Estradiol and nicotine exposure enhances A549 bronchioloalveolar carcinoma xenograft growth in mice through the stimulation of angiogenesis

Int J Oncol. 2006 Feb;28(2):337-44.


Angiogenesis is required for lung cancer growth, which is mediated by various growth factors such as vascular endothelial growth factor (VEGF). Increases in VEGF and angiogenesis have been correlated with poor prognosis and survival in patients with lung cancer. In addition, recent reports show that estradiol and nicotine play important roles in lung tumor initiation and progression. In this report, we demonstrate that estradiol and nicotine exposure enhances the growth of A549 bronchioloalveolar carcinoma xenografts in mice through the stimulation of cell proliferation, VEGF secretion and angiogenesis. We detect a four-fold increase in microvascular density in tumors from mice exposed to estradiol and nicotine compared to control tumors resulting in an increase in tumor growth. Intriguingly, the effects on angiogenesis and tumor growth by the combination of agents were additive when compared to either agent alone. Furthermore, estradiol promotes VEGF secretion from various non-small cell lung carcinoma (NSCLC) cells and this effect is augmented by nicotine in a tumor xenograft model. These results indicate that aside from their roles in promoting cell proliferation, estradiol and nicotine appear to have additive effects on the induction of angiogenesis through the stimulation of VEGF secretion during NSCLC progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma, Bronchiolo-Alveolar / blood supply
  • Adenocarcinoma, Bronchiolo-Alveolar / metabolism*
  • Adenocarcinoma, Bronchiolo-Alveolar / pathology
  • Animals
  • Carcinoma, Non-Small-Cell Lung / blood supply
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Estradiol / administration & dosage
  • Estradiol / pharmacology*
  • Female
  • Humans
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / etiology*
  • Nicotine / administration & dosage
  • Nicotine / pharmacology*
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A / metabolism


  • Vascular Endothelial Growth Factor A
  • Estradiol
  • Nicotine