Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo

Bassili, Muriel; Birman, Elena; Schor, Nina F.; Saragovi, H. Uri

doi:10.1007/s00280-009-1110-x

Cited by 35 publications

(24 citation statements)

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“…In our study, high NGF expression was associated with high histologic grade and the presence of distant metastasis, and predicted poorer survival of BRCA patients. The poor prognosis of the patients with NGF-expressing tumor might be related with the ability of NGF-TrkA signaling to induce chemoresistance [31]. Therefore, there is a possibility that NGF-targeted therapy with a combination of conventional chemotherapy could be helpful for BRCA patients.…”

Section: Discussionmentioning

confidence: 99%

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

et al. 2013

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BackgroundNerve growth factor (NGF) is a neurotrophin and has been suggested to induce heme oxygenase-1 (HO1) expression. Although the role of HO1 in tumorigenesis remains controversial, recent evidence suggests NGF and HO1 as tumor-progressing factors. However, the correlative role of NGF and HO1 and their prognostic impact in breast carcinoma is unknown.MethodsWe investigated the expression and prognostic significance of the expression of NGF and HO1 in 145 cases of breast carcinoma.ResultsImmunohistochemical expression of NGF and HO1 was observed in 31% and 49% of breast carcinoma, respectively. The expression of NGF and HO1 significantly associated with each other, and both have a significant association with histologic grade, HER2 expression, and latent distant metastasis. The expression of NGF and HO1 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis. NGF expression was an independent prognostic indicator for relapse-free survival by multivariate analysis. The combined expression pattern of NGF and HO1 was also an independent prognostic indicator of overall survival and relapse-free survival. The patients with tumors expressing NGF had the shortest survival and the patients with tumor, which did not express NGF or HO1 showed the longest survival time.ConclusionsThis study has demonstrated that individual expression of NGF or HO1, and the combined NGF/HO1 expression pattern could be prognostic indicators for breast carcinoma patients.

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Section: Discussionmentioning

confidence: 99%

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

et al. 2013

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“…Indeed, it has been shown that NGF stimulation of undifferentiated embryonic stem cell proliferation is linked to a combined activation of TrkA and p75 NTR , [42] whereas a higher colony-forming potential of phechromocytoma cells has been measured under expression of TrkA or p75 alone. [43] Because the amino terminus is a critical domain for TrkA receptor binding, metal interaction with NGF probably affects the bioactive conformation suitable for receptor activation, as well as discrimination between TrkA and p75, causing, at least in part, the differential effects observed herein. Focusing on the interaction of the metal ion with this region of NGF, which could play a crucial role in receptor discrimination and signalling modulation, becomes of crucial importance; this aspect should also be considered as a function of the ability of NGF to bind to different receptors (even at the same time).…”

Section: A C H T U N G T R E N N U N G [Cul]mentioning

confidence: 94%

The Inorganic Perspective of Nerve Growth Factor: Interactions of Cu²⁺ and Zn²⁺ with the N‐Terminus Fragment of Nerve Growth Factor Encompassing the Recognition Domain of the TrkA Receptor

Travaglia

Arena

Fattorusso³

et al. 2011

Chemistry A European J

101

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There is a significant overlap between brain areas with Zn(2+) and Cu(2+) pathological dys-homeostasis and those in which the nerve growth factor (NGF) performs its biological role. The protein NGF is necessary for the development and maintenance of the sympathetic and sensory nervous systems. Its flexible N-terminal region has been shown to be a critical domain for TrkA receptor binding and activation. Computational analyses show that Zn(2+) and Cu(2+) form pentacoordinate complexes involving both the His4 and His8 residues of the N-terminal domain of one monomeric unit and the His84 and Asp105 residues of the other monomeric unit of the NGF active dimer. To date, neither experimental data on the coordination features have been reported, nor has one of the hypotheses according to which Zn(2+) and Cu(2+) may have different binding environments or the Ser1 α-amino group could be involved in coordination been supported. The peptide fragment, encompassing the 1-14 sequence of the human NGF amino-terminal domain (NGF(1-14)), blocked at the C terminus, was synthesised and its Cu(2+) and Zn(2+) complexes characterized by means of potentiometric and spectroscopic (UV/Vis, CD, NMR, and EPR) techniques. The N-terminus-acetylated form of NGF(1-14) was also investigated to evaluate the involvement of the Ser1 α-amino group in metal-ion coordination. Our results demonstrate that the amino group is the first anchoring site for Cu(2+) and is involved in Zn(2+) coordination at physiological pH. Finally, a synergic proliferative activity of both NGF(1-14) and the whole protein on SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu(2+). This effect was not observed after treatment with the N-acetylated peptide fragment, demonstrating a functional involvement of the N-terminal amino group in metal binding and peptide activity.

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“…Elevated levels of NGF in pancreatic cancer cells and high levels of its receptors, TRKA and p75 NTR in the surrounding nerves, have been correlated to poor prognosis and PNI in pancreatic cancer patients [17,18,19,20]. Absence of TRKA in nerve cells results in NGF binding to p75 NTR and leads to activation of pro-apoptotic signals [16,21].…”

Section: Introductionmentioning

confidence: 99%

Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells

et al. 2016

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Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, pancreatic cancer cells migrate towards dorsal root ganglia (DRG) in a co-culture assay, indicating a paracrine NGF signaling between the DRGs and pancreatic cancer cells. Knocking down the expression of NGF pathway proteins or inhibiting the activity of TRKA by GW441756 reduced the migratory ability of Mia PaCa2 towards the DRGs. Finally, blocking NGF signaling by NGF neutralizing antibodies or GW441756 inhibited the neurite formation in PC-12 cells in response to conditioned media from pancreatic cancer cells, indicating a reciprocal signaling pathway between the pancreatic cancer cells and nerves. Our results indicate that NGF signaling pathway provides a potential target for developing molecularly targeted therapies to decrease PNI and reduce pain generation. Since there are several TRKA antagonists currently in early clinical trials they could now be tested in the clinical situation of pancreatic cancer induced pain.

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Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo

Cited by 35 publications

References 35 publications

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

The Inorganic Perspective of Nerve Growth Factor: Interactions of Cu²⁺ and Zn²⁺ with the N‐Terminus Fragment of Nerve Growth Factor Encompassing the Recognition Domain of the TrkA Receptor

Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells

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Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo

Cited by 35 publications

References 35 publications

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

The Inorganic Perspective of Nerve Growth Factor: Interactions of Cu2+ and Zn2+ with the N‐Terminus Fragment of Nerve Growth Factor Encompassing the Recognition Domain of the TrkA Receptor

Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells

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The Inorganic Perspective of Nerve Growth Factor: Interactions of Cu²⁺ and Zn²⁺ with the N‐Terminus Fragment of Nerve Growth Factor Encompassing the Recognition Domain of the TrkA Receptor