Low Tumor Strains Research Articles

The middle T proteins of high and low tumor strains of polyomavirus function equivalently in tumor induction

The PTA strain of polyomavirus induces a variety of epithelial as well as mesenchymal tumors at high frequencies, while the RA strain induces only rare mesenchymal tumors following inoculation into newborn mice. DNA sequence analysis has revealed one amino acid difference between the middle T (mT) proteins encoded by these two virus strains. To test for possible biological differences between the mT proteins we constructed a recombinant virus carrying mT-coding sequences of RA on a PTA background. The tumor profile induced by this recombinant is like that of PTA, demonstrating that the transforming protein of the low tumor strain is competent to induce a high tumor profile. We conclude that a structural determinant(s) outside of mT in the PTA virus strain is important in induction of a broad spectrum of tumors and particularly those of epithelial origin.

The middle T proteins of high and low tumor strains of polyomavirus function equivalently in tumor induction

The middle T proteins of high and low tumor strains of polyomavirus function equivalently in tumor induction

Polyomavirus tumor induction in mice: influences of viral coding and noncoding sequences on tumor profiles

We determined the DNA sequences of the noncoding regions of two polyomavirus strains that differ profoundly in their abilities to induce tumors in mice. Differences between strains were found, both on the late side of the replication origin in the region containing known enhancer elements and on the early side of the origin, affecting the number and location of large-T-antigen-binding sites. By constructing and analyzing recombinant viruses between these high- and low-tumor strains, we attempted to localize determinants which affect the frequency and histotype of tumors. Seven recombinants were constructed and propagated in vitro, and the tumor profile of each was established by inoculation into newborn C3H mice. Recombinants containing noncoding sequences from the high-tumor strain and coding sequences from the low-tumor strain behaved like the latter, inducing tumors at a low frequency and strictly of mesenchymal origin. Reciprocal recombinants with noncoding sequences of the low-tumor strain linked to structural determinants from the high-tumor strain induced several types of epithelial tumors typical of the high-tumor strain but at reduced frequency, in addition to mesenchymal tumors. A high frequency and full diversity of epithelial tumors required, in addition to structural regions from the high-tumor strain, noncoding sequences on the early side of the origin also present in this strain. A high-tumor profile thus resulted from the combined effects of structural and regulatory determinants in the high-tumor strain, with the former affecting primarily the tissue tropism and the latter affecting the frequency of tumors. No differential effects of the enhancer regions from the late side of the origin in the two virus strains were seen in this study.

Biophysical and Bioassay Studies on Milk Fractions of Genetically Similar Agent-Bearing and Agent-Free Mouse Substrains<xref ref-type="fn" rid="FN1">2</xref>

Samples of skim milk from 5 mouse strains and substrains (C3H, C3HfB, BALB/c, BALB/cfC3H, BALB/cf wild) were placed on Ficoll density gradients and centrifuged in a Splnee SW39 rotor at 37,000 rpm for 5 hours. The tubes were then arbitrarily divided into quarters, from which samples were taken for bioassay and electron microscopy. Milk from high-tumor-strain mice (C3H, BALB/cf wild, and BALB/cfC3H) contained a dense light-scattering zone, which was absent or greatly diminished in the low-tumor strains (C3HfB, BALB/c), composed of concentrated mammary-tumor virus particles. The zone of high virus-particle concentration in C3H and BALB/cf wild gave positive bioassay (nodule test) at a dilution of 10−5, while the corresponding zone in BALB/c and C3HfB milk was completely negative. Although there is not an absolute correspondence between strain tumor incidence and particle quantity in the milk, nonetheless, high-tumor-strain mice have many more particles than their syngeneic low-tumor-strain counterparts. The 100–110 mµ mammary tumor virions assume a much denser appearance following glutaraldehyde. chrome-osmium fixation than after fixation with chrome-osmium alone.

Heterohemoantibodies in Inbred Strains of Mice

Summary Natural hemagglutinins for sheep and chicken red cells were investigated in mice of 13 inbred strains. In confirmation of earlier work, considerable differences in antibodies were found, depending on the strain tested. Agglutinins for sheep and chicken red cells are independent of each other, as shown by in vitro and in vivo technics. The possible causes and significance of the differences in natural hemoantibodies were discussed, particularly with regard to antigenic composition of mouse tissues, operation of genetic factors, and innate immune response. High incidence of natural sheep agglutinins were found in two low-tumor strains, whereas low incidence and low mean titers were present in 6 high-tumor and 5 low-tumor strains. High mean titers of natural chicken agglutinins were observed in 6 low-tumor strains, whereas low mean titers were obtained in 5 out of 6 high-tumor strains.

Heterohemoantibodies in Inbred Strains of Mice

Summary Titers of immune hemoantibodies in mice of 10 inbred strains revealed characteristic patterns for each strain, with considerable variations between strains. The possible role of genetic, metabolic, and hormonal factors in relation to this difference in response of mice to immunization with hemoantigens was discussed. Among 11 strains tested, all five low-tumor strains showed a high immune response, whereas of six high-tumor or high-leukemia strains, five exhibited a low immune response. A possible interpretation of these findings was presented.

Differences Between High and Low Breast Tumor Strains of Mice When Ovariectomized at Birth.

ConclusionMarked differences appeared in strains of mice when they were ovariectomized at birth and then examined in later life. The high tumor J AX dba and J AX C3H strains showed stimulated uterus, vagina and mammary glands. The adrenal glands exhibited extensive nodular, hyperplastic areas. All of these organs of the low tumor J AX C57 black strain remained essentially unstimulated. To ascertain whether the above differences are characteristic of all high and low tumor strains, other strains are being studied.

Further Studies on Active Milk Influence in Breast Cancer Production in Mice.

ConclusionsThe “breast cancer producing influence” is an actual active “influence” present in the milk of high cancer stock females. It is probably present and active during the entire lactation period.The active influence may be transferred by the inoculation of spleen, thymus, and lactating mammary gland tissue from cancerous stock animals. The active influence probably is not present (or has been destroyed) in the liver of high tumor stock mice. The active influence may be given to 4-week-old females by feeding-by-mouth milk obtained from lactating females of a cancerous stock. Fostered females of low breast tumor strains need not develop breast tumors to transfer the active milk influence by nursing. An active milk influence may be necessary for the development of induced estrogenic breast tumors.(A future publication will show that a low breast tumor strain of mice may “acquire” an active milk influence at any time, resulting in a high breast tumor strain.)

The Incidence of Mammary Tumors among Low-Tumor Strain C57Blk Mice when Foster-Nursed by High-Tumor Strain a Females

In an extensive series of genetic experiments, Murray and Little (11–14) demonstrated that the incidence of mammary tumors among hybrids between strains of mice with a high and a low incidence of such tumors was greatly influenced by an extra-chromosomal factor. The tumor incidence in these hybrids resembled that of the mothers, regardless of the type of cross used. Since only females were considered, the new extra-chromosomal factor appeared to have been due to a maternal influence. Confirmation of these results has been furnished by Korteweg (9) and Bittner (2). In spite of the efficacy of selection in developing strains of mice with a known and predictable incidence of mammary tumors, the extra-chromosomal influence appeared to be much stronger than any possible chromosomal factors. Bittner9s investigations (2–7) indicated that the maternal influence was exerted on the young during the suckling period. He found that the incidence of mammary tumors among hybrids was high if they were foster-nursed by females of a high-mammary-tumor strain and low if suckled by females of a low-tumor strain. These experiments furnished a possible mechanism for the extra-chromosomal maternal influence previously described, since some factor affecting the development of tumors of the mammary gland was obviously transmitted through the milk from the foster parent to the suckling young.

Breast Cancer Produced in Male Mice of the C57 (Black) Strain of Little

Bittner1 has shown that hybrids from a cross between a mouse from a strain having a high incidence of mammary cancer and one from a low tumor strain have a high or low incidence of breast cancer depending on what type of mother they nurse. If the nursing mother comes from the strain having the high incidence of spontaneous tumors, a large percentage of the female hybrids will develop mammary cancer. If they are nursed, on the other hand, by a female from the low tumor strain very few will develop breast cancer. Female mice from a high cancer strain nursed by their own mothers have a high incidence of mammary cancer while if they are foster-nursed by a mouse from a low tumor strain the chance that they will develop breast cancer will be materially reduced.An attempt was made to confirm this observation on a different strain of animals. Mice of the RIII (Paris) strain of Dobrovolskaia Zavadskaia were given to a female of the C57 (black) strain of Little to nurse while the young of the latter were given to t...

Observations on Three Functional Tests in a High-Tumor and a Low-Tumor Strain of Mice

Tar and ultra-violet light both play an important part in the causation of some tumours of the skin in man. This observation has led to many investigations of the effect of light upon experimental tumours produced by tar and benzpyrene. We have found ten relevant papers in the literature. Their results are conflicting and will be reviewed briefly. (1) In an address to the Societe de Biologie , Bang (1922) stated that darkness is without effect upon the production of tar warts in mice. There are but few experimental details in the report. (2) Findlay (1928) found that when mice are tarred and at the same time exposed to a mercury-vapour lamp, the period necessary for the induction of cancer is shorter than with either tar or ultra-violet radiation alone. (3) Kohn-Speyer (1929) repeated Findlay's experiments, but her results showed no summating effect of light. (4) Schorr and Ssobolewa (1930) tarred a small group of mice in the dark. Other mice were tarred and kept in various lights, i.e. , diffuse daylight, red, yellow, green and blue light. Tumours resulted in all the series. The general impression gained was that the dark retarded the appearance of warts and that light increased the dermatitis and caused earlier onset of warts. The various colours had no significant difference in effect. Few mice were used and figures for. the latent period of tumour production are not given.

Some Possible Effects of Nursing on the Mammary Gland Tumor Incidence in Mice

A preliminary report on some possible effects of nursing on the mammary gland tumor incidence in mice is presented. 3 litters of mice from an inbred strain of mice with a mammary gland tumor incidence of 88% were fostered by a strain of mice with a tumor indicence of about 10%. Of the 9 females fostered by the low tumor strain 3 developed mammary gland tumors 4 had primary lung tumors and 2 died nontumorus. Among 40 of their progeny who were fostered 12 developed breast tumors 2 had breast and pulmonary cancers 13 had primary lung tumors and 13 died nontumorus. 10 of the 13 progeny of the fostered females which had breast cancer developed similar growths as compared with 4 of the 24 progeny from fostered females which had lung tumors. The respective proportions were 77% and 17%. These results support the belief in the extrachromosomal influence as a cause in the development of mammary tumor.

SOME POSSIBLE EFFECTS OF NURSING ON THE MAMMARY GLAND TUMOR INCIDENCE IN MICE

A preliminary report on some possible effects of nursing on the mammary gland tumor incidence in mice is presented. 3 litters of mice from an inbred strain of mice with a mammary gland tumor incidence of 88% were fostered by a strain of mice with a tumor indicence of about 10%. Of the 9 females fostered by the low tumor strain 3 developed mammary gland tumors 4 had primary lung tumors and 2 died nontumorus. Among 40 of their progeny who were fostered 12 developed breast tumors 2 had breast and pulmonary cancers 13 had primary lung tumors and 13 died nontumorus. 10 of the 13 progeny of the fostered females which had breast cancer developed similar growths as compared with 4 of the 24 progeny from fostered females which had lung tumors. The respective proportions were 77% and 17%. These results support the belief in the extrachromosomal influence as a cause in the development of mammary tumor.

The Constitutional Factor in the Incidence of Mammary Tumors

The object of the present communication is to establish the fact that, in a mammal which has long been subjected to intensive and extensive laboratory investigations, constitutional factors are normally of prime importance in determining whether or not the individual organism will form a mammary tumor. In addition, constitutional factors may also play an important part in determining what general type of mammary tumor is formed. The material used is mice. It may be well, at the outset, to emphasize the fact that the type of mammary tumor to which reference is ordinarily made in this paper is the common adenoma-carcinoma series in which the epithelial elements are definitely the site of the most pronounced neoplastic development. The distinction between this group and that in which the connective tissue is most active is brought out by a comparison of the incidence of the two types in a reciprocal outcross between two inbred strains, reported by Murray and Little (1935). Cloudman has completed the histological diagnosis of each tumor tabulated. In one outcross (dBF 1 and F 2 ) using females of high mammary tumor stock, there was a total of 239 adenomas and carcinomas, with 4 fibrosarcomas. The percentage of fibrosarcomas is 1.6. In the reciprocal cross (BdF 1 and F 2 ) using females of low mammary tumor stock, among 30 tumors, mammary in position, 9 or 30.0 per cent were fibrosarcomas. The influence of constitution on the incidence of the two types is striking. Long ago Tyzzer, J. A. Murray, Bashford and others showed that mammary tumors occurred much more frequently among the descendants of tumor-forming ancestors than they did among the descendants of mice which did not form mammary tumors. These earlier writers spoke of high-tumor families or strains as contrasted with low-tumor families or strains and expressed their belief that there were constitutional differences at the basis of the distinction between the two groups.

On the Relation between the Incidence of Mammary Cancer and the Nature of the Sexual Cycle in Various Strains of Mice: II. The Relative Constancy of the Characteristics of the Sexual Cycle in these Strains

We recently reported on the character of the estrous cycles of ten different strains of inbred mice (1). These investigations showed variations in the type of estrus, both with respect to individual mice of the same strain, and with respect to the averages in different strains. There was, however, no correlation between the character of the estrous cycle and the incidence of mammary tumors in the various strains; mice of high-tumor strains did not necessarily show more prolonged or more frequent estrous periods than mice of low-tumor strains. Because of the great variation in the character of the estrous cycles of individual mice within any given strain, it was thought possible that the averages found in different strains might be due to coincidence rather than to an inherent characteristic of these strains. In order to determine this point, the estrous cycles of mice, not previously tested, were studied by means of vaginal smears in a new series. For this investigation individuals were selected from two of the same high and two of the same low inbred tumor strains which we had examined in our first series.

STUDIES ON THE RELATION BETWEEN TUMOR SUSCEPTIBILITY AND HEREDITY

A male mouse from a strain with a high incidence of spontaneous lung tumors was crossed with several females derived from a low tumor strain. The first generation of offspring were then backcrossed to individuals of the original strains. The resulting two groups of offspring differed significantly in the incidence of spontaneous tumors of the lung. These facts are discussed in relation to others previously discovered. It seems clear from the evidence presented that there are among mice constitutional types which differ in incidence of tumors of the lung and that the differences are inherited. The number of genetic factors involved has not been determined. No influence of sex was apparent. The possibility of there being genetic factors which affect tumor age will be dealt with later.

STUDIES ON THE RELATION BETWEEN TUMOR SUSCEPTIBILITY AND HEREDITY

Evidence has previously been submitted in favor of the theory that susceptibility to spontaneous tumors of various types is inherited. The question arose whether susceptibility to tumors induced by tar could be shown to be hereditary by experimenting with the same strains of mice which had already been shown to differ significantly in respect to their spontaneous tumor rates. Two strains of mice were selected for observation. One strain, the Bagg albinos, has a low rate of mammary gland tumors but a higher rate of spontaneous lung tumors. The other strain, No. 1194, agouti, has a higher rate of mammary gland tumors but a lower rate of tumors of the lung. A previous test showed no difference in the percentages of skin tumors which arose after tar painting. It has already been shown that the difference in the lung tumor rates is mathematically significant. When the two stocks are treated with tar by applying the irritant, not in the same spot, but on different areas successively, the percentage of lung tumors is increased in each stock, Text-fig. 11. The rate of the Bagg albinos increased from 37.04 to 85 per cent, that of Strain 1194 from 6.73 to 22 per cent. But a difference between them is still maintained, and this difference also is significant mathematically. When the two strains are crossed and the offspring subjected to the tar treatment, the latter give a high percentage of lung tumors-79 per cent in 28 individuals-about the same as the parental high tumor strain. When the F(1) sons are backcrossed to the original See PDF for Structure stocks, the cross to the high tumor strain maintains the high tumor rate, 81 per cent in 37 mice, while in the cross to the low tumor strain the percentage drops to 39 per cent in 38 mice. This result indicates that susceptibility to tar-induced tumors in the lung is hereditary. The number of factors concerned has not yet been ascertained. Possibly one or more of them is dominant. In general, the conception that susceptibility to pulmonary tumors is hereditary seems to be upheld by the fact that the two strains of mice described differ conspicuously in respect to spontaneous tumor rates under ordinary laboratory conditions; the strains differ also under experimental conditions, as described in this report; and when crossed, their offspring by suitable backcrosses, will again show significant differences.

FURTHER INVESTIGATIONS ON THE ORIGIN OF TUMORS IN MICE

FURTHER INVESTIGATIONS ON THE ORIGIN OF TUMORS IN MICE