Abstract
We report here a comparison of serum endostatin levels in Down syndrome patients to normal control subjects. We analysed serum samples from 35 patients with Down syndrome and 54 normal control subjects and found that although serum levels of endostatin vary widely in a normal human population, serum endostatin levels are significantly elevated in patients with Down syndrome. This result may explain the relative decrease in incidence of various solid tissue tumours observed in Down syndrome, given the role of endostatin as a potent inhibitor of tumour-induced angiogenesis in both human and animal models. Based upon these data, we propose that an increase of about one-third of normal endostatin serum levels may represent an effective therapeutic dose to significantly inhibit many solid tumours.
Similar content being viewed by others
Article PDF
References
Epstein CJ . Down syndrome (trisomy 21) in Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York 1995 vol 1: pp 749–794
Satgé D, Sommelet D, Geneix A, Nishi M, Malet P, Vekemans M . A tumor profile in Down Syndrome Am J Med Genet 1998 78: 207–216
Hasle H, Clemmensen IH, Mikkelsen M . Risks of leukaemia and solid tumours in individuals with Down's syndrome Lancet 2000 355: 165–169
Satgé D, Sasco AJ, Carlsen NLT et al. A lack of neuroblastoma in Down Syndrome: A study from 11 European countries Cancer Res 1998 58: 448–452
Hattori M, Fujiyama A, Taylor TD et al. The DNA sequence of human chromosome 21. The chromosome 21 mapping and sequencing consortium Nature 2000 405: 311–319
Sakata K, Tamura G, Nishizuka S et al. Commonly deleted regions on the long arm of chromosome 21 in differentiated adenocarcinoma of the stomach Genes Chromosomes Cancer 1997 18: 318–321
Ohgaki K, Iida A, Kasumi F et al. Mapping of a new target region of allelic loss to a 6-cM interval at 21q21 in primary breast cancers Genes Chromosomes Cancer 1998 23: 244–247
Schwendel A, Richard F, Langreck H et al. Chromosome alterations in breast carcinomas: frequent involvement of DNA losses including chromosomes 4q and 21q Br J Cancer 1998 78: 806–811
O´Reilly MS, Boehm T, Shing Y et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth Cell 1997 88: 277–285
Muragaki Y, Timmons S, Griffith CM et al. Mouse Col18a1 is expressed in a tissue-specific manner as three alternative variants and is localized in basement membrane zones Proc Natl Acad Sci USA 1995 92: 8763–8767
Sauter BV, Martinet O, Zhang WJ, Mandeli J, Woo SL . Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases Proc Natl Acad Sci USA 2000 97: 4802–4807
Feldman AL, Restifo NP, Alexander HR et al. Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice Cancer Res 2000 60: 1503–1506
Saarela J, Rehn M, Oikarinen A, Autio-Harmainen H, Pihlajaniemi T . The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans Am J Path 1998 253: 611–626
Sertie AL, Sossi V, Camargo AA, Zatz M, Brahe C, Passos-Bueno MR . Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome) Hum Mol Genet 2000 9: 2051–2058
Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W . Secreted cathepsin L generates endostatin from collagen XVIII EMBO J 2000 19: 1187–1194
Sasaki T, Fukai N, Mann K, Gohring W, Olsen BR, Timpl R . Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin EMBO J 1998 17: 4249–4256
Musso O, Rehn M, Theret N et al. Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas Cancer Res 2001 61: 45–49
Feldman AL, Tamarkin L, Paciotti GF et al. Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer Clin Cancer Res 2000 6: 4628–4634
Hebbar M, Peyrat J-P, Hornez L, Hatron P-Y, Hachulla E, Devulder B . Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with Systemic Sclerosis Arth Rheum 2000 43: 889–893
Shichiri M, Hirata Y . Antiangiogenesis signals by endostatin FASEB J 2001 15: 1044–1053
Jiang L, Jha V, Dhanabal M, Sukhatme VP, Alper SL . Intracellular Ca2+ signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin AJP Cell Physiol 2001 280: C1140–C1150
Karumanchi SA, Jha V, Ramchandran R et al. Cell surface glypicans are low-affinity endostatin receptors Mol Cell 2001 7: 811–822
Acknowledgements
We thank all the DS patients and the Hospital Darcy Vargas for collaboration, Dr. Sérgio Mattioli for helpful discussions in statistical analysis and Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) for financial support. MRPB is partly funded by an International program of the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zorick, T., Mustacchi, Z., Bando, S. et al. High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours. Eur J Hum Genet 9, 811–814 (2001). https://doi.org/10.1038/sj.ejhg.5200721
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ejhg.5200721
Keywords
This article is cited by
-
Widespread kidney anomalies in children with Down syndrome
Pediatric Nephrology (2022)
-
Aneuploidy as a promoter and suppressor of malignant growth
Nature Reviews Cancer (2021)
-
Deciphering the focal role of endostatin in Alzheimer’s disease
Environmental Science and Pollution Research (2021)
-
iPSC-derived progenitor stromal cells provide new insights into aberrant musculoskeletal development and resistance to cancer in down syndrome
Scientific Reports (2020)
-
Brushfield spots and Wölfflin nodules unveiled in dark irides using near-infrared light
Scientific Reports (2018)