31;249(4972):1049–1051. [PMC free article] [PubMed]
  • Roberts AB, Heine UI, Flanders KC, Sporn MB. Transforming growth factor-beta. Major role in regulation of extracellular matrix. Ann N Y Acad Sci. 1990;580:225–232. [PubMed]
  • Saxon PJ, Srivatsan ES, Stanbridge EJ. Introduction of human chromosome 11 via microcell transfer controls tumorigenic expression of HeLa cells. EMBO J. 1986 Dec 20;5(13):3461–3466. [PMC free article] [PubMed]
  • Saxon PJ, Srivatsan ES, Leipzig GV, Sameshima JH, Stanbridge EJ. Selective transfer of individual human chromosomes to recipient cells. Mol Cell Biol. 1985 Jan;5(1):140–146. [PMC free article] [PubMed]
  • Stanbridge EJ. A case for human tumor-suppressor genes. Bioessays. 1985 Dec;3(6):252–255. [PubMed]
  • Stanbridge EJ. Human tumor suppressor genes. Annu Rev Genet. 1990;24:615–657. [PubMed]
  • Stanbridge EJ, Der CJ, Doersen CJ, Nishimi RY, Peehl DM, Weissman BE, Wilkinson JE. Human cell hybrids: analysis of transformation and tumorigenicity. Science. 1982 Jan 15;215(4530):252–259. [PubMed]
  • Stanbridge EJ, Wilkinson J. Analysis of malignancy in human cells: malignant and transformed phenotypes are under separate genetic control. Proc Natl Acad Sci U S A. 1978 Mar;75(3):1466–1469. [PMC free article] [PubMed]
  • Stanbridge EJ, Wilkinson J. Dissociation of anchorage independence form tumorigenicity in human cell hybrids. Int J Cancer. 1980 Jul 15;26(1):1–8. [PubMed]
  • Steinmeyer K, Deppert W. DNA binding properties of murine p53. Oncogene. 1988 Nov;3(5):501–507. [PubMed]
  • Tanaka K, Oshimura M, Kikuchi R, Seki M, Hayashi T, Miyaki M. Suppression of tumorigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. Nature. 1991 Jan 24;349(6307):340–342. [PubMed]
  • Trent JM, Stanbridge EJ, McBride HL, Meese EU, Casey G, Araujo DE, Witkowski CM, Nagle RB. Tumorigenicity in human melanoma cell lines controlled by introduction of human chromosome 6. Science. 1990 Feb 2;247(4942):568–571. [PubMed]
  • Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. [PubMed]
  • Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y, White R. Allelotype of colorectal carcinomas. Science. 1989 Apr 14;244(4901):207–211. [PubMed]
  • Weissman BE, Saxon PJ, Pasquale SR, Jones GR, Geiser AG, Stanbridge EJ. Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression. Science. 1987 Apr 10;236(4798):175–180. [PubMed]
  • Williams AC, Harper SJ, Paraskeva C. Neoplastic transformation of a human colonic epithelial cell line: in vitro evidence for the adenoma to carcinoma sequence. Cancer Res. 1990 Aug 1;50(15):4724–4730. [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    NCBI Bookshelf books that cite the current articles.
  • Compound
    PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...