Molecular and Chemical Neuropathology

, Volume 21, Issue 2–3, pp 177–188 | Cite as

Colony stimulating factor-1 expression in human glioma

  • Ron L. Alterman
  • E. Richard Stanley


Colony stimulating factor 1 (CSF-1) is a functionally versatile, circulating homodimeric growth factor that stimulates the survival, proliferation, and differentiation of mononuclear phagocytic cells, the differentiation of osteoclast progenitor cells and that regulates cells of the female reproductive tract. CSF-1 is also expressed in the central nervous system where it may regulate the differentiation and activation of microglia. The diverse forms of CSF-1 are all encoded by a single gene. Alternative posttranscriptional splicing and posttranslational cleavage determines whether CSF-1 will be produced as a secreted proteoglycan, secreted glycoprotein, or as a cell-surface glycoprotein that may be involved in cell-cell interactions. CSF-1 is expressed in glioblastoma cell-lines, normal human astrocytes, and in operative specimens of human glioma. The CSF-1 receptor, encoded by the c-fms proto-oncogene, is also expressed in human gliomas. We conclude that coexpression of CSF-1 and its receptor in some human gliomas hints at a possible autocrine or paracrine growth stimulatory role for CSF-1; however, its function in the mammalian CNS remains to be elucidated.

Index Entries

CSF-1 c-fms brain tumors glioblastoma growth factor microglia proteoglycan glycoprotein astrocytes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alterman R. L., Morrison R.S., Goodrich J. T., Papenhausen P., and Moskal J. R. (1991) A primary encephalocele culture yields a pure population of human astrocytes.Brain Res. 550, 319–323.PubMedCrossRefGoogle Scholar
  2. Arceci R. J., Shanahan F., Stanley E. R., and Pollard J. W. (1989) Temporal expression and location of colony stimulating factor 1 (CSF-1) and its receptor in the female reproductive tract are consistent with CSF-1 regulated placental development.Proc. Natl. Acad. Sci. USA 86, 8818–8822.PubMedCrossRefGoogle Scholar
  3. Baiocchi G., Kavanagh J. J., Talpaz M., Wharton J. T., Gutterman J. U., and Kurzrock R. (1991) Expression of the macrophage colony stimulating factor and its receptor in gynecologic malignancies.Cancer. 67, 990–996.PubMedCrossRefGoogle Scholar
  4. Bishop J. M. (1987) The molecular genetics of cancer.Science 235, 305–311.PubMedCrossRefGoogle Scholar
  5. Cockram C. S. (1990) Growth factors, astrocytes and astrocytomas.Seminars in Developmental Biology 1, 421–435.Google Scholar
  6. Cross M. and Dexter T. M. (1991) Growth factors in development, transformation, and tumorigenesis.Cell 64, 271–280.PubMedCrossRefGoogle Scholar
  7. Das S. K., Stanley E. R., Guilbert L. J., and Forman L. W. (1981) Human colony stimulating factor (CSF-1) radioimmunoassy: resolution of three subclasses of human colony stimulating factors.Blood 58, 630–641.PubMedGoogle Scholar
  8. Das S. K. and Stanley E. R. (1982) Structure-function studies of a colony stimulating factor (CSF-1).J. Biol. Chem. 257, 13,679–13,684.Google Scholar
  9. Downing J. R., Rettenmeier C. W., and Sherr C. J. (1988) Ligand induced tyrosine kinase activity of the colony stimulating factor-1 receptor in a murine macrophage cell line.Mol. Cell. Biol. 8, 1795–1799.PubMedGoogle Scholar
  10. Felix R., Cecchini M. G., and Fleisch H. (1990) Macrophage colony simulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse.Endocrinology 127, 2592–2594.PubMedCrossRefGoogle Scholar
  11. Folkman J. and Klagsbrun M. (1987) Angiogenic factors.Science 235, 442–447.PubMedCrossRefGoogle Scholar
  12. Gilbert H. S., Praloran V., and Stanley E. R. (1989) Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension.Blood 74, 1231–1234.PubMedGoogle Scholar
  13. Gross J. L., Behrens D. L., Mullins D. E., Kornblith P. L., and Dexter D. L. (1988) Plasminogen activator and inhibitor activity in human glioma cells and modulation by sodium butyrate.Cancer Res. 48, 291–296.PubMedGoogle Scholar
  14. Guilbert L. J. and Stanley E. R. (1980) Specific interaction of murine colony stimulating factor with mononuclear phagocytic cells.J. Cell Biol. 85, 153–159.PubMedCrossRefGoogle Scholar
  15. Guilbert L. J., and Stanley E. R. (1986) The interaction of125I- colony stimulating factor 1 with bone marrow-derived macrophages.J. Biol. Chem. 261, 4024–4032.PubMedGoogle Scholar
  16. Hao C., Guilbert L. J., and Federoff S. J. (1990) Production of colony stimulating factor I (CSF-1) by mouse astroglia in vitro.J. Neurosci. Res. 27, 314–323.PubMedCrossRefGoogle Scholar
  17. Horiguchi J. M., Sherman M. L., Sampson-Johannes B. L., Weber B. L., and Kufe D. W. (1988) CSF-1 and c-fms expression in human carcinoma cell lines.Biochem. Biophys. Res. Commun. 157, 395–401.PubMedCrossRefGoogle Scholar
  18. Hulkower K. L., Brosnan C. F., and Berman J. W. (1991) Cytokine gene expression in the central nervous system of rats with experimental autoimmune encephalomyelitis (EAE).FASEB J. 5, A8184.Google Scholar
  19. Janowska-Wieczorek A., Belch A. R., Jacobs A., Bowen D., Padua R-A., Paietta E., and Stanley E. R. (1991) Increased circulating colony stimulating factor 1 in patients with preleukemia, leukemia and lymphoid malignancies.Blood 77, 1796–1803.PubMedGoogle Scholar
  20. Kacinski B. M., Carter D., Mittal K., Kohorn E. I., Bloodgood R. S., Donahue J., Donofrio L., Edwards R., Schwartz P. E., Chambers J. T., and Chambers S. K. (1988) High level expression of fms proto-oncogene mRNA is observed in clinically aggressive human endometrial adenocarcinomas.Int. J. Radiat. Oncol. Biol. Phys. 15, 823–829.PubMedGoogle Scholar
  21. Kacinski B. M., Bloodgood R. S., Schwartz P. E., Carter D., and Stanley E. R. (1989a) The macrophage colony stimulating factor CSF-1 is produced by human ovarian and endometrial carcinoma-derived cell lines and is present at abnormally high levels in the plasma of ovarian carcinoma patients with active disease.Cold Spring Harb. Symp. Quant. Biol. Cancer Cells 7, 333–337.Google Scholar
  22. Kacinski B. M., Stanley E. R., Carter D., Chambers J. T., Chambers J. T., Kohorn E. I., and Schwartz P. E. (1989b) Circulating levels of CSF-1 (M-CSF) a lymphohematopoietic cytokine may be a useful marker of disease status in patients with malignant ovarian neoplasms.Int. J. Radiat. Oncol. Biol. Phys. 17, 159–164.PubMedGoogle Scholar
  23. Kacinski B. M., Chambers S. K., Carter D., Filderman A. E., and Stanley E. R. (1990) The macrophage colony stimulating factor CSF-1, an auto- and paracrine tumor cytokine is also a circulating “tumor marker” in patients with ovarian, endometrial, and pulmonary neoplasms.Prog. Leuk. Biol. 108, 393–400.Google Scholar
  24. Kacinski B. M., Scata K. A., Carter D., Yee L. D., Sapi E., King B. L., Chambers S. K., Jones M. A., Pirro M. H., Stanley E. R., and Rohrschneider L. R. (1991) FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro.Oncogene 6, 941–952.PubMedGoogle Scholar
  25. Kawasaki E. S., Ladner M. B., Wang A. M., Van Arsdell J., Warren M. K., Coyne M. Y., Schweikart V. L., Lee M. T., Wilson K. J., Boosman A., Stanley E. R., Ralph P., Mark D. F. (1985) Molecular cloning of a complementary DNA encoding human macrophage specific colony stimulating factor (CSF-1).Science 230, 291–296.PubMedCrossRefGoogle Scholar
  26. Ladner M. B., Martin G. A., Noble J. A., Nikoloff D. M., Tal R., Kawasaki E. S., and White T. J. (1987) Human CSF-1: gene structure and alternative splicing of mRNA precursors.EMBO J. 6, 2693–2698.PubMedGoogle Scholar
  27. Li W. and Stanley E. R. (1991) Role of dimerization and modification of the CSF-1 receptor in its activation and internalization during the CSF-1 response.EMBO J. 10, 277–288.PubMedGoogle Scholar
  28. Morrison R. S., Gross J. L., Herblin W. F., Reilly T. M., LaSala P. A., Alterman R. L., Moskal J. R., Kornblith P. L., and Dexter D. L. (1990) Basic fibroblast growth factor-like activity and receptors are expressed in a human glioma cell lines.Cancer Res. 50, 2524–2529.PubMedGoogle Scholar
  29. Nakamura M., Merchav S., Carter A., Ernst T. J., Demetri G. D., Furukawa Y., Anderson K., Freeman A. S., and Griffin J. D. (1989) Expression of a novel 3.5 kb macrophage colony stimulating factor transcript in human myeloma cells.J. Immunol. 143, 3543–3547.PubMedGoogle Scholar
  30. Paietta E., Racevskis J., Stanley E. R., Andreeff M., Papenhausen P., and Wiernik P. M. (1990) Expression of the macrophage growth factor, CSF-1 and its receptor, C-FMS, by a Hodgkins disease derived cell-line and its variants.Cancer Res. 50, 2049–2055.PubMedGoogle Scholar
  31. Pollard J. W., Bartocci A., Arceci R., Orlofsky A., Ladner M. B., and Stanley E. R. (1987) Apparent role of the macrophage growth factor, CSF-1, in placental development.Nature 330, 484–486.PubMedCrossRefGoogle Scholar
  32. Pollard J. W., Hunt J. S., Wiktor-Jedrzejczak W., and Stanley E. R. (1991). A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility.Dev. Biol. 148, 273–283.PubMedCrossRefGoogle Scholar
  33. Price L. K. H., Choi H. U., Rosenberg L., and Stanley E. R. (1992) The predominant form of secreted colony stimulating factor 1 is a proteoglycan.J. Biol. Chem. 267, 2190–2199.PubMedGoogle Scholar
  34. Rambaldi A., Wakamiya I. V., Vellenga E., Horiguchi J., Warren M. K., Kufe D., and Griffin J. D. (1988) Expression of the macrophage colony stimulating factor and c-fms genes in human acute myeloblastic leukemia cells.J. Clin. Invest. 81, 1030–1035.PubMedCrossRefGoogle Scholar
  35. Salcman M. (1990) Epidemiology and factors affecting survival, inMalignant Cerebral Glioma (Apuzzo M. L. J., ed.), American Association of Neurological Surgeons, Park Ridge, IL.Google Scholar
  36. Sengupta A., Liu W-K, Yeung Y. G., Yeung D. C. Y., Frackelton Jr., A. R., and Stanley E. R. (1988) Identification and subcellular localization of proteins that are rapidly phosphorylated in tyrosine in response to colony stimulating factor 1.Proc. Natl. Acad. Sci. USA 85, 8062–8066.PubMedCrossRefGoogle Scholar
  37. Shafit-Zagardo B., Sharma N., Berman J. W., and Brosnan C. F. (1991) IL-1 and TNF upregulate CSF-1 expression in rat astrocyte cultures.J. Cell. Biol. 115, 2450a.Google Scholar
  38. Sherr C. J., Rettenmier C. W., Sacca R., Roussel M., Look A. T., and Stanley E. R. (1985) The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1.Cell 41, 665–676.PubMedCrossRefGoogle Scholar
  39. Stanley E. R. (1990) Role of colony stimulating factor 1 in monocytopoiesis and placental development, inGenetics of Pattern Formation and Growth Control, Wiley-Liss, pp. 165–180.Google Scholar
  40. Stanley E. R., Guilbert L. J., Tushinski R. J. and Bartelmez S. H. (1983) CSF-1 —a mononuclear phagocyte lineage-specific hemopoietic growth factor.J. Cell. Biochem. 21, 151–159.PubMedCrossRefGoogle Scholar
  41. Stein J., Borzillo G. V., and Rettenmeier C. W. (1990) Direct stimulation of cells expressing receptors for macrophage colony stimulating factor (CSF-1) by a plasma membrane-bound precursor of human CSF-1.Blood 76, 1308–1314.PubMedGoogle Scholar
  42. Takahashi J. A., Fukumoto M., Igarashi K., Oda Y., Kikuchi H., and Hatanaka M. (1992) Correlation of basic fibroblast growth factor expression levels with the degree of malignancy and vascularity in human gliomas.J. Neurosurg. 76, 792–798.PubMedCrossRefGoogle Scholar
  43. Thery C., Hetier E., Evrard C., and Mallat M. (1990) Expression of macrophage colony stimulating factor gene in the mouse brain during development.J. Neurosci. Res. 26, 129–133.PubMedCrossRefGoogle Scholar
  44. Thery C., Stanley E. R., and Mallat M. (1992) Interleukin 1 and tumor necrosis factor alpha stimulate the production of colony stimulating factor 1 by murine astrocytes.J. Neurosci. Res., in press.Google Scholar
  45. Tushinski R. J. and Stanley E. R. (1985) The regulation of mononuclear phagocyte entry into S phase by the colony stimulating factor CSF-1.J. Cell Physiol. 116, 67–75.CrossRefGoogle Scholar
  46. Ulrich A. and Schlessinger J. (1990) Signal transduction by receptors with tyrosine kinase activity.Cell 61, 203–212.CrossRefGoogle Scholar
  47. Wiktor-Jedrzejczak W., Bartocci A., Ferrante A. W., Jr., Ahmed-Ansari A., Sell K. W., Pollard J. W., and Stanley E. R. (1990) Total absence of colony stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse.Proc. Natl. Acad. Sci. USA 87, 4828–4832.PubMedCrossRefGoogle Scholar
  48. Wong A. J., Bigner S. H., Bigner D. D., Kinzler K. W., Hamilton S. R., and Vogelstein B. (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplication.Proc. Natl. Acad. Sci. USA 84, 6899–6903.PubMedCrossRefGoogle Scholar
  49. Wu M. and Yunis A. A. (1980) Common pattern of two distinct types of colony stimulating factor in human tissues and cultured cells.J. Clin. Invest. 65, 772–776.PubMedCrossRefGoogle Scholar
  50. Yeung Y. G., Jubinsky P. T., Sengupta A., Yeung D. C. Y., and Stanley E. R. (1987) Purification of the colony stimulating factor 1 receptor and demonstration of its tyrosine kinase activity.Proc. Natl. Acad. Sci. USA 84, 1268–1271, 1987.PubMedCrossRefGoogle Scholar
  51. Yoshida H., Hayashi S-I, Kunisada T., Ogawa M., Nishikawa S., Okomura H., Sudo T., Shultz L. D., and Nishikawa S-I (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene.Nature 345, 422–424.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1994

Authors and Affiliations

  • Ron L. Alterman
    • 1
  • E. Richard Stanley
    • 2
  1. 1.Department of Neurological SurgeryMontefiore Medical CenterBronx
  2. 2.Department of Developmental Biology and CancerThe Albert Einstein College of MedicineBronx

Personalised recommendations