Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1991 May;63(5):687–692. doi: 10.1038/bjc.1991.156

Tumour suppression associated with expression of human insulin-like growth factor II.

P N Schofield 1, A Lee 1, D J Hill 1, J E Cheetham 1, D James 1, C Stewart 1
PMCID: PMC1972407  PMID: 2039693

Abstract

Recent circumstantial evidence has implicated Insulin-like growth factor II in the genesis of several tumour types, notably developmental tumours (Scott et al., 1985; Schofield & Tate, 1987; Wilkins et al., 1989). This type of tumour, thought to originate during the defective differentiation of organ precursors (Miereau et al., 1987), often expresses greatly elevated levels of mRNA for IGF-II, a known mitogen for these cells and abundantly expressed in their presumed normal counterparts (Scott et al., 1985; Schofield & Tate, 1987; Gray et al., 1987). It has been proposed that continued, inappropriate expression of this gene drives tumour growth by an autocrine mechanism. In order to examine the potential role of IGF-II in the growth of tumour cells an IGF-II cDNA was introduced into a retroviral expression vector, and used to infect a cloned fibroblast cell line. Expression of IGF-II conferred a degree of serum independence of growth in cell culture, however, when cells were injected into nude mice as subcutaneous grafts, clones expressing IGF-II from the retrovirus were found to have a greatly increased (five fold) latency of sarcoma formation. After a prolonged lag all cell lines eventually gave rise to tumours in which the introduced IGF-II genes had either been lost or inactivated, suggesting that in this system IGF-II acts as a tumour suppressor gene.

Full text

PDF
687

Images in this article

688Figure 2
on p.688
690Figure 4
on p.690

Selected References

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

  1. Ali I. U., Lidereau R., Theillet C., Callahan R. Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia. Science. 1987 Oct 9;238(4824):185–188. doi: 10.1126/science.3659909. [DOI] [PubMed] [Google Scholar]
  2. Berstine E. G., Hooper M. L., Grandchamp S., Ephrussi B. Alkaline phosphatase activity in mouse teratoma. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3899–3903. doi: 10.1073/pnas.70.12.3899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biddle C., Li C. H., Schofield P. N., Tate V. E., Hopkins B., Engstrom W., Huskisson N. S., Graham C. F. Insulin-like growth factors and the multiplication of Tera-2, a human teratoma-derived cell line. J Cell Sci. 1988 Jul;90(Pt 3):475–484. doi: 10.1242/jcs.90.3.475. [DOI] [PubMed] [Google Scholar]
  4. Boulter C. A., Wagner E. F. A universal retroviral vector for efficient constitutive expression of exogenous genes. Nucleic Acids Res. 1987 Sep 11;15(17):7194–7194. doi: 10.1093/nar/15.17.7194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boulter C. A., Wagner E. F. The effects of v-src expression on the differentiation of embryonal carcinoma cells. Oncogene. 1988 Mar;2(3):207–214. [PubMed] [Google Scholar]
  6. Brice A. L., Cheetham J. E., Bolton V. N., Hill N. C., Schofield P. N. Temporal changes in the expression of the insulin-like growth factor II gene associated with tissue maturation in the human fetus. Development. 1989 Jul;106(3):543–554. doi: 10.1242/dev.106.3.543. [DOI] [PubMed] [Google Scholar]
  7. Cariani E., Lasserre C., Seurin D., Hamelin B., Kemeny F., Franco D., Czech M. P., Ullrich A., Brechot C. Differential expression of insulin-like growth factor II mRNA in human primary liver cancers, benign liver tumors, and liver cirrhosis. Cancer Res. 1988 Dec 1;48(23):6844–6849. [PubMed] [Google Scholar]
  8. Copeman M. C., Harris H. The extracellular matrix of hybrids between melanoma cells and normal fibroblasts. J Cell Sci. 1988 Oct;91(Pt 2):281–286. doi: 10.1242/jcs.91.2.281. [DOI] [PubMed] [Google Scholar]
  9. Coulombe B., Skup D. Expression of a synthetic human interferon-alpha 1 gene with modified nucleotide sequence in mammalian cells. Gene. 1986;46(1):89–95. doi: 10.1016/0378-1119(86)90170-8. [DOI] [PubMed] [Google Scholar]
  10. Gessler M., Poustka A., Cavenee W., Neve R. L., Orkin S. H., Bruns G. A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774–778. doi: 10.1038/343774a0. [DOI] [PubMed] [Google Scholar]
  11. Gray A., Tam A. W., Dull T. J., Hayflick J., Pintar J., Cavenee W. K., Koufos A., Ullrich A. Tissue-specific and developmentally regulated transcription of the insulin-like growth factor 2 gene. DNA. 1987 Aug;6(4):283–295. doi: 10.1089/dna.1987.6.283. [DOI] [PubMed] [Google Scholar]
  12. Han V. K., D'Ercole A. J., Lund P. K. Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science. 1987 Apr 10;236(4798):193–197. doi: 10.1126/science.3563497. [DOI] [PubMed] [Google Scholar]
  13. Han V. K., Lund P. K., Lee D. C., D'Ercole A. J. Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. J Clin Endocrinol Metab. 1988 Feb;66(2):422–429. doi: 10.1210/jcem-66-2-422. [DOI] [PubMed] [Google Scholar]
  14. Haselbacher G. K., Irminger J. C., Zapf J., Ziegler W. H., Humbel R. E. Insulin-like growth factor II in human adrenal pheochromocytomas and Wilms tumors: expression at the mRNA and protein level. Proc Natl Acad Sci U S A. 1987 Feb;84(4):1104–1106. doi: 10.1073/pnas.84.4.1104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Henry I., Grandjouan S., Couillin P., Barichard F., Huerre-Jeanpierre C., Glaser T., Philip T., Lenoir G., Chaussain J. L., Junien C. Tumor-specific loss of 11p15.5 alleles in del11p13 Wilms tumor and in familial adrenocortical carcinoma. Proc Natl Acad Sci U S A. 1989 May;86(9):3247–3251. doi: 10.1073/pnas.86.9.3247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hill D. J., Clemmons D. R., Wilson S., Han V. K., Strain A. J., Milner R. D. Immunological distribution of one form of insulin-like growth factor (IGF)-binding protein and IGF peptides in human fetal tissues. J Mol Endocrinol. 1989 Jan;2(1):31–38. doi: 10.1677/jme.0.0020031. [DOI] [PubMed] [Google Scholar]
  17. Hill D. J., Crace C. J., Strain A. J., Milner R. D. Regulation of amino acid uptake and deoxyribonucleic acid synthesis in isolated human fetal fibroblasts and myoblasts: effect of human placental lactogen, somatomedin-C, multiplication-stimulating activity, and insulin. J Clin Endocrinol Metab. 1986 Apr;62(4):753–760. doi: 10.1210/jcem-62-4-753. [DOI] [PubMed] [Google Scholar]
  18. Höppener J. W., Mosselman S., Roholl P. J., Lambrechts C., Slebos R. J., de Pagter-Holthuizen P., Lips C. J., Jansz H. S., Sussenbach J. S. Expression of insulin-like growth factor-I and -II genes in human smooth muscle tumours. EMBO J. 1988 May;7(5):1379–1385. doi: 10.1002/j.1460-2075.1988.tb02954.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Irminger J. C., Schoenle E. J., Briner J., Humbel R. E. Structural alteration of the insulin-like growth factor II-gene in Wilms tumour. Eur J Pediatr. 1989 Jun;148(7):620–623. doi: 10.1007/BF00441514. [DOI] [PubMed] [Google Scholar]
  20. Koufos A., Hansen M. F., Copeland N. G., Jenkins N. A., Lampkin B. C., Cavenee W. K. Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature. 1985 Jul 25;316(6026):330–334. doi: 10.1038/316330a0. [DOI] [PubMed] [Google Scholar]
  21. Lehrach H., Diamond D., Wozney J. M., Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. doi: 10.1021/bi00640a033. [DOI] [PubMed] [Google Scholar]
  22. Little M. H., Ablett G., Smith P. J. Enhanced expression of insulin-like growth factor II is not a necessary event in Wilms' tumour progression. Carcinogenesis. 1987 Jun;8(6):865–868. doi: 10.1093/carcin/8.6.865. [DOI] [PubMed] [Google Scholar]
  23. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  24. Massagué J., Kelly B., Mottola C. Stimulation by insulin-like growth factors is required for cellular transformation by type beta transforming growth factor. J Biol Chem. 1985 Apr 25;260(8):4551–4554. [PubMed] [Google Scholar]
  25. Mierau G. W., Beckwith J. B., Weeks D. A. Ultrastructure and histogenesis of the renal tumors of childhood: an overview. Ultrastruct Pathol. 1987;11(2-3):313–333. doi: 10.3109/01913128709048329. [DOI] [PubMed] [Google Scholar]
  26. Ping A. J., Reeve A. E., Law D. J., Young M. R., Boehnke M., Feinberg A. P. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15. Am J Hum Genet. 1989 May;44(5):720–723. [PMC free article] [PubMed] [Google Scholar]
  27. Reeve A. E., Sih S. A., Raizis A. M., Feinberg A. P. Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells. Mol Cell Biol. 1989 Apr;9(4):1799–1803. doi: 10.1128/mcb.9.4.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rose E. A., Glaser T., Jones C., Smith C. L., Lewis W. H., Call K. M., Minden M., Champagne E., Bonetta L., Yeger H. Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene. Cell. 1990 Feb 9;60(3):495–508. doi: 10.1016/0092-8674(90)90600-j. [DOI] [PubMed] [Google Scholar]
  29. Rubin H. Uniqueness of each spontaneous transformant from a clone of BALB/c 3T3 cells. Cancer Res. 1988 May 1;48(9):2512–2518. [PubMed] [Google Scholar]
  30. Schofield P. N., Connor H., Turner R. C., Zapf J. Tumour hypoglycaemia: raised tumour IGFII mRNA associated with reduced plasma somatomedins. Br J Cancer. 1989 Nov;60(5):661–663. doi: 10.1038/bjc.1989.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schofield P. N., Tate V. E. Regulation of human IGF-II transcription in fetal and adult tissues. Development. 1987 Dec;101(4):793–803. doi: 10.1242/dev.101.4.793. [DOI] [PubMed] [Google Scholar]
  32. Scott J., Cowell J., Robertson M. E., Priestley L. M., Wadey R., Hopkins B., Pritchard J., Bell G. I., Rall L. B., Graham C. F. Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues. Nature. 1985 Sep 19;317(6034):260–262. doi: 10.1038/317260a0. [DOI] [PubMed] [Google Scholar]
  33. Su T. S., Liu W. Y., Han S. H., Jansen M., Yang-Fen T. L., P'eng F. K., Chou C. K. Transcripts of the insulin-like growth factors I and II in human hepatoma. Cancer Res. 1989 Apr 1;49(7):1773–1777. [PubMed] [Google Scholar]
  34. Sussenbach J. S. The gene structure of the insulin-like growth factor family. Prog Growth Factor Res. 1989;1(1):33–48. doi: 10.1016/0955-2235(89)90040-9. [DOI] [PubMed] [Google Scholar]
  35. TODARO G. J., GREEN H. Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol. 1963 May;17:299–313. doi: 10.1083/jcb.17.2.299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tepper R. I., Pattengale P. K., Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell. 1989 May 5;57(3):503–512. doi: 10.1016/0092-8674(89)90925-2. [DOI] [PubMed] [Google Scholar]
  37. Tricoli J. V., Rall L. B., Karakousis C. P., Herrera L., Petrelli N. J., Bell G. I., Shows T. B. Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res. 1986 Dec;46(12 Pt 1):6169–6173. [PubMed] [Google Scholar]
  38. Wharton W., Van Wyk J. J., Pledger W. J. Inhibition of BALB/c-3T3 cells in late G1: commitment to DNA synthesis controlled by somatomedin C. J Cell Physiol. 1981 Apr;107(1):31–39. doi: 10.1002/jcp.1041070105. [DOI] [PubMed] [Google Scholar]
  39. Whitelaw E., Hogben P., Hanscombe O., Proudfoot N. J. Transcriptional promiscuity of the human alpha-globin gene. Mol Cell Biol. 1989 Jan;9(1):241–251. doi: 10.1128/mcb.9.1.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. de Pagter-Holthuizen P., Jansen M., van Schaik F. M., van der Kammen R., Oosterwijk C., Van den Brande J. L., Sussenbach J. S. The human insulin-like growth factor II gene contains two development-specific promoters. FEBS Lett. 1987 Apr 20;214(2):259–264. doi: 10.1016/0014-5793(87)80066-2. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES