Nerve growth factor: role in growth, differentiation and controlling cancer cell development

Abstract

Recent progress in the Nerve Growth Factor (NGF) research has shown that this factor acts not only outside its classical domain of the peripheral and central nervous system, but also on non-neuronal and cancer cells. This latter observation has led to divergent hypothesis about the role of NGF, its specific distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. Moreover, other recent studies have shown that NGF has direct clinical relevance in certain human brain neuron degeneration and a number of human ocular disorders. These studies, by suggesting that NGF is involved in a plethora of physiological function in health and disease, warrant further investigation regarding the true role of NGF in carcinogenesis. Based on our long-lasting experience in the physiopathology of NGF, we aimed to review previous and recent in vivo and in vitro NGF studies on tumor cell induction, progression and arrest. Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate.

Keywords: Cell differentiation; Cell proliferation; NGF-receptors; Naïve cell; Tumor cells NGF.

Fig. 1

Photographic illustration of untreated (baseline, left panels) and treated (NGF exposure, right panels) cultured cells. As shown by phase contrast acquisition, exposure to 20 ng/ml NGF for seven consecutive days promoted differentiation and neuritis outgrowth (right panels) rather than cell proliferation of sympathetic (b), tumor PC-12 (d) and beta pancreatic (f) cell lines, as compared to untreated ones (left panels). Magnifications: x400. a-d, phase contrast; e-f, light microscopy

Fig. 2

High levels of exogenous and/or endogenous NGF in tissues without cell proliferation. Illustrations of exogenous NGF-induced trkA^NGFR expression (a-b) and endogenous NGF expression (c). a Representative brain section from a young rat treated with 1 μg purified NGF into the third brain ventricle. Note the trkA^NGFR immunreactivity in the dentate gyrus of the hippocampus (arrows). The absence of any sign of cell proliferation within and nearby the hippocampal tissues is clearly visible. b Representative cutaneous tissue section from a mouse exposed to subcutaneous administration of 10 μg purified NGF. An increased trkA^NGFR immunoreactivity is visible (arrows) in the dermal tissue having no cell proliferation. c Representative submaxillary gland sections from a 10-week-old male-mouse probed with anti-NGF antibody (arrows). Despite the massive NGF immunoreactivity in murine salivary gland (tubular cells; see arrows), no cell proliferation nor cell neoplasy characterized the gland tissue. Magnifications: ab, x100; c, x400, light microscopy