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Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases.

Publication ,  Journal Article
Jeong, H-S; Jones, D; Liao, S; Wattson, DA; Cui, CH; Duda, DG; Willett, CG; Jain, RK; Padera, TP
Published in: J Natl Cancer Inst
September 2015

BACKGROUND: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported. METHODS: Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9-12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided. RESULTS: Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm(2), 95% CI = 149 to 365 vessels/mm(2); bevacizumab group mean = 327 vessels/mm(2), 95% CI = 140 to 514 vessels/mm(2), P = .78). CONCLUSION: 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.

Duke Scholars

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Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

September 2015

Volume

107

Issue

9

Location

United States

Related Subject Headings

  • Sunitinib
  • Pyrroles
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Mice
  • Lymphatic Metastasis
  • Lymph Nodes
  • Indoles
  • Humans
  • Head and Neck Neoplasms
 

Citation

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MLA
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Jeong, H.-S., Jones, D., Liao, S., Wattson, D. A., Cui, C. H., Duda, D. G., … Padera, T. P. (2015). Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases. J Natl Cancer Inst, 107(9). https://doi.org/10.1093/jnci/djv155
Jeong, Han-Sin, Dennis Jones, Shan Liao, Daniel A. Wattson, Cheryl H. Cui, Dan G. Duda, Christopher G. Willett, Rakesh K. Jain, and Timothy P. Padera. “Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases.J Natl Cancer Inst 107, no. 9 (September 2015). https://doi.org/10.1093/jnci/djv155.
Jeong H-S, Jones D, Liao S, Wattson DA, Cui CH, Duda DG, et al. Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases. J Natl Cancer Inst. 2015 Sep;107(9).
Jeong, Han-Sin, et al. “Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases.J Natl Cancer Inst, vol. 107, no. 9, Sept. 2015. Pubmed, doi:10.1093/jnci/djv155.
Jeong H-S, Jones D, Liao S, Wattson DA, Cui CH, Duda DG, Willett CG, Jain RK, Padera TP. Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases. J Natl Cancer Inst. 2015 Sep;107(9).
Journal cover image

Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

September 2015

Volume

107

Issue

9

Location

United States

Related Subject Headings

  • Sunitinib
  • Pyrroles
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Mice
  • Lymphatic Metastasis
  • Lymph Nodes
  • Indoles
  • Humans
  • Head and Neck Neoplasms