Angiogenesis in Cancer
Authors: Orhan Sezer, Christian Jakob, Kathrin Niemöller, Ronnie T.P. Poon, Sheung-Tat Fan, John Wong
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.13.3299 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11432903 Angiogenesis in Cancer Orhan SezerxOrhan SezerSearch for articles by this author , Christian JakobxChristian JakobSearch for articles by this author , Kathrin NiemöllerxKathrin NiemöllerSearch for articles by this author Ronnie T.P. PoonxRonnie T.P. PoonSearch for articles by this author , Sheung-Tat FanxSheung-Tat FanSearch for articles by this author , John WongxJohn WongSearch for articles by this author Show More Universitätsklinikum Charité, Berlin, GermanyUniversity of Hong Kong Medical Center, Hong Kong, China https://doi.org/10.1200/JCO.2001.19.13.3299 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01072001In Reply:We thank Drs Sezer, Jakob, and Niemöller for their comments. We agree that circulating VEGF level may not reflect tumor microvessel density. However, there is quite compelling evidence that circulating VEGF level is of prognostic significance in cancer patients. In our review article, we included 32 studies published up to July 2000 that demonstrated a positive correlation between circulating VEGF level and tumor stage or prognosis.1 At least six additional studies published subsequent to our review have demonstrated the prognostic value of circulating VEGF level in cancer patients.2-7 Sezer et al have also reported that serum VEGF level increased with more advanced stage of multiple myeloma, and that tumor response to chemotherapy was associated with a decrease in the serum VEGF level.8 The most important biologic effect of VEGF known so far is its angiogenic effect, and it has been demonstrated to contribute to tumor angiogenesis in almost every type of cancer. Hence we conclude that “circulating VEGF seems to be a reliable surrogate marker of angiogenic activity and tumor progression in cancer patients.” We have indicated in the text that the source and biologic significance of circulating VEGF remains uncertain, and it is not yet clear whether the circulating VEGF is derived mainly from tumor secretion of VEGF. We have been cautious in not being assertive in our conclusion.We use the term angiogenic activity in a broader sense than do Sezer et al. Tumor microvessel density has been demonstrated to be of prognostic value in many cancers and thus has been widely used as an index of tumor angiogenesis. It is one but not the only one indicator of tumor angiogenic activity. The widespread clinical use of microvessel density has so far been hindered by the difficulty in obtaining objective measurement, which may partly explain why some studies failed to demonstrate its prognostic significance. For example, as opposed to the finding of Sezer et al, a recent study demonstrated no prognostic influence of bone marrow microvessel density in multiple myeloma patients.9 Tumor expression of angiogenic factors is another measure of angiogenic activity. In fact, some studies have demonstrated that tumor expression of VEGF was not correlated with tumor microvessel density, and the former but not the latter was prognostic of outcome in cancer patients.10,11 The main issue regarding circulating VEGF is not whether it is correlated with tumor microvessel density but whether it reflects tumor expression of VEGF. Thus far the evidence for this is limited and controversial. Some studies demonstrated a correlation between serum VEGF and tumor expression of VEGF,12,13 whereas other did not show a significant correlation.14,15 However, these studies used immunohistochemical staining for evaluating tumor expression of VEGF, which is a semiquantitative method. It is important to have a direct quantitative correlation between circulating VEGF and tumor expression of VEGF. We are currently conducting a study of quantitative evaluation of tumor expression of VEGF mRNA by quantitative polymerase chain reaction and serum VEGF level by enzyme-linked immunosorbent assay in hepatocellular carcinoma patients, and we hope that such a study will provide a better clue to the relationship between tumor VEGF expression and circulating VEGF.The relationship between circulating VEGF level and tumor angiogenesis may be more complicated than a simple linear correlation. As pointed out in our article, tumor angiogenesis is the overall result of balanced activity of several angiogenic and antiangiogenic factors, and thus it may be necessary to evaluate multiple factors in the circulation to provide a true reflection of tumor angiogenic activity. Of course, it is possible that circulating VEGF may have other unknown biologic significance that explains its prognostic value. Rather than providing a definite conclusion, our review article summarized the current findings related to circulating angiogenic factors in cancer patients with the aim of providing insights into future directions of research in this area.1. Poon RT, Fan ST, Wong J: Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:: 1195,2001-1206, Link, Google Scholar2. Chin KF, Greenman J, Gardiner E, et al: Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer. Br J Cancer 83:: 1425,2000-1431, Crossref, Medline, Google Scholar3. Werther K, Christensen IJ, Brunner N, et al: Soluble vascular endothelial growth factor levels in patients with primary colorectal carcinoma: The Danish RANX05 Colorectal Cancer Study Group. Eur J Surg Oncol 26:: 657,2000-662, Crossref, Medline, Google Scholar4. Salven P, Orpana A, Teerenhovi L, et al: Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: A single-institution study of 200 patients. Blood 96:: 3712,2000-3718, Crossref, Medline, Google Scholar5. Tabone MD, Landman-Parker J, et al: Are basic fibroblast growth factor and vascular endothelial growth factor prognostic indicators in pediatric patients with malignant solid tumors? Clin Cancer Res 7:: 538,2001-543, Medline, Google Scholar6. Broll R, Erdmann H, Duchrow M, et al: Vascular endothelial growth factor (VEGF): A valuable serum tumour marker in patients with colorectal cancer? Eur J Surg Oncol 27:: 37,2001-42, Crossref, Medline, Google Scholar7. 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