Evidence map›Paper›PMID 26063793›Full record

ArticleJournal of the National Cancer Institute2015

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

Han-Sin Jeong, Dennis Jones, Shan Liao, Daniel A Wattson, Cheryl H Cui, Dan G Duda, Christopher G Willett, Rakesh K Jain, Timothy P Padera

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of the National Cancer Institute, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05754814 (SUper-Resolution Ultrasound Imaging of Erythrocytes), which is not on this map. Cited by 85 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
85citing papers in PubMed, 1 pooled it
6.3field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT05754814 completednot on this mapstarted 2022, after this paper: background citation

SUper-Resolution Ultrasound Imaging of Erythrocytes (SURE) in Normal and Malignant Lymph Nodes

TypeobservationalSponsorRigshospitalet, DenmarkRan2022 to 2026Enrolled20ConditionsHead and Neck Cancer, Lymphoma, Lymph Node MetastasisArmsMalignant lymph nodes
3 · Its place in the literature

Who cites it

85 citing papers in PubMed, 1 synthesis or guideline pooled it, 120 citations in OpenAlex.

  1. Guideline
  2. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.Proceedings of the National Academy of Sciences of the United States of America · 2015
    Trial
  3. Article
  4. Article
  5. Quantitative parameters of dual-layer spectral CT for differentiating metastatic and non-metastatic lymph nodes in colorectal cancer.Cancer imaging : the official publication of the International Cancer Imaging Society · 2026
    Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Review
  12. Review
  13. Advances in lymphatic metastasis of non-small cell lung cancer.Cell communication and signaling : CCS · 2024
    Review
  14. Review
  15. Review
  16. Article
  17. Review
  18. Article
  19. Review
  20. Review

25 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 1 institution in 1 country.

Han-Sin JeongEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Dennis JonesEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Shan LiaoEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Daniel A WattsonEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Cheryl H CuiEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Dan G DudaEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Christopher G WillettEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Rakesh K JainEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL).
Timothy P PaderaEdwin L. Steele Laboratories, Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA (HSJ, DJ, SL, DAW, CC, DGD, RKJ, TPP); Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (HSJ); Department of Radiation Oncology, Duke University Medical Center, Durham, NC (CGW).Current affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada (SL). tpadera@steele.mgh.harvard.edu.
Samsung Medical Center · KR

Funding

Vascular Normalization: Rolse of Perivascular CellsP01CA080124 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI FUKUMURA, DAI · 2000 to 2016
$35.0M
Characterizing lymphatic micrometastases: prognostic and therapeutic implicationsDP2OD008780 · OD · MASSACHUSETTS GENERAL HOSPITAL · PI PADERA, TIMOTHY P · 2011 to 2011
$2.6M
Role of SDF1a pathway in prostate cancer relapse and metastasis post-radiotherapyR01CA159258 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI DUDA, DAN GABRIEL · 2011 to 2015
$1.6M
Lymphatic RadiobiologyR00CA137167 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI PADERA, TIMOTHY P · 2011 to 2013
$699k
The role of lymphatic contraction in inflammation and cancer metastasisK99HL111343 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI LIAO, SHAN · 2012 to 2013
$260k
INVESTIGATION OF THE VASCULAR RESPONSE IN LYMPH NODE METASTASESF32CA183465 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JONES, DENNIS · 2014 to 2016
$111k
PROTON THERAPY RESEARCH AND TREATMENT CENTERC06CA059267 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI GOITEIN, MICHAEL · 1992 to 1995
–
NCI NIH HHS C06 CA059267NCI NIH HHS F32 CA183465NCI NIH HHS F32CA183465NCI NIH HHS P01 CA080124NCI NIH HHS R00 CA137167NCI NIH HHS R00CA137167NCI NIH HHS R01 CA159258NCI NIH HHS R01-CA159258NHLBI NIH HHS K99 HL111343NHLBI NIH HHS K99HL111343-01A1NIH HHS DP2 OD008780NIH HHS DP2OD008780
6 · The paper itself

Abstract

backgroundTo 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.

methodsHere, 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.

resultsUsing 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).

conclusionWe 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.

Indexed as

Angiogenesis InhibitorsAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedBevacizumabColonic NeoplasmsHead and Neck NeoplasmsHumansIndolesLymphatic MetastasisLymph NodesMiceNeovascularization, PathologicPyrrolesSunitinibAngiogenesis InhibitorsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedBevacizumabDC101 monoclonal antibodyIndolesPyrrolesSunitinib

Identifiers

PMID26063793
PMCPMC4651102
OpenAlexW2198386817

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.