David Jin, Jeffrey L. Port, Robert Korst, Paul Lee, Li Zhang, Kathleen A. McDonald, Cathy A. Ferrara, Danish Meherally, Shahin Rafii, Nasser Altorki; Cardiothoracic Surgery, Weill Medical College of Cornell University, New York, NY
Objective: Growth of lung cancer involves a prominent proliferative vascular component. In response to pro-angiogenic cytokines, chemokines and growth factors, endothelial progenitors and other pro-angiogenic hematopoietic cells are mobilized from the bone marrow and recruited to the tumor neovascular site, a process so called "hemangiogenesis". Biomarkers that predict the hemangiogenic propensity of lung cancer and the impact of surgery on their levels remain unknown.Methods: A multimodular approach was devised to assess a panel of hemangiogenic parameters in a cohort of chemotherapy naïve patients with non-small cell lung cancer pre- and post-complete surgical resection. This panel includes 5 components: 1) a novel human umbilical vein endothelial cell (HUVEC)-based angiogenic scale (0-5) to assess the functional plasma angiogenic activity, 2) 2-color flow cytometry to assess levels of CD133+VEGFR2+ circulating endothelial progenitors (CEPs), 3) colony-forming assay to quantify circulating hematopoietic progenitors (CHPs), 4) plasma levels of chemokine SDF-1 alpha, and 5) VEGF-A levels in platelet lysates.
Results: The cohort consists of 25 consecutive patients (12 men, 13 women) with median age of 65. Analysis of the specimens collected at 2-week post-surgery revealed a global suppression of hemangiogenic parameters with reduction of the functional HUVEC-based angiogenic scale (23/25; mean score of 3.2 versus 1.0; p<0.05), 2.5-fold decrease in CEPs (p<0.05), and 4-fold decrease in CHPs (p<0.05) as compared to the pre-surgery baseline specimens. This trend also correlated with decreased levels of SDF-1 alpha in the plasma and VEGF-A levels in platelet lysates. All hemangiogenic parameters tested were significantly elevated in the pre-surgical specimens as compared to that in healthy volunteer controls.
Conclusion: Lung cancer development involved a hemangiogenic switch toward increased CEPs, CHPs, and functional plasma pro-angiogenic activity. Surgical removal of primary lung cancer led to a normalization of hemangiogenic profile. Collective assessment of hemangiogenic biomarkers may be a promising resource for predicting clinical outcomes, recurrence, and for validating the potential impact of anti-angiogenic therapy on lung cancer.
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