Neem leaf glycoprotein prophylaxis transduces immune dependent stop signal for tumor angiogenic switch within tumor microenvironment

PLoS One. 2014 Nov 12;9(11):e110040. doi: 10.1371/journal.pone.0110040. eCollection 2014.

Abstract

We have reported that prophylactic as well as therapeutic administration of neem leaf glycoprotein (NLGP) induces significant restriction of solid tumor growth in mice. Here, we investigate whether the effect of such pretreatment (25µg/mice; weekly, 4 times) benefits regulation of tumor angiogenesis, an obligate factor for tumor progression. We show that NLGP pretreatment results in vascular normalization in melanoma and carcinoma bearing mice along with downregulation of CD31, VEGF and VEGFR2. NLGP pretreatment facilitates profound infiltration of CD8+ T cells within tumor parenchyma, which subsequently regulates VEGF-VEGFR2 signaling in CD31+ vascular endothelial cells to prevent aberrant neovascularization. Pericyte stabilization, VEGF dependent inhibition of VEC proliferation and subsequent vascular normalization are also experienced. Studies in immune compromised mice confirmed that these vascular and intratumoral changes in angiogenic profile are dependent upon active adoptive immunity particularly those mediated by CD8+ T cells. Accumulated evidences suggest that NLGP regulated immunomodulation is active in tumor growth restriction and normalization of tumor angiogenesis as well, thereby, signifying its clinical translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azadirachta / chemistry*
  • CD8-Positive T-Lymphocytes / cytology
  • Carcinoma, Ehrlich Tumor
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Glycoproteins / chemistry*
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Neovascularization, Pathologic / prevention & control*
  • Pericytes / cytology
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Tumor Microenvironment / immunology*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Wound Healing

Substances

  • Glycoproteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2

Grants and funding

The work was partially supported by Council of Scientific and Industrial Research, New Delhi (grant no. 09/030(0050)/2008-EMR-I to S. Banerjee, grant no. 09/030(0063)/2011-EMRI to S. Barik and grant SRA, Scientists' Pool Scheme No: 8463A to A. Bose). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.