Rolle des Nerve Growth Factor (NGF) im Modell der pulmonalen Metastasierung

Metastasis of tumor cells to distant organs remains the major cause of mortality in cancer patients. Generally, lungs are often affected by metastasis since they comprise one of the densest capillary beds in the body and they are one of the first organs reached by systemic venous as well as lymphatic drainage. The pathological mechanisms underlying pulmonary metastasis are still barely understood. In view of new findings, one possible mediator of metastasis and tumor growth is the neurotrophin nerve growth factor (NGF). NGF was first identified as an essential factor for the development and maintenance of the nervous system. Recent studies show that NGF also regulates a variety of biological functions in several organs and cell types. In lung tumors the influence of NGF is controversially discussed. On the one hand, NGF promotes tumor cell proliferation in an autocrine manner and on the other hand, NGF inhibits proliferation of small cell lung carcinoma cells (SCLC) in vitro and abrogates their tumorigenic properties in vivo. Previously, our group has shown that NGF is an autocrine growth factor for airway epithelial cells and leads to the augmentation of airway inflammation in a mouse model of experimental asthma. Since increased proliferation of tumor cells and a pro-tumorigenic microenvironment are characteristics of metastatic foci, the proliferative and immune-stimulating features of NGF led to the hypothesis that NGF also contributes to pulmonary metastasis. In a mouse model, quantification of lung surface metastases and pulmonary metastases volume in wild type mice (WT) and transgenic mice over-expressing NGF in the airway epithelium (NGF-Tg) showed a significant reduction of these parameters in NGF-Tg mice. However, this outcome was only accompanied by a minor local inflammation. Eventhough no direct effect of NGF on tumor cell functionality was detectable, NGF over-expression affected pulmonary blood vessel function. The ex vivo measurement of vascular permeability in the lungs revealed the protection of NGF-Tg animals from perfusion damage and edema formation. In accordance with this, extravasation of tumor cells to the lung parenchyma was reduced in NGF-Tg mice. Altogether, these data demonstrate for the first time that local NGF over-expression alters pulmonary blood vessel function leading to reduced vascular permeability and retention of cancer cells in the vasculature resulting in decreased pulmonary metastasis.