Inhibition of VEGF-C modulates distal lymphatic remodeling and secondary metastasis

PLoS One. 2013 Jul 16;8(7):e68755. doi: 10.1371/journal.pone.0068755. Print 2013.

Abstract

Tumor-associated lymphatics are postulated to provide a transit route for disseminating metastatic cells. This notion is supported by preclinical findings that inhibition of pro-lymphangiogenic signaling during tumor development reduces cell spread to sentinel lymph nodes (SLNs). However, it is unclear how lymphatics downstream of SLNs contribute to metastatic spread into distal organs, or if modulating distal lymph transport impacts disease progression. Utilizing murine models of metastasis, longitudinal in vivo imaging of lymph transport, and function blocking antibodies against two VEGF family members, we provide evidence that distal lymphatics undergo disease course-dependent up-regulation of lymph transport coincidental with structural remodeling. Inhibition of VEGF-C activity with antibodies against VEGF-C or NRP2 prevented these disease-associated changes. Furthermore, utilizing a novel model of adjuvant treatment, we demonstrate that antagonism of VEGF-C or NRP2 decreases post SLN metastasis. These data support a potential therapeutic strategy for inhibiting distant metastatic dissemination via targeting tumor-associated lymphatic remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use
  • Female
  • Lymph / physiology
  • Lymph Nodes / drug effects
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology*
  • Lymphatic Metastasis / pathology*
  • Lymphatic Metastasis / physiopathology
  • Lymphatic Metastasis / prevention & control
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Signal Transduction / drug effects
  • Vascular Endothelial Growth Factor C / antagonists & inhibitors
  • Vascular Endothelial Growth Factor C / metabolism*

Substances

  • Antibodies
  • Vascular Endothelial Growth Factor C

Grant support

All research funded by Genentech. Funders had no role in study design, data collection, analysis or preparation of manuscript. There are no current external funding sources for this study.