High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours

Zorick, Todd; Mustacchi, Zan; Bando, Sílvia Yumi; Zatz, Mayana; Moreira-Filho, Carlos Alberto; Olsen, Bjørn R.; Passos‐Bueno, Maria Rita

doi:10.1038/sj.ejhg.5200721

Cited by 143 publications

(111 citation statements)

References 18 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…This observation was reinforced by the observation that B16F10 xenograft growth was suppressed in a mouse line engineered to overexpress endostatin resulting in a 1.6-fold increase in circulating endostatin levels. This latter model recapitulates the clinical observation that patients with Down's syndrome (trisomy 21) who have three copies of the collagen XVIII gene and 70% higher serum endostatin levels (Zorick et al, 2001) have much lower standardised mortality odds ratios for death from solid malignant tumours at all ages than the rest of the population , suggesting that endostatin may have an endotheliumspecific tumour suppressor function in humans.…”

Section: A Physiological Role?supporting

confidence: 66%

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Clamp

Jayson

2005

Br J Cancer

View full text Add to dashboard Cite

Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments.

show abstract

Section: A Physiological Role?supporting

confidence: 66%

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Clamp

Jayson

2005

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…It was also reported that patients with Down syndrome have elevated levels of endostatin which potentially contribute to their low incidence of various solid tumors. 13 Taken together, these observations indicate the significant role of these endogenous proteins in antiangiogenesis.…”

mentioning

confidence: 75%

Upregulation of endogenous angiogenesis inhibitors: A mechanism of action of metronomic chemotherapy

Ng¹,

Figg²

2004

Cancer Biology & Therapy

View full text Add to dashboard Cite

“…Individuals with Down's syndrome exhibit a significant protection from developing many forms of solid tumors (25,26). Interestingly, it was noted that due to trisomy-21 and an extra copy of type XVIII collagen on chromosome 21, these individuals circulate Ϸ1.7-fold more endostatin than do normal individuals (normal; 20.3 Ϯ 11.5 ng͞ml vs. Down's syndrome; 38.6 Ϯ 20.1 ng͞ml) (26).…”

mentioning

confidence: 99%

Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors

Sund

Hamano

Sugimoto

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

165

112

View full text Add to dashboard Cite

Disruption of the systemic angiogenesis balance to favor enhanced angiogenesis is speculated to represent a key step in the growth of tumors. Although a major emphasis has been placed on the increase of angiogenesis stimulators, such as VEGF, on the disruption of the angiogenic balance, the potential role of the physiological levels of endogenous inhibitors of angiogenesis on tumor growth is poorly understood. Here, we use three independent lines of mice deficient in tumstatin, endostatin, or thrombospondin-1 (TSP-1), to address the role that these endogenous angiogenesis inhibitors play in tumor growth. Our experiments demonstrate that normal physiological levels of these inhibitors serve to retard the growth of tumors, and that their absence leads to enhanced angiogenesis and a 2-to 3-fold increase in tumor growth. The tumor-suppressive action of TSP-1, endostatin, and tumstatin correlates with expression of CD36 receptor, ␣5␤1 integrin, and ␣v␤3 integrin on proliferating endothelial cells, respectively. Moreover, tumors grow 2-fold faster in the tumstatin͞TSP-1 double-knockout mice, compared with either the tumstatin-or the TSP-1-deficient mice, strongly suggesting that ceiling rate of cancer growth is not completely dependent on the genetic defects of cancer cells but also depends on the host-derived tumor microenvironment. Additionally, tumor growth in transgenic mice overproducing endostatin specifically in the endothelial cells (a 1.6-fold increase in the circulating levels; mimicking Down's syndrome condition) is 3-fold slower than the tumor growth in wild-type mice. Collectively, our data suggest that physiological levels of endogenous inhibitors of angiogenesis can serve as endothelium-specific tumor suppressors.cancer ͉ endostatin ͉ tumstatin ͉ thrombospondin-1

show abstract

High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours

Cited by 143 publications

References 18 publications

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Upregulation of endogenous angiogenesis inhibitors: A mechanism of action of metronomic chemotherapy

Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors

Contact Info

Product

Resources

About