Role of Serum Vascular Endothelial Growth Factor in the Prediction of Angiogenesis and Prognosis for Non-small Cell Lung Cancer

Shimanuki, Yuri; Takahashi, Kazuhisa; Cui, Ri; Hori, Satoshi; Takahashi, Fumiyuki; Miyamoto, Hideaki; Fukurchi, Yoshinosuke

doi:10.1007/s00408-004-2521-4

Cited by 64 publications

(51 citation statements)

References 24 publications

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“…Similarly, the serum VEGF-A levels did not correlate with tumor volume or tumor weight on day 35 post-tumor cell inoculation in our study. VEGF may be secreted from the tumor, platelets and muscle contraction (19,34). Poon et al demonstrated that the serum VEGF165 levels/platelet count ratio correlated significantly with tumor cytosolic VEGF165 (33).…”

Section: Discussionmentioning

confidence: 99%

“…Shimanuki et al measured the serum VEGF levels preoperatively in patients with non-small cell lung cancer and revealed a correlation with microvessel density in the resected tumor. Their results showed that the average overall survival and disease-free survival time were significantly longer when the VEGF levels were lower (19). VEGF also plays a significant role in the rapid growth of micrometastasis in the lungs (5).…”

Section: Introductionmentioning

confidence: 99%

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Vascular endothelial growth factor-A and changes in a tumor-bearing mouse model with Lewis lung cancer

et al. 2011

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Abstract. Vascular endothelial growth factor-A (VEGF-A)affects tumor growth and metastasis through stimulation of angiogenesis. The purpose of this study was to describe features of Lewis lung cancer (LLC) in mice and compare the serum VEGF-A levels with those of normal control mice. Two groups of mice were compared: one was subcutaneously injected with LLC cells (n=16) and the other served as the normal control (n=6). The serum VEGF-A levels were measured by ELISA prior to inoculation, and at 7, 21 and 35 days post-inoculation. The tumor weight and the metastatic condition were evaluated on day 35. Changes in body weight and serum VEGF-A concentration over a period of time were compared between the groups using generalized estimating equations. The relationship between the primary tumor and the metastatic condition was analyzed using the Spearman's rank correlation test. The survival rate was 56.3% on day 35 post-tumor inoculation. No difference was found between the groups with regard to gastrocnemius muscle weight on day 35 post-inoculation [0.1315±0.0066 g vs. 0.1308±0.0069 g (normal control)]. In tumor-bearing mice, the weight gain at sacrifice was less (0.24±0.45 vs. 1.93±0.47 g, P= 0.01), the final mean tumor volume and weight were 4264.69±1038.32 mm 3 and 3.70±0.83 g, the number of nodules in the lungs and livers was 6.33 (range 0-20) and 2.22 (range 0-11), respectively, and the serum VEGF-A levels were significantly higher than those of control mice. In conclusion, lower body weight gain, metastasis in the liver and lungs, and elevated VEGF-A levels are features of LLC in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor-A and changes in a tumor-bearing mouse model with Lewis lung cancer

et al. 2011

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“…Furthermore, VEGF is present at substantial levels within platelets and released upon their lysis such that preparation of peripheral blood samples that avoid contamination from platelet-derived VEGF becomes difficult. These limitations are reflected in the disparate values reported for circulating VEGF levels in cancer patients, which range from 0.04 to 1 ng/ml, calling into question the utility of plasma VEGF levels as a useful biomarker for guiding anti-angiogenic therapy (11,(13)(14)(15)(16)(17)(18)(19).…”

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confidence: 99%

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

Rudge

Holash

Hylton

et al. 2007

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

191

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VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in the efficacious range.

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“…Vascular endothelial growth factor seems to play a major role in tumour neoangiogenesis: transfection of tumour cells with VEGF results in enhanced angiogenesis and tumour growth in animal models (Zhang et al, 1995), antibodies blocking VEGF bioactivity inhibit tumour growth (Kim et al, 1993) and VEGF expression correlates with the degree of tumour vascularisation and the prognosis of several cancers (Vlaykova et al, 1999;Han et al, 2001). Therefore, VEGF measurements in peripheral blood are often performed as surrogate markers for angiogenesis (Tamura et al, 2001;Shimanuki et al, 2005).…”

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confidence: 99%

Real-time PCR of CD146 mRNA in peripheral blood enables the relative quantification of circulating endothelial cells and is an indicator of angiogenesis

et al. 2005

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Angiogenesis is a fundamental process in tumour growth and metastatic dissemination. Possible surrogate markers for tumour angiogenesis are the amounts of circulating endothelial cells (CEC) in peripheral blood and the plasma concentration of vascular endothelial growth factor (VEGF). We tested the suitability of real-time PCR for CD146, an endothelial cell-specific antigen, to quantify CEC numbers in comparison to a flow cytometry quantification. Real-time PCR of CD146 mRNA showed high sensitivity and linearity for the quantification of cultivated primary endothelial cells added in different amounts to blood samples. Circulating endothelial cell numbers were quantified in peripheral blood samples of breast cancer patients and healthy controls by four-colour flow cytometry analysis and CD146 real-time PCR, and VEGF plasma concentrations were measured by ELISA. The amounts of CEC detected with both methods correlated significantly and CEC numbers were significantly increased in newly diagnosed breast cancer patients compared to healthy controls. Vascular endothelial growth factor concentrations correlated significantly with CEC numbers, but there was no significant difference in VEGF levels between breast cancer patients and healthy controls indicating that VEGF plasma levels cannot be used as surrogate marker for tumour angiogenesis. Taken together, the quantification of CEC by CD146 realtime PCR showed equivalent results to the flow cytometry analysis. Thus, CD146 real-time PCR may be an easy and reliable approach to quantify CEC in peripheral blood samples and could facilitate the integration of CEC measurements in clinical studies exploring the efficacy of antiangiogenic therapies.

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Role of Serum Vascular Endothelial Growth Factor in the Prediction of Angiogenesis and Prognosis for Non-small Cell Lung Cancer

Cited by 64 publications

References 24 publications

Vascular endothelial growth factor-A and changes in a tumor-bearing mouse model with Lewis lung cancer

Vascular endothelial growth factor-A and changes in a tumor-bearing mouse model with Lewis lung cancer

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

Real-time PCR of CD146 mRNA in peripheral blood enables the relative quantification of circulating endothelial cells and is an indicator of angiogenesis

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