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

Abstract

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.

Differential expression of vascular endothelial growth factor-A, -C and -D for the diagnosis and prognosis of cancer patients with malignant effusions

“…The altered expression of VEGF-A has been reported to be associated with the poor prognosis of various types of human cancer (13,14). Multiple clinical studies have also demonstrated the potential benefit of VEGF-A inhibition in patients with malignant effusions (15). Anti-angiogenic therapy (such as bevacizumab, a monoclonal antibody targeting VEGF-A) adjuvant to chemotherapy serves a potential function in the management of pleural effusions in advanced non-squamous non-small cell lung cancer (5,16).…”

Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers

“…Because ascites fluid contains many cells of tumor origin in addition to other soluble growth factors that have been associated with invasion and metastasis (11,12), this fluid contains the secretome of ovarian cancer cells while reflecting other microenvironmental factors of the malignancy. Thus, applying the ever advancing technique of proteomics analysis on ascites, it may be possible to discover novel biomarkers that are more sensitive and specific than those currently available.…”

Potent anti-tumor killing activity of the multifunctional Treg cell line HOZOT against human tumors with diverse origins

“…Highly efficient anti-tumor effects were observed in HOZOT-treated mice which demonstrated almost complete eradication of inoculated WiDr cells in the peritoneal cavity and no accumulation of tumor ascites. In clinical oncology of cancers at advanced stages, especially the advanced stage caused by aggressive carcinomas mainly from digestive organs, it is important to manage cancer cell dissemination in the peritoneal/thoracic cavity and to reduce the accumulation of tumor ascites (18,19). Taking these issues into consideration, our results emphasize the promising clinical utility of HOZOT against advanced stage colon cancer.…”