The intestinal epithelium and its neoplasms: Genetic, cellular and tissue interactions

William F. Dove, Robert T. Cormier, Karen A. Gould, Richard B. Halberg, Anita J. Merritt, Michael A. Newton, Alexander R. Shoemaker

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and finally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion. The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these, Mom1, has now been rigorously identified at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when tumours arise in Moral heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post-mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modifier gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question. Beyond Mom1, other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to find ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors influence the epidemiology of human colon cancer. Even if a candidate modifier does not explain any of the genetic epidemiology of colon cancer in human populations, modifier activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.

Original languageEnglish (US)
Pages (from-to)915-923
Number of pages9
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Volume353
Issue number1370
DOIs
StatePublished - Jun 29 1998

Fingerprint

Intestinal Mucosa
intestinal mucosa
allele
Genes
Tissue
Tumors
neoplasms
Phospholipases
tumor
gene
cancer
mice
Alleles
Neoplasms
epidemiology
loci
modifiers (genes)
Bearings (structural)
adenoma
alleles

Keywords

  • APC/Apc
  • Cancer genetics
  • Clonality
  • Knudson hypothesis
  • Min mouse
  • Mom1 modifier locus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

The intestinal epithelium and its neoplasms : Genetic, cellular and tissue interactions. / Dove, William F.; Cormier, Robert T.; Gould, Karen A.; Halberg, Richard B.; Merritt, Anita J.; Newton, Michael A.; Shoemaker, Alexander R.

In: Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 353, No. 1370, 29.06.1998, p. 915-923.

Research output: Contribution to journalArticle

Dove, William F. ; Cormier, Robert T. ; Gould, Karen A. ; Halberg, Richard B. ; Merritt, Anita J. ; Newton, Michael A. ; Shoemaker, Alexander R. / The intestinal epithelium and its neoplasms : Genetic, cellular and tissue interactions. In: Philosophical Transactions of the Royal Society B: Biological Sciences. 1998 ; Vol. 353, No. 1370. pp. 915-923.
@article{496909fdb89c4c228abc4e32f7712029,
title = "The intestinal epithelium and its neoplasms: Genetic, cellular and tissue interactions",
abstract = "The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and finally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion. The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these, Mom1, has now been rigorously identified at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when tumours arise in Moral heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post-mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modifier gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question. Beyond Mom1, other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to find ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors influence the epidemiology of human colon cancer. Even if a candidate modifier does not explain any of the genetic epidemiology of colon cancer in human populations, modifier activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.",
keywords = "APC/Apc, Cancer genetics, Clonality, Knudson hypothesis, Min mouse, Mom1 modifier locus",
author = "Dove, {William F.} and Cormier, {Robert T.} and Gould, {Karen A.} and Halberg, {Richard B.} and Merritt, {Anita J.} and Newton, {Michael A.} and Shoemaker, {Alexander R.}",
year = "1998",
month = "6",
day = "29",
doi = "10.1098/rstb.1998.0256",
language = "English (US)",
volume = "353",
pages = "915--923",
journal = "Philosophical Transactions of the Royal Society B: Biological Sciences",
issn = "0800-4622",
publisher = "Royal Society of London",
number = "1370",

}

TY - JOUR

T1 - The intestinal epithelium and its neoplasms

T2 - Genetic, cellular and tissue interactions

AU - Dove, William F.

AU - Cormier, Robert T.

AU - Gould, Karen A.

AU - Halberg, Richard B.

AU - Merritt, Anita J.

AU - Newton, Michael A.

AU - Shoemaker, Alexander R.

PY - 1998/6/29

Y1 - 1998/6/29

N2 - The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and finally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion. The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these, Mom1, has now been rigorously identified at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when tumours arise in Moral heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post-mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modifier gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question. Beyond Mom1, other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to find ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors influence the epidemiology of human colon cancer. Even if a candidate modifier does not explain any of the genetic epidemiology of colon cancer in human populations, modifier activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.

AB - The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and finally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion. The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these, Mom1, has now been rigorously identified at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when tumours arise in Moral heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post-mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modifier gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question. Beyond Mom1, other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to find ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors influence the epidemiology of human colon cancer. Even if a candidate modifier does not explain any of the genetic epidemiology of colon cancer in human populations, modifier activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.

KW - APC/Apc

KW - Cancer genetics

KW - Clonality

KW - Knudson hypothesis

KW - Min mouse

KW - Mom1 modifier locus

UR - http://www.scopus.com/inward/record.url?scp=0032577987&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032577987&partnerID=8YFLogxK

U2 - 10.1098/rstb.1998.0256

DO - 10.1098/rstb.1998.0256

M3 - Article

C2 - 9684289

AN - SCOPUS:0032577987

VL - 353

SP - 915

EP - 923

JO - Philosophical Transactions of the Royal Society B: Biological Sciences

JF - Philosophical Transactions of the Royal Society B: Biological Sciences

SN - 0800-4622

IS - 1370

ER -