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Anti-VEGFR-3 Therapy and Lymph Node Metastasis

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

To the Editor:

We read with interest the report by Roberts et al. (1), which showed that inhibition of the vascular endothelial growth factor receptor-3 (VEGFR-3) activation can prevent the formation of lymph node metastasis. This is in agreement with published reports (2–6). The authors also claim that "the blockade of VEGFR-3 signaling also reduced lymph node metastasis when the antibody was administered after the metastases were established" (p. 2655). As enumerated below, the data presented in Roberts et al. (1) do not support this claim.

1. The data presented in Roberts et al. show that 8/10 mice treated with PBS versus 7/10 mice treated with a monoclonal antibody that inhibits VEGFR-3 signaling (mF4-31C1) develop lymph node metastasis when treatment is started 4 weeks after primary tumor implantation (Table 1, ref. 1). The authors even state that the "number of mice with lymph node metastases was comparable between the mF4-31C1–treated and control group" (p. 2652). In contrast to the authors' conclusion, no difference in lymph node metastasis was observed when the mF4-31C1 was administered after metastases were established.
   
2. Inspection of the remaining data in the intervention group shows that (a) subsequent measurements were not independent of the number of mice in each group that develop metastasis, and (b) there were no significant differences justifying the authors' claim. As an example, the authors evaluated the presence of metastases in four lymph nodes of each of the 10 animals per treatment group. The authors claim that "the number of lymph nodes with metastasis in each mouse was lower in the anti–VEGFR-3–treated group" based on the consideration of the data as 40 independent trials (Table 1), which is clearly not the case. Each of the 10 animals per group equals a single independent trial, and the samples of lymph nodes from the same animal are almost redundant: in seven mF4-31C1–treated animals with a lymph node metastasis, 86% of sampled nodes (24 out of 28) were positive. Similarly, in eight PBS-treated animals that contained a lymph node metastasis, all 100% of sampled lymph nodes were positive. On a per-animal basis, there is no statistical significance. Incidentally, when these data were considered as independent trials, the data also did not reach a significance value of P = 0.05 using both two-sided Fisher and ² tests. Thus, the statement, "the number of lymph nodes with metastasis in each mouse was lower in the anti–VEGFR-3–treated group" (p. 2652), is not correct.
   
3. A 47% decrease in the number of tumor cells in lymph nodes was reported when mF4-31C1–treated animals were compared with control. No standard errors or statistics were given for this latter data. However, similar data showed that a 64% decrease was not statistically significant [Fig. 1A; "However, anti–VEGFR-2 blocking antibody DC101 decreased overall tumor burden in the lymph nodes by 64% in the prevention regimen (control, 0.035 ± 0.0836 versus DC101, 0.0128 ± 0.019; P > 0.05), although the effect was not statistically significant" (p. 2652)]. The authors also acknowledge that the "low average number of tumor cells reflects mainly the lesser number of lymph nodes containing tumor cells in anti–VEGFR-3–treated mice" (p. 2652). Thus, this experiment also was not independent of the data describing the number of mice in each treatment group that develop metastases.
   

Collectively, this paper does not have any statistically significant data showing that mF4-31C1 treatment can reduce lymph node metastasis when given 4 weeks after primary tumor implantation. Thus, inhibiting VEGFR-3 is not effective in treating lymph node metastasis after cells have arrived in the lymph node in this tumor model. As recently shown (7), when VEGFR-3 is present on tumor cells or blood vessels, inhibiting VEGFR-3 under similar conditions may lead to tumor suppression and reduce tumor burden in lymph nodes. This, however, does not apply to the work presented in Roberts et al. (1).

References

1. Roberts N, Kloos B, Cassella M, et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 2006;66:2650–7.[Abstract/Free Full Text]
2. He Y, Kozaki K, Karpanen T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor-3 signalling. J Natl Cancer Inst 2002;94:819–25.[Abstract/Free Full Text]
3. He Y, Rajantie I, Pajusola K, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 2005;65:4739–46.[Abstract/Free Full Text]
4. Lin J, Lalani AS, Harding TC, et al. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res 2005;65:6901–9.[Abstract/Free Full Text]
5. Chen Z, Varney ML, Backora MW, et al. Down-regulation of vascular endothelial cell growth factor-C expression using small interfering RNA vectors in mammary tumors inhibits tumor lymphangiogenesis and spontaneous metastasis and enhances survival. Cancer Res 2005;65:9004–11.[Abstract/Free Full Text]
6. Hoshida T, Isaka N, Hagendoorn J, et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 2006;66:8065–75.[Abstract/Free Full Text]
7. Laakkonen P, Waltari M, Holopainen T, et al. Vascular endothelial growth factor receptor 3 (VEGFR-3) is involved in tumor angiogenesis and growth. Cancer Res 2007;67:593–9.[Abstract/Free Full Text]

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				Correction: Anti-VEGFR-3 Therapy and Lymph Node Metastasis Cancer Res., July 1, 2007; 67(13): 6528 - 6528. [Full Text] [PDF]

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