Abstract 987: NGF promotes gastrointestinal cancer development through tumor-associated neurogenesis
Authors: Hayakawa Yoku , Asfaha Samuel , Renz Bernhard W. , Westphalen Christoph B. , Tailor Yagnesh , Nagar Karan , Worthley Daniel L. , Chen Duan , Wang Timothy C. 
Published: August 2015

The nervous system regulates epithelial homeostasis and tumorigenesis. However, the precise mechanism of tumor-associated neurogenesis in gut is still poorly understood. Here, we show that nerve growth factor (NGF), a member of the neurotrophin family, is markedly upregulated in the tumor microenvironment and plays a key role in tumor-associated neurogenesis and carcinogenesis. We established Rosa26-LSL-NGF-IRES-eGFP knockin mice to obtain conditional NGF overexpression in the gut, by mating to epithelial-specific Cre-expressing mice. To obtain stomach-specific Cre expression, we generated Tff2-Cre BAC transgenic mice which specifically traces the entire gastric epithelium. Tff2-Cre; Rosa26-LSL-NGF-IRES-eGFP (Tff2-NGF) mice show a marked increase in both neuronal and glial cells, especially in the distal stomach. Similarly, in Villin-Cre; Rosa26-LSL-NGF-IRES-eGFP (Villin-NGF) mice, the density of nerves and glia is increased, especially in the rectum. Strikingly, Tff2-NGF mice spontaneously develop high-grade dysplasia in the stomach after 8 months, with an increase in proliferation and stem cell markers. Villin-NGF mice also show dysplastic tumors in the rectum. When these NGF mice are treated with chemical carcinogens such as N-nitroso-N-methylurea (MNU) or azoxymethane (AOM), gastric or colon tumor formation is promoted by NGF overexpression. Enhanced gastrointestinal tumor development in NGF overexpression mice is also seen in genetic models such as H/K-ATPase-IL-1β mice and ApcMin mice. In contrast, treatment with a pan-Trk kinase inhibitor PLX7486 successfully suppresses the increased innervation in tumors and inhibits stem cell expansion and tumor progression. We have previously shown that cholinergic denervation by vagotomy inhibited gastric tumor development. Although both the cholinergic (parasympathetic) and adrenergic (sympathetic) nerve densities are expanded in the NGF mice, sympathetic nerve ablation is not effective for the prevention of gastric cancer development, suggesting that cholinergic signal is more important in gastric cancer development. In fact, Tff2-Cre; Rosa26-LSL-NGF; Chrm3flox/flox mice lacking the muscarinic receptor 3 in the gastric epithelium are no longer responsive to the tumor promoting effect of NGF overexpression, suggesting that the effect is mediated through a cholinergic pathway. Taken together, our findings highlight the novel interaction between neurogenesis and tumor development, and suggest that inhibition of NGF/Trk axis, perhaps in combination with chemical/surgical denervation, could be an effective therapy against gastrointestinal cancers.

Citation Format: Yoku Hayakawa, Samuel Asfaha, Bernhard W. Renz, Christoph B. Westphalen, Yagnesh Tailor, Karan Nagar, Daniel L. Worthley, Duan Chen, Timothy C. Wang. NGF promotes gastrointestinal cancer development through tumor-associated neurogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 987. doi:10.1158/1538-7445.AM2015-987