Pneumologie 2012; 66 - A603
DOI: 10.1055/s-0032-1315526

Nerve Growth Factor overexpression in Clara cells suppresses metastasis and tumor growth in a mouse model of experimental lung metastasis

K Seidler 1, A Sydykov 2, S Müller-Brüsselbach 3, R Müller 3, N Weißmann 2, H Renz 1, A Nockher 1
  • 1Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg
  • 2Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardiopulmonary System (ECCPS), Gießen
  • 3Institute of Molecular Biology and Tumor Research (IMT), Philipps-University of Marburg, Marburg

Background: Metastasis is a multistep process terminating in extravasation of cancer cells and growth at the secondary tumor site. The lung is often affected by metastasis since it is one of the first organs reached by systemic venous drainage. However the pathological mechanisms underlying tumor dissemination are still barely understood. One possible mediator of metastasis and tumor growth is the neurotrophin, nerve growth factor (NGF). NGF was originally identified as an essential factor for the development and maintenance of the nervous system. Recent studies show that the secretion of neurotrophins in the lung promotes tumor cell proliferation in an autocrine manner and a lack of NGF signaling leads to apoptosis of carcinoma cells. On the other hand, NGF inhibits proliferation of small cell lung carcinoma cells (SCLC) in vitro and abrogates their tumorigenic properties. Previously, our group has shown that NGF is an autocrine growth factor for airway epithelial cells and promotes epithelial regeneration.

Objective: To investigate the impact of NGF on lung metastasis and tumor growth.

Methods: In this study, a mouse model of experimental lung metastasis was used. Surface metastasis and tumor growth in wild type mice (WT) and transgenic mice overexpressing NGF in Clara cells in the airway epithelium (NGF-Tg) were examined. Tumor volume was quantified histologically by use of a computer assisted stereological toolbox system (CAST) Since tumor cells have to cross the vascular barrier to form metastases, measurement of vascular permeability in the lungs was performed in an ex vivo model of ischemia and reperfusion.

Results: In an in vivo model of experimental lung metastasis, we found tumor growth significantly reduced in NGF-Tg mice. This result was verified by the use of two cancer cell lines with different metastatic potential (Lewis lung carcinoma cells and B16/F10 melanoma cells). Interestingly, the measurement of vascular permeability in the lungs in an ex vivo model of ischemia and reperfusion revealed the protection of NGF-Tg animals from reperfusion damage and edema.

Conclusion: Our recent findings indicate that NGF overexpression alters blood vessel structure leading to reduced vascular permeability and retention of cancer cells in the vasculature.

Keywords: Nerve Growth Factor (NGF), Lewis Lung Carcinoma (LLC), metastasis