Nerve growth factor overexpression and autocrine loop in breast cancer cells

Abstract

We show here that nerve growth factor (NGF), the canonical neurotrophic factor, is synthesized and released by breast cancer cells. High levels of NGF transcript and protein were detected in breast cancer cells by reverse transcription-PCR, Western blotting, ELISA assay and immunohistochemistry. Conversely, NGF production could not be detected in normal breast epithelial cells at either the transcriptional or protein level. Confocal analysis indicated the presence of NGF within classical secretion vesicles. Breast cancer cell-produced NGF was biologically active, as demonstrated by its ability to induce the neuronal differentiation of embryonic neural precursor cells. Importantly, the constitutive growth of breast cancer cells was strongly inhibited by either NGF-neutralizing antibodies or K-252a, a pharmacological inhibitor of NGF receptor TrkA, indicating the existence of an NGF autocrine loop. Together, our data demonstrate the physiological relevance of NGF in breast cancer and its potential interest as a marker and therapeutic target.

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).…”

“…For phosphorylated TrkA, a mouse monoclonal anti-p-TrkA antibody (sc-8058, Santa Cruz Biotechnology Inc.) (diluted 1 : 200) was used. Lysate from the breast cancer cell line MCF-7 was used as a positive control for NGF (Dolle et al, 2003), TrkA, and p75NTR (Descamps et al, 2001b).…”

“…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).…”

“…Nerve growth factor has also been found to be an autocrine survival factor for B lymphocytes (Torcia et al, 1996), and Dolle et al (2003) reported that NGF is involved in an autocrine loop in breast cancer. In oesophageal cancer, however, only one small clinical study on NGF expression has been reported (Zhu et al, 2000), which is very different from other studies in that they showed downregulation of NGF in tumours with poorer differentiation and in advanced stage.…”