Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Sep 13;91(19):8817–8821. doi: 10.1073/pnas.91.19.8817

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

M M Matzuk 1, M J Finegold 1, J P Mather 1, L Krummen 1, H Lu 1, A Bradley 1
PMCID: PMC44697  PMID: 8090730

Abstract

Activins and inhibins, members of the type beta transforming growth factor superfamily of growth regulatory proteins, are produced in multiple tissues and affect diverse physiologic processes. Using embryonic stem cell technology, we previously demonstrated that inhibin can function as a gonadal tumor suppressor. In this study, we show that development of gonadal tumors is rapidly followed by a cancer cachexia-like wasting syndrome. Cachectic inhibin-deficient mice develop hepatocellular necrosis around the central vein and parietal cell depletion and mucosal atrophy in the glandular stomach, are anemic, and demonstrate severe weight loss. The liver pathology is consistent with studies demonstrating an effect of elevated activins on rat hepatocytes. In inhibin-deficient mice with tumors, activins are > 10-fold elevated in the serum and are likely causing some of the cachexia symptoms. In contrast, inhibin-deficient mice gonadectomized at an early age do not develop this wasting syndrome. However, these gonadectomized, inhibin-deficient mice eventually develop adrenal cortical sex steroidogenic tumors with nearly 100% penetrance, demonstrating that inhibin is also a tumor suppressor for the adrenal gland.

Full text

PDF
8817

Images in this article

8819Image
on p.8819
8820Image
on p.8820

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Black K., Garrett I. R., Mundy G. R. Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinology. 1991 May;128(5):2657–2659. doi: 10.1210/endo-128-5-2657. [DOI] [PubMed] [Google Scholar]
  2. Conrad M. E., Umbreit J. N. A concise review: iron absorption--the mucin-mobilferrin-integrin pathway. A competitive pathway for metal absorption. Am J Hematol. 1993 Jan;42(1):67–73. doi: 10.1002/ajh.2830420114. [DOI] [PubMed] [Google Scholar]
  3. Crawford R. J., Hammond V. E., Evans B. A., Coghlan J. P., Haralambidis J., Hudson B., Penschow J. D., Richards R. I., Tregear G. W. Alpha-inhibin gene expression occurs in the ovine adrenal cortex, and is regulated by adrenocorticotropin. Mol Endocrinol. 1987 Oct;1(10):699–706. doi: 10.1210/mend-1-10-699. [DOI] [PubMed] [Google Scholar]
  4. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  5. Ge W., Gallin W. J., Strobeck C., Peter R. E. Cloning and sequencing of goldfish activin subunit genes: strong structural conservation during vertebrate evolution. Biochem Biophys Res Commun. 1993 Jun 15;193(2):711–717. doi: 10.1006/bbrc.1993.1683. [DOI] [PubMed] [Google Scholar]
  6. Kingsley D. M. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994 Jan;8(2):133–146. doi: 10.1101/gad.8.2.133. [DOI] [PubMed] [Google Scholar]
  7. Langstein H. N., Norton J. A. Mechanisms of cancer cachexia. Hematol Oncol Clin North Am. 1991 Feb;5(1):103–123. [PubMed] [Google Scholar]
  8. Mathews L. S., Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991 Jun 14;65(6):973–982. doi: 10.1016/0092-8674(91)90549-e. [DOI] [PubMed] [Google Scholar]
  9. Matthys P., Dijkmans R., Proost P., Van Damme J., Heremans H., Sobis H., Billiau A. Severe cachexia in mice inoculated with interferon-gamma-producing tumor cells. Int J Cancer. 1991 Aug 19;49(1):77–82. doi: 10.1002/ijc.2910490115. [DOI] [PubMed] [Google Scholar]
  10. Matzuk M. M., Finegold M. J., Su J. G., Hsueh A. J., Bradley A. Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature. 1992 Nov 26;360(6402):313–319. doi: 10.1038/360313a0. [DOI] [PubMed] [Google Scholar]
  11. Meunier H., Rivier C., Evans R. M., Vale W. Gonadal and extragonadal expression of inhibin alpha, beta A, and beta B subunits in various tissues predicts diverse functions. Proc Natl Acad Sci U S A. 1988 Jan;85(1):247–251. doi: 10.1073/pnas.85.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Meunier H., Rivier C., Evans R. M., Vale W. Gonadal and extragonadal expression of inhibin alpha, beta A, and beta B subunits in various tissues predicts diverse functions. Proc Natl Acad Sci U S A. 1988 Jan;85(1):247–251. doi: 10.1073/pnas.85.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mine T., Kojima I., Ogata E. Stimulation of glucose production by activin-A in isolated rat hepatocytes. Endocrinology. 1989 Aug;125(2):586–591. doi: 10.1210/endo-125-2-586. [DOI] [PubMed] [Google Scholar]
  14. Mitrani E., Ziv T., Thomsen G., Shimoni Y., Melton D. A., Bril A. Activin can induce the formation of axial structures and is expressed in the hypoblast of the chick. Cell. 1990 Nov 2;63(3):495–501. doi: 10.1016/0092-8674(90)90446-l. [DOI] [PubMed] [Google Scholar]
  15. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  16. Paquis-Flucklinger V., Michiels J. F., Vidal F., Alquier C., Pointis G., Bourdon V., Cuzin F., Rassoulzadegan M. Expression in transgenic mice of the large T antigen of polyomavirus induces Sertoli cell tumours and allows the establishment of differentiated cell lines. Oncogene. 1993 Aug;8(8):2087–2094. [PubMed] [Google Scholar]
  17. Peschon J. J., Behringer R. R., Cate R. L., Harwood K. A., Idzerda R. L., Brinster R. L., Palmiter R. D. Directed expression of an oncogene to Sertoli cells in transgenic mice using mullerian inhibiting substance regulatory sequences. Mol Endocrinol. 1992 Sep;6(9):1403–1411. doi: 10.1210/mend.6.9.1331774. [DOI] [PubMed] [Google Scholar]
  18. Roberts V. J., Sawchenko P. E., Vale W. Expression of inhibin/activin subunit messenger ribonucleic acids during rat embryogenesis. Endocrinology. 1991 Jun;128(6):3122–3129. doi: 10.1210/endo-128-6-3122. [DOI] [PubMed] [Google Scholar]
  19. Schwall R. H., Robbins K., Jardieu P., Chang L., Lai C., Terrell T. G. Activin induces cell death in hepatocytes in vivo and in vitro. Hepatology. 1993 Aug;18(2):347–356. doi: 10.1016/0270-9139(93)90018-i. [DOI] [PubMed] [Google Scholar]
  20. Smith J. C., Price B. M., Van Nimmen K., Huylebroeck D. Identification of a potent Xenopus mesoderm-inducing factor as a homologue of activin A. Nature. 1990 Jun 21;345(6277):729–731. doi: 10.1038/345729a0. [DOI] [PubMed] [Google Scholar]
  21. Tapanainen J. S., Tilly J. L., Vihko K. K., Hsueh A. J. Hormonal control of apoptotic cell death in the testis: gonadotropins and androgens as testicular cell survival factors. Mol Endocrinol. 1993 May;7(5):643–650. doi: 10.1210/mend.7.5.8316250. [DOI] [PubMed] [Google Scholar]
  22. Thomsen G., Woolf T., Whitman M., Sokol S., Vaughan J., Vale W., Melton D. A. Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures. Cell. 1990 Nov 2;63(3):485–493. doi: 10.1016/0092-8674(90)90445-k. [DOI] [PubMed] [Google Scholar]
  23. Voutilainen R., Erämaa M., Ritvos O. Hormonally regulated inhibin gene expression in human fetal and adult adrenals. J Clin Endocrinol Metab. 1991 Nov;73(5):1026–1030. doi: 10.1210/jcem-73-5-1026. [DOI] [PubMed] [Google Scholar]
  24. Wong W. L., Garg S. J., Woodruff T., Bald L., Fendly B., Lofgren J. A. Monoclonal antibody based ELISAs for measurement of activins in biological fluids. J Immunol Methods. 1993 Sep 27;165(1):1–10. doi: 10.1016/0022-1759(93)90100-l. [DOI] [PubMed] [Google Scholar]
  25. Woodruff T. K., Krummen L., Chen S. A., Lyon R., Hansen S. E., DeGuzman G., Covello R., Mather J., Cossum P. Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat. II. Tissue distribution of [125I]rh-inhibin A and [125I]rh-activin A in immature female and male rats. Endocrinology. 1993 Feb;132(2):725–734. doi: 10.1210/endo.132.2.8425491. [DOI] [PubMed] [Google Scholar]
  26. Yasuda H., Mine T., Shibata H., Eto Y., Hasegawa Y., Takeuchi T., Asano S., Kojima I. Activin A: an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. J Clin Invest. 1993 Sep;92(3):1491–1496. doi: 10.1172/JCI116727. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES