ANIMAL MODEL OF HUMAN DISEASE ~
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Pituitary Tumors m
Animal Model: Pituitary Tumors in Rats
Contrbuted by. Akihiro Ito, MD, Institute of Cancer Research and Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032.
Fsb
Five types of functional cells are well recognized in the anterior lobe of the pituitary (pars distalis). Of these, four are known to give rise to tumors in both man and the rat: a) The prolactin-secreting tumors (MtT) can be induced almost invariably by sustained adminstration of natural or synthetic estrogen or by ionizing radiations.1 b) The onlv available somatotorpic tumors (StT) are variants (mutants) of a radiation-induced, originally mammotropic tumor.2 The animals grafted with MtT show invariably stimulated mammary glands with milk secretion, associated with somatotropic activity. c) The available adrenotropic tumor (AtT) in the rat is also a variant of mammosomatotropic tumor that retains some capacity to secrete prolactin and growth hormone (MtT-F4). In this strain, increase in the adrenal weights may become 13 times as much as normal.' The purely adrenotropic tumors are available only in mice.' d) The thyrotropic tumors can be readily induced by keeping the animals on a iodine-deficient or an antithyroidal diet over long periods of time.5'6 These tumors are initially transplantable only in animals deficient in thyroid hormone. With successive transplantation, they may grow in the euthyroid host, in which thyroidal enlargement is characteristic. Tumors arising from gonadotrope cells (GtT) may exist but have not been convincingly demonstrated in either man or rodents. Publication sponsored by the Registry of Comparative Pathology of the Armed Forces Institute of Pathology and supported by Public Health Service Grant RR 00301 from the Division of Research Resources, US Department of Health, Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. Supported by Grant CA-02332 from the National Cancer Institute. 423
Figures 1-5-The five types of normal functional pituitary cells 1-Normal visualized by immunohistochemical staining. female rat pituitary stained with antirat prolactin (x 390). 2-Normal female rat pituitary stained with antirat 3-Pituitary of normal female rat growth hormone ( 390). 4-Pituitary of norstained with antimouse TSH ( 390). mal female mouse. Darkly staining cells are TSH-secreting cells: pale staining cells are gonadotropin-secreting cells. (x 5-Normal female mouse pituitary stained with anti390) porcine (17-39) ACTH ( X 1200).
Vol. 83, No. 2 May 1976
PITUITARY TUMORS
425
According to the literature, the most common types of pituitary tumors in both man and the rat are chromophobic, followed with acidophilic and basophilic adenomas. Most of them are functional tumors and appear to be chromophobic either because they produce very little hormone or rapidly discharge the hormone they produce as a result of hvperstimulation or neoplastic transformation. These diagnoses, based on tinctorial features, reveal the unreliability or morphologic criteria in evaluation of secretory function. These methods are gradually being replaced by others, such as the highly sensitive radioimmunoassay7 and immunohistochemical staining 8 which permit the recognition of various tvpes of pituitary cells on the basis of their specific immunologic reactions (Figures 1-5). Conas W Anth uan Di#m And U5.fufsso This Model The most common, usually asymptomatic, primarv pituitary tumors in rats have little functional activity. However, various hormone-producing activities can be amplified in syngeneic animals with transplanted tumors. Such pituitary tumors in rats are models of human pituitary svndromes: MtT in rats is comparable to Forbes-Albright syndrome in women in whom amenorrhea and galactorrhea occur without somatotropic activity. StT is associated with effects comparable to gigantism in human beings. AtT produces changes which correspond to Cushing's disease. Tumors of thyrotrope cells give rise to thyrotropic adenomas in man or rat. Studies of normal vs. neoplastic pituitary cells disclose a remarkable difference between them; normal pituitary cells have a uniform, fixed range of potentialities, while neoplastic cells acquire multiglandular characteristics that could be useful for analysis of numerous human multiglandular syndromes and the neoplasms which secrete ectopic hormone.
The rat pituitary tumors are available from the Mason Research Institute, 20 Harvard Street, Worcester, MA 01608. Cell lines from these tumors are available from the American Tvpe Culture Collection, 12301 Park Lawn Drive, Rockville, MD 20852. References 1. Furth J, Clifton KH: The Pituitary Gland, Vol 2. Edited by GW Harris, BT Donovan. London, Butterworths, 1966, pp 460497 2. Ito A, Furth J, Mov P: Growth hormone-secreting variant of a mammotropic tumor. Cancer Res 32:48-6, 1972 3. Ueda G, Takizawa S, Mov P, Nlarolla F, Furth J: Characterization of four transplantable mammotropic pituitary tumor variants in the rat. Cancer Res 28:1963-1975. 1968
426
ITO
American Journal of Pathology
4. Furth J, Gadsden EL, Upton AC: ACTH secreting transplantable pituitarv tumors. Proc Soc Exp Biol Med 84:253-254, 1953 3. Furth J, Ueda G, Clifton KH: The pathophysiology of pituitaries and their tumors: Methodological advances. Methods in Cancer Research, Vol 10. Edited by H Busch. New York, Academic Press, Inc., 1973, pp 201-277 6. Axelrad AA, Leblond CP: Induction of thyroid tumors in rats by a low iodine diet. Cancer 8:339-367, 1955 Berson SA, Yalow RS: Radioimmunoassay: General. Peptide Hormones, Vol 2A, Part I, Methods in Investigative and Diagnostic Endocrinology. Edited by SA Berson, RS Yalow. New York, American Elsevier Publishing Co., 1973, pp 84-120 8. Furth J, Nakane PK, Pasteels JL: Pathology and pathogenesis of spontaneous and experimental pituitary tumors. Pathology of Tumors in Laboratory Animals, Vol 1, Part 2, The Rat. Edited by V Turusov. Lyon, France, International Agency for Research on Cancer. (In press)
The author wishes to thank Dr. Jacob Furth and Judith Grauman for their assistance in the preparation of the manuscript. Dr. Ito is on leave from the Department of Pathology, Research Institute for Nuclear Medicine and Biology, Hiroshima University, Japan.
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Pituitary Tumors m
Animal Model: Pituitary Tumors in Rats
Contrbuted by. Akihiro Ito, MD, Institute of Cancer Research and Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032.
Fsb
Five types of functional cells are well recognized in the anterior lobe of the pituitary (pars distalis). Of these, four are known to give rise to tumors in both man and the rat: a) The prolactin-secreting tumors (MtT) can be induced almost invariably by sustained adminstration of natural or synthetic estrogen or by ionizing radiations.1 b) The onlv available somatotorpic tumors (StT) are variants (mutants) of a radiation-induced, originally mammotropic tumor.2 The animals grafted with MtT show invariably stimulated mammary glands with milk secretion, associated with somatotropic activity. c) The available adrenotropic tumor (AtT) in the rat is also a variant of mammosomatotropic tumor that retains some capacity to secrete prolactin and growth hormone (MtT-F4). In this strain, increase in the adrenal weights may become 13 times as much as normal.' The purely adrenotropic tumors are available only in mice.' d) The thyrotropic tumors can be readily induced by keeping the animals on a iodine-deficient or an antithyroidal diet over long periods of time.5'6 These tumors are initially transplantable only in animals deficient in thyroid hormone. With successive transplantation, they may grow in the euthyroid host, in which thyroidal enlargement is characteristic. Tumors arising from gonadotrope cells (GtT) may exist but have not been convincingly demonstrated in either man or rodents. Publication sponsored by the Registry of Comparative Pathology of the Armed Forces Institute of Pathology and supported by Public Health Service Grant RR 00301 from the Division of Research Resources, US Department of Health, Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. Supported by Grant CA-02332 from the National Cancer Institute. 423
Figures 1-5-The five types of normal functional pituitary cells 1-Normal visualized by immunohistochemical staining. female rat pituitary stained with antirat prolactin (x 390). 2-Normal female rat pituitary stained with antirat 3-Pituitary of normal female rat growth hormone ( 390). 4-Pituitary of norstained with antimouse TSH ( 390). mal female mouse. Darkly staining cells are TSH-secreting cells: pale staining cells are gonadotropin-secreting cells. (x 5-Normal female mouse pituitary stained with anti390) porcine (17-39) ACTH ( X 1200).
Vol. 83, No. 2 May 1976
PITUITARY TUMORS
425
According to the literature, the most common types of pituitary tumors in both man and the rat are chromophobic, followed with acidophilic and basophilic adenomas. Most of them are functional tumors and appear to be chromophobic either because they produce very little hormone or rapidly discharge the hormone they produce as a result of hvperstimulation or neoplastic transformation. These diagnoses, based on tinctorial features, reveal the unreliability or morphologic criteria in evaluation of secretory function. These methods are gradually being replaced by others, such as the highly sensitive radioimmunoassay7 and immunohistochemical staining 8 which permit the recognition of various tvpes of pituitary cells on the basis of their specific immunologic reactions (Figures 1-5). Conas W Anth uan Di#m And U5.fufsso This Model The most common, usually asymptomatic, primarv pituitary tumors in rats have little functional activity. However, various hormone-producing activities can be amplified in syngeneic animals with transplanted tumors. Such pituitary tumors in rats are models of human pituitary svndromes: MtT in rats is comparable to Forbes-Albright syndrome in women in whom amenorrhea and galactorrhea occur without somatotropic activity. StT is associated with effects comparable to gigantism in human beings. AtT produces changes which correspond to Cushing's disease. Tumors of thyrotrope cells give rise to thyrotropic adenomas in man or rat. Studies of normal vs. neoplastic pituitary cells disclose a remarkable difference between them; normal pituitary cells have a uniform, fixed range of potentialities, while neoplastic cells acquire multiglandular characteristics that could be useful for analysis of numerous human multiglandular syndromes and the neoplasms which secrete ectopic hormone.
The rat pituitary tumors are available from the Mason Research Institute, 20 Harvard Street, Worcester, MA 01608. Cell lines from these tumors are available from the American Tvpe Culture Collection, 12301 Park Lawn Drive, Rockville, MD 20852. References 1. Furth J, Clifton KH: The Pituitary Gland, Vol 2. Edited by GW Harris, BT Donovan. London, Butterworths, 1966, pp 460497 2. Ito A, Furth J, Mov P: Growth hormone-secreting variant of a mammotropic tumor. Cancer Res 32:48-6, 1972 3. Ueda G, Takizawa S, Mov P, Nlarolla F, Furth J: Characterization of four transplantable mammotropic pituitary tumor variants in the rat. Cancer Res 28:1963-1975. 1968
426
ITO
American Journal of Pathology
4. Furth J, Gadsden EL, Upton AC: ACTH secreting transplantable pituitarv tumors. Proc Soc Exp Biol Med 84:253-254, 1953 3. Furth J, Ueda G, Clifton KH: The pathophysiology of pituitaries and their tumors: Methodological advances. Methods in Cancer Research, Vol 10. Edited by H Busch. New York, Academic Press, Inc., 1973, pp 201-277 6. Axelrad AA, Leblond CP: Induction of thyroid tumors in rats by a low iodine diet. Cancer 8:339-367, 1955 Berson SA, Yalow RS: Radioimmunoassay: General. Peptide Hormones, Vol 2A, Part I, Methods in Investigative and Diagnostic Endocrinology. Edited by SA Berson, RS Yalow. New York, American Elsevier Publishing Co., 1973, pp 84-120 8. Furth J, Nakane PK, Pasteels JL: Pathology and pathogenesis of spontaneous and experimental pituitary tumors. Pathology of Tumors in Laboratory Animals, Vol 1, Part 2, The Rat. Edited by V Turusov. Lyon, France, International Agency for Research on Cancer. (In press)
The author wishes to thank Dr. Jacob Furth and Judith Grauman for their assistance in the preparation of the manuscript. Dr. Ito is on leave from the Department of Pathology, Research Institute for Nuclear Medicine and Biology, Hiroshima University, Japan.
