Prognostic significance of angiogenic factors in uterine cervical cancer.
ABSTRACT Angiogenesis is pivotal in tumour development and progress, and targeted tumour therapies, such as bevacizumab, have shown promising results. However, in unselected patient populations, the treatment with angiogenesis-targeted combination regimens is marred by a variable response, non-negligible toxicity and questionable economy. The present study summarizes research to identify individual circulating angiogenic factors as markers for disease severity and possibly treatment response.
A total of 125 patients with cervical cancer from the ongoing cervical cancer monitoring database of the University Hospital Charité, Berlin, Germany, were included. Information obtained from the database included tumour stage, malignancy grade, presence of nodal metastases, lymph vessel invasion, patient age, HER2, HPV, smoking and menopausal status, and serum concentrations of vascular endothelial growth factor (VEGF), VEGF-D, VEGF-C, endoglin, endostatin, angiogenin, basic fibroblast growth factor (FGFb), vascular endothelial growth factor receptor (VEGF-R1), VEGF-R2, soluble inter-cellular adhesion molecule 1 (sICAM 1), soluble vascular adhesion molecule 1 (sVCAM 1), insulin-like growth factor 1 (IFG-1) and insulin like growth factor binding protein 3 (IGF-BP3).
There was a clear association of angiogenic factor concentrations with stage of disease. Angiogenin showed an independent discrimination for cervical intraepithelial neoplasia (CIN) and invasive stages, and endoglin did so for invasive stages vs. recurrent disease. However, none of the potential markers under investigation was anywhere near selective enough to allow for a clinically meaningful prediction of prognosis or response.
The association of circulating angiogenic factors with disease progression in cervical cancer is confirmed, but its utility for prognosis prediction and patient stratification for targeted therapies is doubtful.
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ABSTRACT: Introduction:The importance of the endothelium in angiogenesis and cancer is undisputed, and its integrity may be assessed by laboratory markers such as circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), plasma von Willebrand factor (vWf), soluble E selectin, vascular endothelial growth factor (VEGF) and angiogenin. Antiantigenic therapy may be added to standard cytotoxic chemotherapy as a new treatment modality. We hypothesised that additional antiangiogenic therapy acts in a contrasting manner to that of standard chemotherapy on the laboratory markers.Methods:We recruited 68 patients with CRC, of whom 16 were treated with surgery alone, 32 were treated with surgery followed by standard chemotherapy (5-flurouracil), and 20 were treated with surgery followed by standard chemotherapy plus anti-VEGF therapy (Avastin). Peripheral blood was taken before surgery, and again 3 months and 6 months later. CD34(+)/CD45(-)/CD146(+) CECs and CD34(+)/CD45(-)/CD309[KDR](+) EPCs were measured by flow cytometry, plasma markers by ELISA.Results:In each of the three groups, CECs and EPCs fell at 3 months but were back at pre-surgery levels at 6 months (P<0.05). VEGF was lower in both 3-and 6-month samples in the surgery-only and surgery plus standard chemotherapy groups (P<0.05), but in those on surgery followed by standard chemotherapy plus anti-VEGF therapy, low levels at 3 months (P<0.01) increased to pre-surgery levels at 6 months. In those having surgery and standard chemotherapy, soluble E selectin was lower, whereas angiogenin was higher at 6 months than at baseline (both P<0.05).Conclusions:We found disturbances in endotheliod cells regardless of treatment, whereas VEGF returned to levels before surgery in those on antiangiogenic therapy. These observations may have clinical and pathophysiological implications.British Journal of Cancer advance online publication, 11 September 2014. doi:10.1038/bjc.2014.491 www.bjcancer.com.British Journal of Cancer 09/2014; 111(9). DOI:10.1038/bjc.2014.491 · 4.82 Impact Factor
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ABSTRACT: Elevated serum levels of a secreted glycoprotein chitinase 3 like 1 (CHI3L1) are associated with poor prognosis and short survival time of patients with cervical cancer (CxCa). Our previous microarray data showed the increased expression of CHI3L1 in invasive CxCa compared to normal tissue, implicating a potential role of CHI3L1 in CxCa. To establish the pathological role of CHI3L1 in the development of CxCa, this study focused on its expression in CxCa and angiogenic impacts in tumor vessel formation. CHI3L1 activated angiogenesis by promoting endothelial cell migration and tube formation in vitro but failed to protect CxCa cell lines, CaSki and HeLa against apoptosis induced by γ-irradiation. In addition, the capability of CHI3L1 to induce proliferation and migration of CaSki and HeLa cells was cell type specific. In an analysis of 103 specimens from CxCa patients, increased expression levels of CHI3L1 mRNA and protein in invasive CxCa were 4-fold (P < 0.05) and 2-fold (P < 0.01), respectively, stronger than those in normal subjects. The immunostaining of CHI3L1 was positively correlated with VEGF expression (P = 0.0019) and microvessel density (P = 0.0110). Moreover, CHI3L1 expression was also positively associated with cancer metastasis (P = 0.011). The data suggest the crucial role of CHI3L1 by promoting angiogenesis, which may contribute to the development and progression of CxCa. The findings help establish CHI3L1 as a prognostic biomarker and therapeutic target for CxCa patients.The international journal of biochemistry & cell biology 06/2014; 51. DOI:10.1016/j.biocel.2014.03.021 · 4.24 Impact Factor
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ABSTRACT: Experimental data imply that endostatin, a proteolytically cleaved fragment of collagen XVIII, could be involved in the development of cardiovascular disease and cancer. Prospective data concerning the relation between circulating endostatin and mortality are lacking. Accordingly, we aimed to study associations between circulating endostatin and mortality risk. Serum endostatin was analyzed in 2 community-based cohorts: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 50%, n=748; mean age, 77 years; median follow-up, 7.9 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=748; mean age, 77 years; median follow-up, 9.7 years). During follow-up, 90 participants died in PIVUS (1.28/100 person-years at risk), and 417 participants died in ULSAM (6.7/100 person-years at risk). In multivariable Cox regression models adjusted for age and established cardiovascular risk factors, 1 SD higher ln(serum endostatin level) was associated with a hazard ratio of mortality of 1.39 and 95% confidence interval, 1.26 to 1.53, on average in both cohorts. In the ULSAM cohort, serum endostatin was also associated with cardiovascular mortality (177 deaths; hazard ratio per SD of ln[endostatin] 1.45, 95% confidence interval [1.25-1.71]) and cancer mortality (115 deaths; hazard ratio per SD of ln[endostatin] 1.35, 95% confidence interval [1.10-1.66]). High serum endostatin was associated with increased mortality risk in 2 independent community-based cohorts of the elderly. Our observational data support the importance of extracellular matrix remodeling in the underlying pathophysiology of cardiovascular disease and cancer.Arteriosclerosis Thrombosis and Vascular Biology 09/2013; 33(11). DOI:10.1161/ATVBAHA.113.301704 · 5.53 Impact Factor