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

Michele C. Goyette, Kathleen Cho, Clare L. Fasching, Daniel B. Levy, Kenneth W Kinzler, Christos Paraskeva, Bert Vogelstein, Eric J. Stanbridge

Research output: Contribution to journalArticle

Abstract

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 5 express the APC gene present on that chromosome as well as the endogenous mutant transcript. Expression of the putative tumor suppressor gene, DCC, was seen in the clones containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of the irrelevant chromosome 15 had no effect on in vitro cell growth or tumorigenic potential. Responsiveness to the inhibitory growth effects of transforming growth factor β1 was also examined. The introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer of 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.

Original languageEnglish (US)
Pages (from-to)1387-1395
Number of pages9
JournalMolecular and Cellular Biology
Volume12
Issue number3
StatePublished - Mar 1992

Fingerprint

Chromosomes, Human, Pair 18
Chromosomes, Human, Pair 5
Tumor Suppressor Genes
Colorectal Neoplasms
Chromosomes
Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 17
Growth
Cell Line
Clone Cells
APC Genes
Neoplasms
ras Genes
Human Chromosomes
Transforming Growth Factors
Tumor Cell Line
Oncogenes
Molecular Biology
Carcinogenesis
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

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. / Goyette, Michele C.; Cho, Kathleen; Fasching, Clare L.; Levy, Daniel B.; Kinzler, Kenneth W; Paraskeva, Christos; Vogelstein, Bert; Stanbridge, Eric J.

In: Molecular and Cellular Biology, Vol. 12, No. 3, 03.1992, p. 1387-1395.

Research output: Contribution to journalArticle

@article{637967ab110b470a8b6d6725afbb3aad,
title = "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",
abstract = "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 5 express the APC gene present on that chromosome as well as the endogenous mutant transcript. Expression of the putative tumor suppressor gene, DCC, was seen in the clones containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of the irrelevant chromosome 15 had no effect on in vitro cell growth or tumorigenic potential. Responsiveness to the inhibitory growth effects of transforming growth factor β1 was also examined. The introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer of 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.",
author = "Goyette, {Michele C.} and Kathleen Cho and Fasching, {Clare L.} and Levy, {Daniel B.} and Kinzler, {Kenneth W} and Christos Paraskeva and Bert Vogelstein and Stanbridge, {Eric J.}",
year = "1992",
month = "3",
language = "English (US)",
volume = "12",
pages = "1387--1395",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "3",

}

TY - JOUR

T1 - 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

AU - Goyette, Michele C.

AU - Cho, Kathleen

AU - Fasching, Clare L.

AU - Levy, Daniel B.

AU - Kinzler, Kenneth W

AU - Paraskeva, Christos

AU - Vogelstein, Bert

AU - Stanbridge, Eric J.

PY - 1992/3

Y1 - 1992/3

N2 - 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 5 express the APC gene present on that chromosome as well as the endogenous mutant transcript. Expression of the putative tumor suppressor gene, DCC, was seen in the clones containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of the irrelevant chromosome 15 had no effect on in vitro cell growth or tumorigenic potential. Responsiveness to the inhibitory growth effects of transforming growth factor β1 was also examined. The introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer of 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.

AB - 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 5 express the APC gene present on that chromosome as well as the endogenous mutant transcript. Expression of the putative tumor suppressor gene, DCC, was seen in the clones containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of the irrelevant chromosome 15 had no effect on in vitro cell growth or tumorigenic potential. Responsiveness to the inhibitory growth effects of transforming growth factor β1 was also examined. The introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer of 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.

UR - http://www.scopus.com/inward/record.url?scp=0026515183&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026515183&partnerID=8YFLogxK

M3 - Article

VL - 12

SP - 1387

EP - 1395

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 3

ER -