Genes and Signal Transduction in Multistage Carcinogenesis

Nancy H. Colburn

• Publisher: CRC Press
• Year: 2020
• Print ISBN: 9780824779962
• eBook ISBN: 9781000147278
• Topic: Medicine
• Subtopic: Genetics in Medicine

This book describes the identification and characterization of genetic loci that determine susceptibility to liver, mammary, or skin carcinogenesis in rodents. It focuses on protein kinases and phospholipases, and stress-related signal transduction.

I GENETIC VARIANTS FOR RESPONSES TO CARCINOGENS, TUMOR PROMOTERS, AND GROWTH FACTORS

1 Genetic Control of Hepatocarcinogenesis in Inbred Mice

Norman R. Drinkwater
University of Wisconsin-Madison, Madison, Wisconsin

INTRODUCTION

Studies of skin tumor induction in mice have allowed the division of carcinogenesis into two experimentally distinguishable stages, initiation and promotion [1], With these observations as a paradigm, two-stage carcinogenesis also has been described for the liver [2] and other tissues [3].

Initiation of carcinogenesis is widely thought to result from the induction of a mutation in the target cell [4]. Recent studies of tumor induction in breast [5,6,], skin [7], and liver [8-10] in rats or mice have implicated at least one family of genes, the ras cellular proto-oncogenes, as targets for initiation of carcinogenesis. A large proportion of chemically induced tumors of these tissues contained mutant c-ras genes capable of transforming NIH3T3 cells after transfection of tumor deoxyribonucleic acid (DNA). It is likely that the induction of these mutations represents initiating events because the DNA sequence changes that resulted in the transforming activity of the mutant genes depended on the chemicals used to induce the tumors [5,6,10].

In contrast to the essentially instantaneous nature of initiation in the target cell, the promotion stage of carcinogenesis represents over time a composite of events involving alterations in the expression of specific genes, proliferation of the initiated cell and its clonal descendants, and the accumulation of additional genetic alterations [11]. Studies of the interaction of specific tumor promoters with cellular components have yielded a powerful biochemical approach to characterizing these events. For example, the identification of protein kinase C as the receptor for the phorbol esters has provided a molecular basis for the diverse activities of this family of tumor promoters [12].

A complementary genetic approach to understanding the complex process of promotion is the characterization of host genes that act as physiological modulators or targets for postinitiation events in carcinogenesis. These genes may be identified by their effects on the susceptibility of the animal to tumor induction. This chapter will describe studies of hepatocarcinogenesis in inbred mouse strains that demonstrate the existence of several polymorphic loci that control susceptibility to liver tumor induction. Also discussed is the characterization of a specific gene, identified through studies of the high susceptibility of C3H mice to hepatocarcinogenesis, that exerts its effect during liver tumor promotion.

VARIATION AMONG INBRED MOUSE STRAINS IN SUSCEPTIBILITY TO SPONTANEOUS AND INDUCED HEPATOCARCINOGENESIS

The earliest demonstration of genetic factors in the development of cancer was the observation of characteristic patterns of spontaneous tumor incidence among inbred mouse strains [13], Most of the common inbred mouse strains were developed between 1910 and 1930 by brother-sister mating of mice derived from various stocks obtained from dealers in the pet mouse trade [14]. In spite of the relatively small population sizes of the progenitor stocks and the common origins of many of the strains, the collection of inbred mouse strains demonstrates an extraordinary degree of genetic variation [15,16]. One measure of genetic diversity is heterozygosity; that is, the probability that an individual will carry two different alleles at a randomly chosen locus. Estimates of the degree of heterozygosity in wild mouse populations range between 0.07 and 0.11 [15,17]. In contrast, the estimated heterozygosity for a population of mice derived from equal numbers of mice from common inbred strains is 0.3-0.4 [15]. Thus, comparison of inbred mouse strains provides a reasonable starting point for the identification of polymorphic loci that influence the susceptibility of mice to hepatocarcinogenesis.

The lifetime liver tumor incidences for untreated male mice from selected inbred strains are summarized in Table 1. These data were obtained from several studies (see Table 1 for references) in which the animals were allowed to live out their natural lifespan under standard laboratory conditions. The data in the table are grouped by families of inbred strains in which the strains share to varying degrees common origins [14]. In addition to the incidence of liver tumors, the 90%-confidencc interval [24] has been calculated to allow comparisons between experiments involving widely differing numbers of animals. Data for liver tumor incidence in female mice are available from the same sources; the

Table Lifetime Spontaneous Incidences of Liver Tumors in Male Inbred Mice

Mouse strain	Median survival (months)	No. mice	Incidence (%)	Refs.
C57/C58 family^a
C57BL/KaLwRij	24.0	232	5.0 (3.1,7.9)^b	18
C57BL/10Sn	32.7	39	2.6 (0.6,5.9)	19
C57BL/6J	19.1	609	3.6 (2.5,5.1)	20
C57BR/cdJ	23.1	48	25 (16,36)	21
C58/J	12.3	51	0 (0,5.0)	21
DBA/Bagg albino family
CBA/BrRij	28.8	179	44 (38,50)	18
C3H/HeDiSn	21.9	61	51 (40,61)	19
DBA/2J	19.8	67	1.5 (0.3,6.5)	22
A/WySn	20.3	61	15 (8.8,24)	19
Balb/cStCrl	17.5	637	3.9 (2.8,5.4)	20
SM/J	18.8	64	0 (0,4.1)	21
101/129/LP family
129/J	29.4	54	0 (0,4.8)	22
LP/J	24.7	77	6.5 (3.2, 13)	22
Swiss family
RF/J	21.4	23	0 (0,11)	21
RFM/UnRij	19.8	326	0 (0,0.8)	18
SWR	23.9	269	1.1 (0.4,2.7)	23
New Zealand family
NZB/lac	18.0	153	2.0 (0.8,4.9)	18

^a Mice are grouped as families of related strains according to [14].

^b Values in parentheses are the lower and upper 90% confidence limits for the incidence of liver tumors.

frequency of liver tumors in female mice is generally lower than for male mice of the same strain and is appreciable (5-20%) only for the C3H and CBA strains [18,19,25].

Few studies of chemically induced hepatocarcinogenesis have compared many inbred mouse strains for their relative susceptibilities to tumor induction. In addition, comparisons between studies are hampered by the variety of agents and protocols used for inducing tumors. In order to provide a basis for comparison, the rank order for susceptibility of inbred strains to induced hepatocarcinogenesis is summarized in Table for several studies in which at least three strains

Table 2 Susceptibilities of Inbred Male Mice to Chemically Induced Hepatocarcinogenesis

Goodall and Lijinksy [26]

(N-nitrosohexamethyleneimine, p.o. for 8 weeks, adults)^a

Male (range 10-53% incidence):

NZB/BIGd, NZC/BIGd #x003C; NZO/BIGd, NZY/BlGd^b

Female (range 0-40% incidence):

NZY/BIGd #x003C; NZB/BIGd,NZC/BIGd, NZO/BIGd

Matsuyama and Suzuki [27]

(ethylcarbamate, four weekly s.c. injections, preweanling)

Male and Female range 12-91% incidence):

AKR/JMs, A/J, dd/I #x003C; SMA #x003C; C57BL/6Ms #x003C; CBA/H

Searle and Jones [28]

(N-ethyl-N-nitrosourea, single i.p. injection, newborn)

Male and Female (range 7-65% incidence):

IF/Bcr, A/Bcr #x003C; DBAf/Bcr #x003C; C57BL/Bcr

Flaks [29]

(7,1...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Preface
• Contents
• Contributors
• Part I Genetic Variants for Responses to Carcinogens, Tumor Promoters, and Growth Factors
• Part II Genes That Confer Susceptibility to Neoplastic Transformation
• Part III Signal Transduction: Protein Kinases and Phospholipases
• Part IV Stress-Associated Signals and Gene Regulation
• Index