Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Feb 21;82(6):1171–1176. doi: 10.1054/bjoc.1999.1058

Reduced expression of transforming growth factor-beta receptor type III in high stage neuroblastomas

A Iolascon 1, L Giordani 1, A Borriello 2, R Carbone 1, A Izzo 1, G P Tonini 4, C Gambini 3, F Della Ragione 2
PMCID: PMC2363349  PMID: 10735501

Abstract

Transforming growth factor beta (TGF-β) is a powerful inhibitor of cell proliferation and a potent inducer of differentiation. Resistance to TGF-β action is a characteristic of many malignancies and has been attributed to alterations of TGF-β receptors as well as disturbance of downstream transduction pathways. To analyse the TGF-β response in neuroblastoma, the expression of TGF-β1 and TGF-β type I, II and III receptor genes was investigated in 61 cancer samples by means of reverse transcription polymerase chain reaction. The specimens analysed belong to different stages, namely nine samples of stage 1, ten of stage 2, nine of stage 3 and 28 of stage 4. Moreover, five samples were of stage 4S, which represents a tumour form undergoing spontaneous regression. The results obtained show that TGF-β1 and TGF-β type I and II receptor genes appear to be almost equally expressed in neuroblastomas of all stages. Conversely, TGF-β type III receptor gene expression, which is required for an efficacious TGF-β binding and function, is strongly reduced exclusively in neuroblastomas of stages 3 and 4. These findings were directly confirmed by immunohistochemical analyses of ten neuroblastoma specimens. Our results suggest the occurrence of an altered TGF-β response in advanced neuroblastomas which might be an important mechanism for escaping growth control and for developing invasiveness. Moreover, our findings allow the proposal of a novel mechanism, namely down-regulation of TGF-β type III receptor gene expression, to avoid TGF-β inhibitory activity. © 2000 Cancer Research Campaign

Keywords: TGF-β1, TGF-βRI, TGF-βRII, TGF-βRIII, neuroblastoma

Full Text

The Full Text of this article is available as a PDF (126.5 KB).

Selected References

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

  1. Bristow R. E., Baldwin R. L., Yamada S. D., Korc M., Karlan B. Y. Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma. Cancer. 1999 Feb 1;85(3):658–668. doi: 10.1002/(sici)1097-0142(19990201)85:3<658::aid-cncr16>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  2. Brodeur G. M., Pritchard J., Berthold F., Carlsen N. L., Castel V., Castelberry R. P., De Bernardi B., Evans A. E., Favrot M., Hedborg F. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug;11(8):1466–1477. doi: 10.1200/JCO.1993.11.8.1466. [DOI] [PubMed] [Google Scholar]
  3. Chen C., Wang X. F., Sun L. Expression of transforming growth factor beta (TGFbeta) type III receptor restores autocrine TGFbeta1 activity in human breast cancer MCF-7 cells. J Biol Chem. 1997 May 9;272(19):12862–12867. doi: 10.1074/jbc.272.19.12862. [DOI] [PubMed] [Google Scholar]
  4. Coffey R. J., Jr, Kost L. J., Lyons R. M., Moses H. L., LaRusso N. F. Hepatic processing of transforming growth factor beta in the rat. Uptake, metabolism, and biliary excretion. J Clin Invest. 1987 Sep;80(3):750–757. doi: 10.1172/JCI113130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cohen P. S., Letterio J. J., Gaetano C., Chan J., Matsumoto K., Sporn M. B., Thiele C. J. Induction of transforming growth factor beta 1 and its receptors during all-trans-retinoic acid (RA) treatment of RA-responsive human neuroblastoma cell lines. Cancer Res. 1995 Jun 1;55(11):2380–2386. [PubMed] [Google Scholar]
  6. Filmus J., Kerbel R. S. Development of resistance mechanisms to the growth-inhibitory effects of transforming growth factor-beta during tumor progression. Curr Opin Oncol. 1993 Jan;5(1):123–129. [PubMed] [Google Scholar]
  7. Filmus J., Zhao J., Buick R. N. Overexpression of H-ras oncogene induces resistance to the growth-inhibitory action of transforming growth factor beta-1 (TGF-beta 1) and alters the number and type of TGF-beta 1 receptors in rat intestinal epithelial cell clones. Oncogene. 1992 Mar;7(3):521–526. [PubMed] [Google Scholar]
  8. Fynan T. M., Reiss M. Resistance to inhibition of cell growth by transforming growth factor-beta and its role in oncogenesis. Crit Rev Oncog. 1993;4(5):493–540. [PubMed] [Google Scholar]
  9. Heldin C. H., Miyazono K., ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997 Dec 4;390(6659):465–471. doi: 10.1038/37284. [DOI] [PubMed] [Google Scholar]
  10. Hougaard S., Nørgaard P., Abrahamsen N., Moses H. L., Spang-Thomsen M., Skovgaard Poulsen H. Inactivation of the transforming growth factor beta type II receptor in human small cell lung cancer cell lines. Br J Cancer. 1999 Mar;79(7-8):1005–1011. doi: 10.1038/sj.bjc.6690161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Iolascon A., Giordani L., Moretti A., Basso G., Borriello A., Della Ragione F. Analysis of CDKN2A, CDKN2B, CDKN2C, and cyclin Ds gene status in hepatoblastoma. Hepatology. 1998 Apr;27(4):989–995. doi: 10.1002/hep.510270414. [DOI] [PubMed] [Google Scholar]
  12. Iolascon A., Giordani L., Moretti A., Tonini G. P., Lo Cunsolo C., Mastropietro S., Borriello A., Ragione F. D. Structural and functional analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in neuroblastoma. Pediatr Res. 1998 Jan;43(1):139–144. doi: 10.1203/00006450-199801000-00021. [DOI] [PubMed] [Google Scholar]
  13. Iolascon A., Lo Cunsolo C., Giordani L., Cusano R., Mazzocco K., Boumgartner M., Ghisellini P., Faienza M. F., Boni L., De Bernardi B. Interstitial and large chromosome 1p deletion occurs in localized and disseminated neuroblastomas and predicts an unfavourable outcome. Cancer Lett. 1998 Aug 14;130(1-2):83–92. doi: 10.1016/s0304-3835(98)00122-0. [DOI] [PubMed] [Google Scholar]
  14. Johnson D., Lanahan A., Buck C. R., Sehgal A., Morgan C., Mercer E., Bothwell M., Chao M. Expression and structure of the human NGF receptor. Cell. 1986 Nov 21;47(4):545–554. doi: 10.1016/0092-8674(86)90619-7. [DOI] [PubMed] [Google Scholar]
  15. Kadin M. E., Cavaille-Coll M. W., Gertz R., Massagué J., Cheifetz S., George D. Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6002–6006. doi: 10.1073/pnas.91.13.6002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kiefer M. C., Stephans J. C., Crawford K., Okino K., Barr P. J. Ligand-affinity cloning and structure of a cell surface heparan sulfate proteoglycan that binds basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6985–6989. doi: 10.1073/pnas.87.18.6985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kimchi A., Wang X. F., Weinberg R. A., Cheifetz S., Massagué J. Absence of TGF-beta receptors and growth inhibitory responses in retinoblastoma cells. Science. 1988 Apr 8;240(4849):196–199. doi: 10.1126/science.2895499. [DOI] [PubMed] [Google Scholar]
  18. Lu S. L., Akiyama Y., Nagasaki H., Saitoh K., Yuasa Y. Mutations of the transforming growth factor-beta type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer. Biochem Biophys Res Commun. 1995 Nov 13;216(2):452–457. doi: 10.1006/bbrc.1995.2644. [DOI] [PubMed] [Google Scholar]
  19. López-Casillas F., Cheifetz S., Doody J., Andres J. L., Lane W. S., Massagué J. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell. 1991 Nov 15;67(4):785–795. doi: 10.1016/0092-8674(91)90073-8. [DOI] [PubMed] [Google Scholar]
  20. López-Casillas F., Wrana J. L., Massagué J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell. 1993 Jul 2;73(7):1435–1444. doi: 10.1016/0092-8674(93)90368-z. [DOI] [PubMed] [Google Scholar]
  21. MacDonald R. G., Pfeffer S. R., Coussens L., Tepper M. A., Brocklebank C. M., Mole J. E., Anderson J. K., Chen E., Czech M. P., Ullrich A. A single receptor binds both insulin-like growth factor II and mannose-6-phosphate. Science. 1988 Mar 4;239(4844):1134–1137. doi: 10.1126/science.2964083. [DOI] [PubMed] [Google Scholar]
  22. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995 Jun 2;268(5215):1336–1338. doi: 10.1126/science.7761852. [DOI] [PubMed] [Google Scholar]
  23. Matoba H., Sugano S., Yamaguchi N., Miyachi Y. Expression of transforming growth factor-beta1 and transforming growth factor-beta Type-II receptor mRNA in papillary thyroid carcinoma. Horm Metab Res. 1998 Oct;30(10):624–628. doi: 10.1055/s-2007-978946. [DOI] [PubMed] [Google Scholar]
  24. Morgan D. O., Edman J. C., Standring D. N., Fried V. A., Smith M. C., Roth R. A., Rutter W. J. Insulin-like growth factor II receptor as a multifunctional binding protein. Nature. 1987 Sep 24;329(6137):301–307. doi: 10.1038/329301a0. [DOI] [PubMed] [Google Scholar]
  25. Polyak K. Negative regulation of cell growth by TGF beta. Biochim Biophys Acta. 1996 Mar 18;1242(3):185–199. doi: 10.1016/0304-419x(95)00009-5. [DOI] [PubMed] [Google Scholar]
  26. Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A., Shooter E. M. Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature. 1987 Feb 12;325(6105):593–597. doi: 10.1038/325593a0. [DOI] [PubMed] [Google Scholar]
  27. Royuela M., De Miguel M. P., Bethencourt F. R., Sanchez-Chapado M., Fraile B., Paniagua R. Transforming growth factor beta 1 and its receptor types I and II. Comparison in human normal prostate, benign prostatic hyperplasia, and prostatic carcinoma. Growth Factors. 1998;16(2):101–110. doi: 10.3109/08977199809002121. [DOI] [PubMed] [Google Scholar]
  28. Saunders S., Jalkanen M., O'Farrell S., Bernfield M. Molecular cloning of syndecan, an integral membrane proteoglycan. J Cell Biol. 1989 Apr;108(4):1547–1556. doi: 10.1083/jcb.108.4.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sun L., Wu G., Willson J. K., Zborowska E., Yang J., Rajkarunanayake I., Wang J., Gentry L. E., Wang X. F., Brattain M. G. Expression of transforming growth factor beta type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells. J Biol Chem. 1994 Oct 21;269(42):26449–26455. [PubMed] [Google Scholar]
  30. Wang J., Han W., Zborowska E., Liang J., Wang X., Willson J. K., Sun L., Brattain M. G. Reduced expression of transforming growth factor beta type I receptor contributes to the malignancy of human colon carcinoma cells. J Biol Chem. 1996 Jul 19;271(29):17366–17371. doi: 10.1074/jbc.271.29.17366. [DOI] [PubMed] [Google Scholar]
  31. Wang X. F., Lin H. Y., Ng-Eaton E., Downward J., Lodish H. F., Weinberg R. A. Expression cloning and characterization of the TGF-beta type III receptor. Cell. 1991 Nov 15;67(4):797–805. doi: 10.1016/0092-8674(91)90074-9. [DOI] [PubMed] [Google Scholar]
  32. White R. L. Tumor suppressing pathways. Cell. 1998 Mar 6;92(5):591–592. doi: 10.1016/s0092-8674(00)81124-1. [DOI] [PubMed] [Google Scholar]

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

RESOURCES