Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells

Abstract

Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on neuronal and certain non-neuronal tumors. In pancreatic cancer NGF is overexpressed, and this overexpression is associated with increased perineural invasion. NGF has the potential to stimulate the growth of some pancreatic cancer cell lines, and this effect is mediated by the phosphorylation of tyrosine kinase receptor A and mitogen-activated protein kinase activation; it is dependent on the expression levels of tyrosine kinase receptor A and p75 receptors. To determine whether cancer cell-derived NGF can participate in the regulation of pancreatic cancer cell proliferation, PANC-1 human pancreatic cancer cells were stably transfected with a full-length human beta-NGF expression vector. In vitro and in vivo growth characteristics were analyzed by proliferation assays and invasion assays and in a nude mouse tumor model. Stable transfection of NGF in PANC-1 cells resulted in enhanced anchorage-dependent growth, with a decrease in doubling times of up to 50%, and in an approximately twofold increase in anchorage-independent cell growth and cell invasion. Furthermore, stably transfected PANC-1 cells showed enhanced tumorigenicity in nude mice. These results suggest that NGF has the capacity to act in a paracrine and/or an autocrine manner in pancreatic cancer and that it enhances cancer cell growth and invasion in vivo, thereby contributing to the aggressiveness and poor prognosis of this disease.

Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma

“…However, among 41 patients of their study, nearly half of them had adenocarcinoma, thus number of OESCC patients is much lower than our study, which might lead to insufficient evaluation. On the contrary, as our results, most of previous reports regarding other cancers have shown the positive relationship between malignant potential of tumours and expression of NGF or its receptors (Geldof et al, 1998;Schneider et al, 2001;Zhu et al, 2001Zhu et al, , 2002Sakamoto et al, 2001a, b;Kishibe et al, 2002;Davidson et al, 2003;Dolle et al, 2003).…”

“…These are compatible with our clinical findings from more than 100 cases of immunohistochemistry that overexpression of NGF is associated with lymph node metastasis and associated with poorer clinical outcome. To our knowledge, this is the first time to demonstrate NGF autocrine secretion in gastrointestinal cancer, although several previous studies have shown NGF autocrine secretion in other types of cancer (Weeraratna et al, 2000;Zhu et al, 2001Zhu et al, , 2002Dolle et al, 2003), as well as in noncancerous tissues (Torcia et al, 1996;Pincelli and Marconi, 2000).…”

“…A major biological function of NGF is the maintenance and survival of postmitotic neurons, suggesting it may be useful for the treatment of neurodegenerative diseases. In addition to its role in the development and maintenance of neuronal cells, recent studies have shown that NGF and its receptors are found and sometimes even overexpressed outside the nervous system, where it may promote cancer cell proliferation, growth, and invasion in several types of cancer such as breast, pancreas, and prostate cancer (Pflug et al, 1995;Walch and Marchetti, 1999;Sakamoto et al, 2001a, b;Schneider et al, 2001;Zhu et al, 2001Zhu et al, , 2002Kishibe et al, 2002;Davidson et al, 2003;Dolle et al, 2003).…”

Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer

“…23 NGF exerts both stimulatory and inhibitory effects on PanCa cells, depending on the NGF expression level and ratio of TrkA to p75. 24,25 Overexpression of NGF may contribute to PNI of PanCa cells by inducing hyperplasia of nerves, which reduces apoptosis of PanCa cells due to the combined signaling effects of NGF and TrkA in PanCa. 26 The most common morphological abnormality in patients with diabetic polyneuropathy is axon loss, segmental demyelination and remyelination.…”

Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression

“…The binding of NGF to TrkA induces phosphorylation of an intracellular tyrosine kinase and activation of signaling pathways that, in turn, induce numerous biologic effects (Hempstead et al, 1991;Bothwell, 1995;Barrett, 2000). NGF and its receptors are expressed in neural tumors like neuroblastoma (Nakagawara et al, 1992;Suzuki et al, 1993) and glioma (Eberhart et al, 2001) and also in nonneural tumors like prostate (George et al, 1998), breast (Descamps et al, 2001), lung (Ricci et al, 2004), and pancreatic cancers (Zhu et al, 2002), suggesting that the NGF-TrkA signaling system is frequently involved in cell migration, growth, and survival during cancer progression. Although reports are not consistent, immunohistochemical studies have revealed that TrkA expression is observed mainly in the cytoplasm of pancreatic cancer cells, whereas intense NGF and p75 NGFR expression is observed in the peripheral nerve (Miknyoczki et al, 1999;Zhu et al, 1999;Sakamoto et al, 2001).…”