Vascular Endothelial Growth Factor in Pleural Fluid

Cheng, Dong-Sheng; Rodriguez, R. Michael; Perkett, Elizabeth A.; Rogers, June; Bienvenu, Gary; Lappalainen, Urpo; Light, Richard W.

doi:10.1378/chest.116.3.760

Cited by 108 publications

(116 citation statements)

References 22 publications

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“…However, if blockage of the lymphatic vessels were the primary cause, the pleural fluids would be transudate rather than exudate (high protein content), as seen in fluids associated with malignancies [25]. Our data support this statement because high levels of VEGF in these fluid accumulations are biologically active in vitro and thus presumably active in vivo.…”

Section: Figure 1 Stimulation Of Human Vascular Endothelial Cells Bysupporting

confidence: 62%

Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation

Verheul

2000

The Oncologist

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Primary Purpose. Formation of ascites and pleural effusion (PE) is a common problem for patients with advanced-stage cancer. These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. Preclinical models have demonstrated that vascular endothelial growth factor (VEGF) plays a pivotal role in the accumulation of malignant PE or ascites. This study investigated whether blockade of VEGF activity would reduce biological activity of PE and ascites on endothelial cells of cancer patients.Patients and Methods. The activity of VEGF in PE and ascites of 58 patients (39 with PE and 19 with ascites) was measured. An endothelial cell proliferation assay with human umbilical vein endothelial cells was used to determine the biological activity of ascites and PE.Results. VEGF concentrations ranged from 67-6,245 pg/ml. A significantly higher concentration of VEGF was detected in the ascites and PE of patients with cancer (median, 1,290 pg/ml) than in patients with nonmalignant disease (median, 250 pg/ml; p = 0.02). Of the 58 PE and ascites samples, 41 were biologically active, based on a two-to fourfold stimulation of endothelial cell proliferation in 72 hours. VEGF concentrations were significantly higher in the biologically active samples compared with the 17 nonactive samples (2,056 pg/ml versus 771 pg/ml; p = 0.02). Coincubation of the samples with either a neutralizing polyclonal antibody against VEGF or SU5416, a small molecule inhibitor of the VEGF receptor Flk-1/KDR, inhibited endothelial cell proliferation by 66% and 100%, respectively. The inhibition caused by the antibody and that caused by SU5416 correlated significantly (r = 0.8, p < 0.001).Conclusion. We conclude that malignant ascites and PE contain high levels of biologically active VEGF. This study strongly supports the hypothesis that blockade of VEGF, such as that afforded by SU5416, may benefit cancer patients with recurrent ascites or PE formation.

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Section: Figure 1 Stimulation Of Human Vascular Endothelial Cells Bysupporting

confidence: 62%

Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation

Verheul

2000

The Oncologist

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“…This might be associated with the selectiveness of samples. Compared with previous studies, the PF VEGF level in malignant group here is very close to some reported [7,15]. Strictly complying with the principles of clinical epidemiology for a diagnostic test, this study has acquired the diagnostic accuracy of VEGF in malignant PE with the cut-off points obtained by ROC analysis.…”

Section: Discussionsupporting

confidence: 81%

“…The former might be because that, we postulate, detectable VEGF is overexpressed by most malignant tumors, but probably not by all types of human cancer, especially when combined with complications that can lead to decreased level of VEGF. Previous studies suggested that, even for those malignant tumors of different types or histology with overexpression of VEGF, the VEGF levels vary [7,15]. Some circumstances, such as the initial phase of acute lung injury, may result in downregulation of VEGF level, in which endothelial permeability could be limited partly [18].…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, VEGF is a multifunctional cytokine with critical roles in vasculogenesis and in both pathological and physiological angiogenesis and lymphangiogenesis [19]. Excluding malignancy, some other pathological conditions, such as hypoxia, pulmonary embolism, hemorrhagic effusions and empyema, could also lead to or present with heightened levels of VEGF [15,16,20]. VEGF also has a central role in wound healing and inflammation [11].…”

Section: Discussionmentioning

confidence: 99%

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Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusions

2007

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“…In two previous studies, using the same material herein analysed, we showed that VEGF is directly associated with the expression of HIF1a and HIF2a, while CA9 expression was marginally associated with HIF1a (Giatromanolaki et al, 2001b,c). A significant association between LDH and VEGF levels in the pleural fluid of patients with various diseases has been reported (Cheng et al, 1999). The strong association of LDH with bFGF activated pathway, however, may be due to HIF-independent reasons.…”

Section: Discussionmentioning

confidence: 97%

Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

et al. 2003

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Lactate dehydrogenase-5 (LDH-5) catalyses the reversible transformation of pyruvate to lactate, having a principal position in the anaerobic cellular metabolism. Induction of LDH-5 occurs during hypoxia and LDH-5 transcription is directly regulated by the hypoxia-inducible factor 1 (HIF1). Serum LDH levels have been correlated with poor prognosis and resistance to chemotherapy and radiotherapy in various neoplastic diseases. The expression, however, of LDH in tumours has never been investigated in the past. In the present study, we established an immunohistochemical method to evaluate the LDH-5 overexpression in tumours, using two novel antibodies raised against the rat muscle LDH-5 and the human LDH-5 (Abcam, UK). The subcellular patterns of expression in cancer cells were mixed nuclear and cytoplasmic. In direct contrast to cancer cells, stromal fibroblasts were reactive for LDH-5 only in a minority of cases. Serum LDH, although positively correlated with, does not reliably reflect the intratumoral LDH-5 status. Lactate dehydrogenase-5 overexpression was directly related to HIF1a and 2a, but not with the carbonic anhydrase 9 expression. Patients with tumours bearing high LDH-5 expression had a poor prognosis. Tumours with simultaneous LDH-5 and HIF1a (or HIF2a) overexpression, indicative of a functional HIF pathway, had a particularly aggressive behaviour. It is concluded that overexpression of LDH-5 is a common event in non-small-cell lung cancer, can be easily assessed in paraffin-embedded material and provides important prognostic information, particularly when combined with other endogenous markers of hypoxia and acidity.

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Vascular Endothelial Growth Factor in Pleural Fluid

Cited by 108 publications

References 22 publications

Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation

Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation

Clinical utility of vascular endothelial growth factor in diagnosing malignant pleural effusions

Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

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