Many inbred strains of mice have been selected which differ in their inherent ability to develop various types of spontaneous neoplasms. This material is to the biologist what pure chemicals are to the chemist. However, as animals are subject to mutational changes, each experimental series should have adequate controls. Many studies have been reported on the influence of environmental factors upon the genesis of cancer and consequently data obtained in one laboratory should never be used as controls for those secured elsewhere. Only the experimental variable being tested should exist between the animals of the two groups. Reciprocal crosses between inbred strains with either high or low incidences of tumors have demonstrated that the genetic constitution of the host plays an important part in the genesis of leukemia, pulmonary and mammary cancer in mice. In the case of leukemia, while most of the workers agree that susceptibility may be transmited as a dominant complex, the number of genes could not be ascertained because of the action of undetermined environmental factors or, according to MacDowell, a complex interrelationship of modifying influences. Certain unknown factors probably operate also in the development of lung carcinoma and the development of the disease in very old animals makes it difficult to obtain ratios for genetic interpretation. Three primary factors have been demonstrated to interact in the development of spontaneous mammary tumors— genetic susceptibility, hormonal stimuli and a virus, the mammary tumor milk agent. In several studies low incidences have been found in mice that possessed the milk agent and had an adequate hormonal stimulation. Such groups may be considered to be relatively resistant; whether they may be called “non-susceptible” or not is problematic. The interaction of these primary causative factors is complex as shown by the observations that reciprocal hybrids between various cancerous strains may or may not have the same incidences and average cancer ages. The difference observed between two groups of susceptible mice with different agents may be of statistical significance whereas reciprocal groups with the same genetic constitution and milk agent may or may not show comparable data. If two groups of virgin females show a significant variation in incidence and average cancer age, there may be no difference in the incidences in the breeders and the group with the later age as virgins may have an earlier cancer age when maintained as breeders (unpublished). Although not characteristic for all series, in one study the incidence found among the progeny was influenced by the age at which the mothers developed cancer and the litter in which the young were born. Also, the young fostered by mothers that die either cancerous or non-cancerous may show different incidences, regardless of the genetic constitution of the mothers. Analogous results may be noted for the progeny of females of the same litter of an inbred stock. The genetic constitution of the animals also plays an important role in controlling various hormonal mechanisms, one of which, called the inherited hormonal influence, may influence the development of mammary cancer in virgin mice. Various studies were cited to determine the physiologic effects of these hormonal factors and their possible relationship to the genesis of mammary cancer in inbred stocks and their hybrids. Recently it was observed that mice of inbred strains and their hybrids with the mammary tumor milk agent excreted less 17-ketosteroids than did mice of the same stock, or hybrid generation, without the agent. The injection of extracts with the agent altered the excretion rate to that found for animals which obtained the milk virus by nursing. Considerable difference was noted between various susceptible strains. In most of the groups, but not all, the presence of the milk agent was associated with an increased number of positive smears observed during a definite period. The long interval between the introduction of the mammary tumor milk agent, a virus, and the appearance of spontaneous mammary cancer would become apparent if the virus had some role in controlling the metabolism of the hormones. Through such a process the mice with the milk agent might possess an excess of what might be called “carcinogenic” hormones as compared with mice without the agent. These hormones, acting upon susceptible cells, could be the “primary” cause of mammary cancer in mice although the interaction of all the causative factors would be required before a high incidence would be obtained. Thus genetic factors have been demonstrated in the etiology of several types of tumors in mice. The exact genic make-up of the susceptibilities has not been definitely determined because of the possible interaction of other genetic and perhaps unknown “environmental” influences. In the cancerous A strain, linkage between one of the susceptibility genes for spontaneous mammary cancer and the brown gene has been demonstrated.
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Sep 1, 1951
Franz Halberg + 2
Open Access
