Preclinical and Clinical Evidence of Lack of Sprouting Angiogenesis in Development of Lymph Node Metastases
In preclinical and clinical studies reported in the Journal of the National Cancer Institute, Jeong et al found a lack of sprouting angiogenesis in the formation of lymph node metastases, suggesting a potential mechanism for resistance to antiangiogenic treatments in adjuvant settings. The study used a newly developed chronic lymph node window model to investigate growth and spread of lymph node metastases. The model is a modification of the mammary fat pad chamber and allows intravital imaging for up to 14 days with minimal morphologic, cellular, or biochemical changes in inguinal lymph nodes.
Preclinical Study
Use of the window model in models of spontaneous lymphatic metastases in mice showed a lack of sprouting angiogenesis during metastatic growth, despite the finding of hypoxia (which generally induces VEGF expression) in some lesions. Treatment with two antiangiogenic therapies produced no effect on growth or vascular density of lymph node metastases; day 10 mean vessel densities were 1.2% in untreated animals, 0.7% in controls, 0.4% with the antiangiogenic agent DC101, and 0.5% with sunitinib (Sutent) (P = .34 on analysis of variance).
Vessel Densities in Cancer Patients
In 20 colon cancer patients with lymphatic metastasis, blood vessel densities in metastatic lymph nodes and large metastatic lesions in which node tissue was completely replaced with tumor cells were lower than those in tumor-negative nodes, with average densities of 220 vessels/mm3 in nonmetastatic nodes, 135/mm2 in metastatic nodes, and 104/mm2 in nodes replaced by cancer (P < .001 for both comparisons vs nonmetastatic nodes). Further, vessel density within metastatic lesions was significantly lower than in the remaining lymph node tissue (148 vs 115/mm2, P = .03). Findings were similar in 20 patients with head and neck cancers.
Effect of Antiangiogenic Treatment
A study of 10 patients with rectal cancer who had received neoadjuvant chemoradiation and bevacizumab (Avastin) and 10 who received neoadjuvant chemoradiation without bevacizumab showed no difference in vessel density in lymph node metastases, with mean densities of 327 vessels/mm2 in the bevacizumab group vs 257/mm2 in the no bevacizumab group (P = .78). There was also no difference in vascular densities in tumors (318 vs 307/mm2, P = .60).
The investigators concluded: “We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases.”
Timothy P. Padera, PhD, of Massachusetts General Hospital and Harvard Medical School, is the corresponding author for the Journal of the National Cancer Institute article.
The study was supported by the National Institutes of Health, National Cancer, Department of Defense, and others. For full disclosures of the study authors, visit jnci.oxfordjournals.org
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