Overexpression of Collagen XVIII Is Associated with Poor Outcome and Elevated Levels of Circulating Serum Endostatin in Non–Small Cell Lung Cancer

Iwamoto, Toshihiko; Chang, Hao; Suzuki, Makoto; Otsuji, Mizuto; Yokoi, Sana; Chiyo, Masako; Motohashi, Shinichiro; Yasufuku, Kazuhiro; Sekine, Yasuo; Iyoda, Akira; Shibuya, Kiyoshi; Hiroshima, Kenzo; Fujisawa, Takehiko

doi:10.1158/1078-0432.ccr-04-0443

Cited by 60 publications

(43 citation statements)

References 26 publications

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“…Although the correlation index was relatively weaker, we found that a stronger endostatin expression correlates with higher serum levels of endostatin, suggesting that serum endostatin originated partially from tumor cells. Our findings are in concordance with the result found in NSCLC by Iizasa et al (34). However, in 12 patient-matched cases, serum endostatin concentration manifested no significant association with immunohistochemical staining, although this maybe due to the small sample size (11).…”

Section: Discussionsupporting

confidence: 92%

Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer

Zhang

et al. 2014

Biomedical Reports

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Abstract. Endostatin, as the most potential antiangiogenic factor, is a naturally occurring fragment of collagen XVIII in bloodstream capable of inhibiting tumor growth and metastasis. This study was conducted to explore the clinical value of endostatin in serum and tumor tissue in patients with operable non-small cell lung cancer (NSCLC). ELISA and immunohistochemistry were applied to detect the expression of endostatin in serum and tumor tissue in 105 patient-matched operable NSCLC patients. The serum level of endostatin was significantly higher in NSCLC patients than healthy individuals (P=0.0018). Cases with poorer differentiation showed a higher endostatin serum level (P=0.008). There was no significant correlation between tumor tissue expression and clinical parameters, such as TNM stage, differentiation degree, histological type and lymph node invasion status. A stronger expression of endostain in tumor tissue was associated with a higher serum level (r=0.223). The univariate and multivariate analyses with Cox proportional hazards model for overall survival showed that tumor stage and node status were independent prognostic factors, whereas neither endostatin levels in serum nor in tumor tissue showed potential in predicting the long-term survival of operable NSCLC patients. In conclusion, the results observed in the present study did not support the prediction of overall survival in operable NSCLC based on the expression levels of endostatin in serum and tumor tissue.

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Section: Discussionsupporting

confidence: 92%

Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer

Zhang

et al. 2014

Biomedical Reports

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“…With regard to endostatin expression in lung cancer, the presence of its precursor, collagen XVIII, in lung cancer cells was confirmed previously [17]. Notably, some investigators from the same institute reported previously that its expression in lung cancer tissue was associated with tumor progression and poor outcomes in assessment of patients at various stages [17,18].…”

Section: Commentsmentioning

confidence: 53%

Surgical Results in T2N0M0 Nonsmall Cell Lung Cancer Patients With Large Tumors 5 cm or Greater in Diameter: What Regulates Outcome?

Ohta

Waseda

Minato

et al. 2006

The Annals of Thoracic Surgery

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Background:We assessed the surgical results along with the clinical and biological features of non-small cell lung cancer (NSCLC) patients with localized large tumors. Methods:The study population consisted of 86 NSCLC patients who underwent complete resection of tumors 5 cm or larger in diameter in stage IB (T2N0M0). We immunohistochemically assessed the expression of angiostatin and endostatin. Results:The median tumor size was 6.0 cm (range, 5-14 cm). The operative procedures used were lobectomy in 71 cases, bilobectomy in 8 cases, and pneumonectomy in 11 cases. Fifty patients (58.1%) relapsed during the mean follow-up period of 33.6 ± 4.5 months. The median disease-free interval (DFI) was 9 months. Of 44 recurrent patients whose DFI could be identified, 25 patients (56.8%) relapsed within 12 months after the operation. The overall 5-and 10-year survival rates were 42.0% and 24.2%, respectively.Multivariate analysis showed that the degree of pleural involvement and angiostatin expression within the tumor were independent prognostic indicators. The endostatin expression within tumors also had a weaker relationship with outcome.Conclusions: Long-term surgical results were poor and early relapse was common in this cohort. In addition to pleural involvement, the tumor-induced expression of angiostatin and endostatin merit further investigation to gain possible insights into selection of patients who will benefit from surgery as the first line treatment.2

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“…Endostatin is present at detectable levels in the serum of normal individuals (Feldman et al, 2002;IIzasa et al, 2004) and canstatin/arresten has been isolated from human placenta, suggesting physiological function. Further indirect evidence is provided by the study of mouse strains with null mutations in the parental ECM molecule and rare single gene disorders in humans (see Table 2).…”

Section: A Physiological Role?mentioning

confidence: 99%

“…It is unclear whether these elevated endostatin levels are due to direct intratumoral production or a coordinated 'host' response to proangiogenic stimuli, in particular VEGF produced by the cancer (Feldman et al, 2002;Glenjen et al, 2002;Iizasa et al, 2004). What such findings do suggest however is that if this endogenous endostatin is in an active form, further increasing serum endostatin levels to pharmacological levels may not have a significant additional antiangiogenic effect as it is possible that in clinically manifest tumours, once the angiogenic switch has been tripped, raising the levels of endogenous antiangiogenic agents further is not very effective in resetting this.…”

Section: Targeting An Already Overloaded Systemmentioning

confidence: 99%

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Clamp

Jayson

2005

Br J Cancer

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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.

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Overexpression of Collagen XVIII Is Associated with Poor Outcome and Elevated Levels of Circulating Serum Endostatin in Non–Small Cell Lung Cancer

Cited by 60 publications

References 26 publications

Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer

Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer

Surgical Results in T2N0M0 Nonsmall Cell Lung Cancer Patients With Large Tumors 5 cm or Greater in Diameter: What Regulates Outcome?

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

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