A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene

Sanford D. Markowitz, Lois Myeroff, Mark J. Cooper, June Traicoff, Mary Kochera, James Lutterbaugh, Margaret Swiriduk, James K V Willson

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonie cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation.

Original languageEnglish (US)
Pages (from-to)1005-1013
Number of pages9
JournalJournal of Clinical Investigation
Volume93
Issue number3
StatePublished - Mar 1994

Fingerprint

Tumor Suppressor Genes
Oncogenes
Transforming Growth Factor beta
Adenoma
Colonic Neoplasms
Colon
Epidermal Growth Factor
Cell Line
Agar
Intercellular Signaling Peptides and Proteins
Growth
Alleles
Mutation
Serum
Heterografts
Nude Mice
Clone Cells
Genotype

Keywords

  • APC
  • DCC
  • k-ras
  • p53
  • Transforming growth factors

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene. / Markowitz, Sanford D.; Myeroff, Lois; Cooper, Mark J.; Traicoff, June; Kochera, Mary; Lutterbaugh, James; Swiriduk, Margaret; Willson, James K V.

In: Journal of Clinical Investigation, Vol. 93, No. 3, 03.1994, p. 1005-1013.

Research output: Contribution to journalArticle

Markowitz, Sanford D. ; Myeroff, Lois ; Cooper, Mark J. ; Traicoff, June ; Kochera, Mary ; Lutterbaugh, James ; Swiriduk, Margaret ; Willson, James K V. / A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene. In: Journal of Clinical Investigation. 1994 ; Vol. 93, No. 3. pp. 1005-1013.
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abstract = "We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonie cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation.",
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