Isozyme alterations, gene regulation and the neoplastic transformation

doi:10.1016/0065-2571(83)90024-9

Advances in Enzyme Regulation

Volume 21, 1983, Pages 369-386

https://doi.org/10.1016/0065-2571(83)90024-9 Get rights and content

Abstract

Studies of isozyme composition in the rat liver-hepatocellular carcinoma model system have revealed wide-ranging abnormalities of gene expression. Isozymes geared for adult liver function are lost in tumors to varying degrees, depending on growth rate and degree of tumor dedifferentiation; whereas isozymes low or absent in normal adult liver become predominant or sole forms in fast growing, poorly differentiated hepatic tumors. The prevailing pattern is a switch from the adult to fetal forms, thereby indicating that genes coding for adult isozymes are suppressed in liver neoplasms, while genes active in fetal stages but inactivated during normal embryonic development become re-activated in cancer. These isozyme alterations not only are a key to neoplastic behavior, but are a striking example, among many, of pervasive abnormalities of gene expression involving virtually every means of identification of gene products; for example, the expression in tumors of fetal antigens, growth factors, angiogenesis factors, membrane components, and ectopic polypeptide hormones. Most important is the recently discovered activation of normally silent host oncogenes associated with and probably causally related to viral or chemical carcinogenesis.

Despite compelling evidence for somatic mutation, these findings argue for abnormal gene regulation in cancer rather than gene mutation. Uriel has proposed that retrodifferentiation to an embryonal stage is a normal response to cell injury, and is an essential step preceding normal re-ordering of gene regulation. Under the influence of a carcinogen, however, normal differentiation may be aborted before differentiation is complete and the resultant transformed cell would then not be subject to normal regulatory restraiants. A similar hyothesis has been expressed by Potter in the aphorism “Oncogeny is blocked ontogeny.”

Evidence exists for a role of 5-methylcytosine as a regulatory site in gene transcription. Jonathan Nyce, in a Ph.D. thesis presented to the Biology Department of Temple University, has proposed a mechanism of chemical carcinogenesis, based on the loss of cytosine residues, and therefore of methylation sites, in DNA as a result either of mispairing of bases resulting from O₆-alkylation of guanines in DNA: or by inhibition of cytosine methylation. This plausible proposal provides a molecular basis for the many aberrations of gene regulation in cancer.

References (78)

S. Weinhouse
Oxidative metabolism of neoplastic tissues
Advances in Cancer Res.
(1955)
C.T. Gregg
Some aspects of the energy metabolism of mammalian cells
H.P. Morris
Studies on the development, biochemistry and biology of experimental hepatomas
Advances in Cancer Res.
(1965)
S. Weinhouse
Regulation of glucokinase in liver
Curr. Top. Cell. Regul.
(1976)
K.H. Ibsen et al.
Developmental gene expression in cancer
Biochim. Biophys. Acta
(1979)
J.H. Coggin et al.
Embryonic and fetal antigens in cancer
R.G. Martin
The transformation of cell growth and transmogrification of DNA synthesis by simian virus 40
Advances in Cancer Res.
(1981)
S. Strickland et al.
Plasminogen activator in early embryogenesis: enzyme production of trophoblast and parietal endoderm
Cell
(1976)
H. Imura
Ectopic hormone production viewed as an abnormality in regulation of gene expression
Advances in Cancer Res.
(1980)
J.M. Bishop
Retroviruses and cancer genes
Advances in Cancer Res.
(1982)

R.A. Weinberg

Oncogenes of spontaneous and chemically induced tumors

Advances in Cancer Res.

(1982)

A.G. Knudson

Mutation and human cancer

Advances in Cancer Res.

(1973)

G.V. Sherbet

Epigenetic processes and their relevance to the study of neoplasia

Advances in Cancer Res.

(1970)

B. Mintz et al.

Teratocarcinomas and other neoplasms as developmental defects in gene expression

Advances in Cancer Res.

(1981)

C. Basilico

Temperature-sensitive mutations in cancer cells

Advances in Cancer Res.

(1977)

J. Uriel

Retrodifferentiation and the fetal patterns of gene expression in cancer

Advances in Cancer Res.

(1979)

L.L. Gerchman et al.

The properties of O⁶-methylguanine in templates for RNA polymerase

Biochim. Biophys. Acta

(1973)

T. Bryngelsson et al.

Purine base composition analysis of normal and tumor rat DNA

Chem. Biol. Inter.

(1980)

J.-N. Lapeyre et al.

5-Methylcytosine content of nuclear DNA during chemical carcinogenesis and in carcinomas which result

Biochem. Biophys. Res. Commun.

(1979)

P.A. Jones et al.

Cellular differentiation, cytidine analogs and DNA methylation

Cell

(1980)

A.G. Weinberg et al.

The occurrence of hepatoma in the chronic form of hereditary tyrosinemia

J. Pediatrics

(1976)

P.I. Forrester et al.

Theoretical mechanisms for synthesis of carcinogen-induced embryonic protein

Medical Hypotheses

(1978)

O. Warburg

The Metabolism of Tumors

(1930)

S. Weinhouse

On respiratory impairment in cancer cells

Science

(1956)

C.E. Wenner

Regulation of energy metabolism in normal and tumor tissues

A. C. AISENBERG, The Glycolysis and Respiration of Tumors. Academic Press, and London and New York...

S. Weinhouse

Glycolysis, respiration and anomalous gene expression in experimental hepatomas

Cancer Res.

(1972)

S. Weinhouse

The Warburg hypothesis fifty years later

Z. Krebsforschung

(1976)

S. Weinhouse

Changing perceptions of carbohydrate metabolism in tumors

S. Weinhouse

Metabolic fuels of cancer cells

G. Weber et al.

Comparative biochemistry of hepatomas

V.R. Potter

Transplantable animal cancer

J.B. Shatton et al.

Kinetic, electrophoretic, and chromatographic studies on glucose-ATP phosphotransferases in rat liver and hepatomas

Cancer Res.

(1969)

F. Schapira et al.

Anomaly of aldolase in primary liver cancer

Nature

(1963)

R.C. Adelman et al.

Fructokinase, triokinase, and aldolases in liver tumors of the rat

Cancer Res.

(1967)

M. Gosalvez et al.

Stimulation of tumor-cell respiration by inhibitors of pyruvate kinase

Europ. J. Biochem.

(1975)

K. Sato et al.

Characterization of glycogen synthetases and phosphorylases in transplantable rat hepatomas

Cancer Res.

(1973)

P. Gold

Embryonic origin of human tumor-specific antigens

Prog. Exp. Tumor Res.

(1971)

D.M. Goldenberg

Oncofetal and other tumor-associated antigens of the human digestive system

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Isozyme alterations, gene regulation and the neoplastic transformation

Abstract

Advances in Cancer Res.

Advances in Cancer Res.

Curr. Top. Cell. Regul.

Biochim. Biophys. Acta

Advances in Cancer Res.

Cell

Advances in Cancer Res.

Advances in Cancer Res.

Advances in Cancer Res.

Advances in Cancer Res.

Advances in Cancer Res.

Advances in Cancer Res.

Advances in Cancer Res.

Advances in Cancer Res.

Biochim. Biophys. Acta

Chem. Biol. Inter.

Biochem. Biophys. Res. Commun.

Cell

J. Pediatrics

Medical Hypotheses

The Metabolism of Tumors

On respiratory impairment in cancer cells

Science

Regulation of energy metabolism in normal and tumor tissues

Glycolysis, respiration and anomalous gene expression in experimental hepatomas

Cancer Res.

The Warburg hypothesis fifty years later

Z. Krebsforschung

Changing perceptions of carbohydrate metabolism in tumors

Metabolic fuels of cancer cells

Comparative biochemistry of hepatomas

Transplantable animal cancer

Kinetic, electrophoretic, and chromatographic studies on glucose-ATP phosphotransferases in rat liver and hepatomas

Cancer Res.

Anomaly of aldolase in primary liver cancer

Nature

Fructokinase, triokinase, and aldolases in liver tumors of the rat

Cancer Res.

Stimulation of tumor-cell respiration by inhibitors of pyruvate kinase

Europ. J. Biochem.

Characterization of glycogen synthetases and phosphorylases in transplantable rat hepatomas

Cancer Res.

Embryonic origin of human tumor-specific antigens

Prog. Exp. Tumor Res.

Oncofetal and other tumor-associated antigens of the human digestive system