Publisher Summary This chapter provides information on lung tumors in mice, with emphasis on the use of mouse lung for quantitative investigations in carcinogenesis, especially bioassay of chemicals for carcinogenic activity. The lung-tumor response in strain A mice is easily and clearly positive to all major types of chemical carcinogens. Strain A mice are the most susceptible to a wide variety of carcinogens, in terms of the earlier appearance and greater multiplicity of tumors. The lung-tumor response in strain A mice is easily and clearly positive to all major types of chemical carcinogens. Estrogenic and other steroid hormones, with the targets of endocrine-regulated tissues, are an exception. The lung tumor of the mouse has demonstrated its ability to pick up undetected, unpredicted neoplastic responses such as to urethane and to isoniazid. The carcinogens picked up by the lung tumor system have been shown to be carcinogenic for other tissues and in other species of animals. The mouse lung tumor is a reproducible, stable, and rapid biological model for a wide variety of quantitative investigations in carcinogenesis. It provides a three-dimensional lattice of the lung in which a known, identifiable subpopulation of cells—the type 2 alveolar pneumocytes—can be accelerated into conversion into neoplasms.

Lung tumors in mice: application to carcinogenesis bioassay.

An extensive literature suggesting that PRL, GH, IGF-I, and thyroid hormones play an important role in immunity has evolved. Because the use of one or more of these hormones as immunostimulants in humans is being considered, it is of critical importance to resolve their precise role in immunity. This review addresses new experimental evidence from analysis of lymphocyte development and function in mice with genetic defects in expression of these hormones or their receptors that calls into question the presumed role played by some of these hormones and reveals unexpected effects of others. These recent findings from the mutant mouse models are integrated and placed in context of the wider literature on endocrine-immune system interactions. The hypothesis that will be developed is that, with the exception of a role for thyroid hormones in B cell development, PRL, GH, and IGF-I are not obligate immunoregulators. Instead, they apparently act as anabolic and stress-modulating hormones in most cells, including those of the immune system.

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The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency.

Publisher Summary This chapter reviews some of the experimental and clinical findings linking immunodepression with malignant development. This material has accumulated for the past two decades and sufficient information, whether contradictory or not, is now available to permit an appraisal of the role of immune functions as the regulators of tumor development in animals and man. The idea that immunodepression enhances malignant development has become an integral part of the experimental support of the immune surveillance theory. In its more formal presentations, the theory of immunological surveillance against neoplasia included some basic points, with variations in terminology, but which have appeared with regularity as an integral part of the theory. The degree of immunodepression obtained in many experiments is quite profound and is clearly of a different magnitude than the immune defects occasionally observed in tumor-bearing humans. If immune mechanisms are important in host resistance to antigenic malignancies, any interference with the normal expression of host immunity should facilitate malignant development. Thus, both clinical and experimental evidence indicates that the diseases or procedures that lower the immune functions in mammals are associated with a higher incidence of malignancies.

Immunodepression and malignancy.

The Snell dwarf mutation Pit1dw can increase life span in mice

The haemopoietic microenvironment.

NEWBORN and very young Snell/Bagg pituitary dwarf mice have nearly normal lymphoid systems and immunological responses. Beyond the age of weaning, however, the mice fail to grow and show progressive depletion of the lymphoid system and increasing failure to respond to certain antigenic stimuli1,4. Deficiencies of both the lymphoid system and the immune response have, however, proved susceptible to correction by injection of growth hormone and thyroxine5,6. In suckling mice, the inadequate anterior pituitary secretion is to some extent compensated for by the hormones from the mother, but after weaning, growth ceases and the lymphoid system becomes progressively less normal. The corollary of this argument is that there is a critical stage in the development of either the whole animal or the lymphoid system in an intact animal which requires growth hormone and thyroxine. If these materials are made available by injection during this critical period into an animal which cannot make them in adequate amounts, the further history of the animal is unremarkable. The further description of the phenomenon requires delineation of the target organ or organs of the hormones. One step is to determine which axis (either thymus-derived (T) or bone marrow-derived (B)) of the lymphoid system is most affected in dwarf mice. The case has been made out that it is the T cell system7. This study gives information which is not compatible with such a simple notion.

Delayed hypersensitivity in the hereditary pituitary dwarf snell-bagg mouse.

The effects of ALS (anti-lymphocyte serum) and NRS (normal rabbit serum) treatments on the development of malignant lymphoma, lung, subcutaneous and skin tumors induced in mice by 7,12-dimethylbenz (a) anthracene (DMBA) are described. Groups of Charles-River mice, injected at birth with a dose of 100 μg of DMBA, received a single injection of ALS or NRS at the same time as DMBA administration or 10, 20, 30, 40 and 50 days after birth. Incidence, latency, histology and spread of the tumors were studied in all groups. It was found that both ALS and NRS increased tumor incidence and shortened their latency period. Malignant lymphomas were the main tumors whose latency was shortened either by ALS or NRS treatment. In addition ALS treatment apparently increased dissemination of DMBA induced lymphoma in bone marrow.

[Effects of a single dose of antilymphocyte serum on tumors induced in mice by 7,12-dimethylbenz(a)anthracene injected at birth].

The present paper describes the effects of repeated administration of rabbit anti-mouse lymphocyte serum (ALS) or normal rabbit serum (NRS) on tumors induced in Charles–River mice by 7,12-dimethylbenz (a) anthracene (DMBA) given at birth. ALS or NRS were given at the same time of DMBA administration and subsequently at weekly intervals for the first 10 weeks of life or at daily intervals for 7 days during the first, second, third or fourth week of life. Incidence, latency, diffusion and histology of the tumors were studied. It was found that either chronic administration of ALS or treatment of very young mice with the serum, greatly reduced the mean survival time of mice, markedly increased the number of tumor bearing mice and the incidence of all histological types of tumors, and decreased their latency period. Administration of ALS in the other experimental groups gave results essentially similar to those observed in DMBA control and NRS treated mice.

Anna Cavallero

Papers

Delayed hypersensitivity in the hereditary pituitary dwarf snell-bagg mouse.

[Effects of a single dose of antilymphocyte serum on tumors induced in mice by 7,12-dimethylbenz(a)anthracene injected at birth].

[Effects of repeated administration of antilymphocyte serum on tumors induced in mice by 7,12-dimethylbenz(a)anthracene injected at birth].