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© 2001 American Society for Clinical Oncology
Angiogenesis in CancerUniversitätsklinikum Charité, Berlin, Germany To the Editor:Two stimulating reviews1,2 on angiogenesis in cancer were published in the February 15, 2001, issue of the Journal of Clinical Oncology, which we read with great interest. Miller et al1 pointed out that microvessel density returned to normal after remission in acute myeloid leukemia and myeloma. In multiple myeloma we reported for the first time that a significant decrease in the microvessel density occurred in patients who achieved a complete or partial remission after chemotherapy in comparison to their pretreatment values (P < .01).3,4 On the contrary, in patients who did not achieve a remission, no significant change in the bone marrow microvessel density could be detected. In the article cited by Miller et al, a significant difference in bone marrow angiogenesis was found in patients with active versus nonactive myeloma, but this was a comparison of two different patient groups.5 Poon et al2 concluded in the abstract of their review that circulating vascular endothelial growth factor (VEGF) levels were a "reliable surrogate marker of angiogenic activity" in cancer patients, but this conclusion seems premature before a correlation between tumor angiogenesis and circulating VEGF levels has been shown for a variety of malignant tumors. Although the number of publications on tumor angiogenesis or circulating VEGF levels is comparatively high, studies showing a correlation between circulating VEGF levels and tumor angiogenesis are extremely rare. Furthermore, in some of these studies a significant difference in dichotomized groups was shown but not a correlation on an individual level. The clinical value of microvessel density has been established, for example, in breast cancer.6,7 VEGF is known to be released by several types of blood cells. Circulating VEGF was shown not to be correlated with microvessel density or VEGF expression in breast cancer in recent studies.8,9 In another report, tumor vascularity was correlated directly with VEGF production by the tumor, but once again no correlation was found either between the number of vessels in the tumor or the production of VEGF by tumor cells and the level of serum VEGF.10 In the study11 that was cited by Poon et al as having shown a positive correlation between serum VEGF levels and tumor VEGF expression in breast cancer, only 19% of patients with VEGF expression in the tumor tissue had elevated VEGF serum levels, so that the sensitivity of the serum VEGF in this study seems to be too low for calling it a reliable marker. To give another example among malignant diseases, in multiple myeloma we were unable to find a correlation between serum VEGF levels12 and bone marrow microvessel density, which has been shown to be a prognostic factor for survival.13 Thus prognostic significance of circulating VEGF in cancer patients as reviewed by Poon et al does not necessarily mean that "circulating VEGF level is a good reflection of tumor angiogenic activity." This issue may be important in the context of future antiangiogenic treatment strategies that should be aimed against tumor angiogenesis rather than circulating VEGF levels. REFERENCES
1.
Miller KD, Sweeney CJ, Sledge GW: Redefining the Target: Chemotherapeutics as antiangiogenics. J Clin Oncol 19: 1195-1206, 2001
2.
Poon RT, Fan ST, Wong J: Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19: 1207-1225, 2001 3. Sezer O, Niemöller K, Schweigert M, et al: Bone marrow microvessel density is a prognostic factor for survival in multiple myeloma and a significant decrease in microvessel density occurs in patients who achieve a remission after chemotherapy. Blood 96: 363a, 2000 (abstr, suppl) 4. Sezer O, Niemöller K, Kaufmann O, et al: Decrease of bone marrow angiogenesis in myeloma patients achieving a remission after chemotherapy. Eur J Haematol 66: 238-244, 2001[Medline]
5.
Vacca A, Ribatti D, Presta M, et al: Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93: 3064-3073, 1999 6. Weidner N, Semple JP, Welch WR, et al: Tumor angiogenesis and metastasis: Correlation in invasive breast carcinoma. N Engl J Med 324: 1-8, 1991[Abstract]
7.
Gasparini G, Harris AL: Clinical importance of the determination of tumor angiogenesis in breast carcinoma: Much more than a new prognostic tool. J Clin Oncol 13: 765-782, 1995
8.
Adams J, Carder PJ, Downey S, et al: Vascular endothelial growth factor (VEGF) in breast cancer: Comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res 60: 2898-2905, 2000 9. Byrne GJ, Bundred NJ: Surrogate markers of tumoral angiogenesis. Int J Biol Markers 15: 334-339, 2000[Medline] 10. Balsari A, Maier JA, Colnaghi MI, et al: Correlation between tumor vascularity, vascular endothelial growth factor production by tumor cells, serum vascular endothelial growth factor levels, and serum angiogenic activity in patients with breast carcinoma. Lab Invest 79: 897-902, 1999[Medline] 11. Yamamoto Y, Toi M, Kondo S, et al: Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients. Clin Cancer Res 2: 821-826, 1996[Abstract] 12. Sezer O, Jakob C, Eucker J, et al: Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur J Haematol 66: 83-88, 2001[Medline] 13. Sezer O, Niemöller K, Eucker J, et al: Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma. Ann Hematol 79: 574-577, 2000[Medline]
ResponseUniversity of Hong Kong Medical Center, Hong Kong, China In 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. REFERENCES 1. Poon RT, Fan ST, Wong J: Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19: 1195-1206, 2001 2. 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: 1425-1431, 2000[Medline] 3. 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: 657-662, 2000[Medline]
4.
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: 3712-3718, 2000
5.
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: 538-543, 2001 6. 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: 37-42, 2001[Medline]
7.
Ugurel S, Rappl G, Tilgen W, et al: Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival. J Clin Oncol 19: 577-583, 2001 8. Sezer O, Jakob C, Eucker J, et al: Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur J Haematol 66: 83-88, 2001 9. Ahn MJ, Park CK, Choi JH, et al: Clinical significance of microvessel density in multiple myeloma patients. J Korean Med Sci 16: 45-50, 2001[Medline] 10. Shen GH, Ghazizadeh M, Kawanami O, et al: Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma. Br J Cancer 83: 196-203, 2000[Medline] 11. Konno H, Baba M, Tanaka T, et al: Overexpression of vascular endothelial growth factor is responsible for the hematogenous recurrence of early-stage gastric carcinoma. Eur Surg Res 32: 177-181, 2000[Medline] 12. Li XM, Tang ZY, Qin LX, et al: Serum vascular endothelial growth factor is a predictor of metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 18: 511-517, 1999[Medline] 13. Cascinu S, Del Ferro E, Ligi M, et al: Inhibition of vascular endothelial growth factor by octreotide in colorectal cancer patients. Cancer Invest 19: 8-12, 2001[Medline] 14. Balsari A, Maier JA, Colnaghi MI, et al: Correlation between tumor vascularity, vascular endothelial growth factor production by tumor cells, serum vascular endothelial growth factor levels, and serum angiogenic activity in patients with breast carcinoma. Lab Invest 79: 897-902, 1999 15. Adams J, Carder PJ, Downey S, et al: Vascular endothelial growth factor (VEGF) in breast cancer: Comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res 60: 2898-2905, 2000 This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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