Neurotrophins and Their Receptors Stimulate Melanoma Cell Proliferation and Migration

Truzzi, Francesca; Marconi, Alessandra; Lotti, Roberta; Dallaglio, Katiuscia; French, Lars E.; Hempstead, Barbara L.; Pincelli, Carlo

doi:10.1038/jid.2008.21

Cited by 150 publications

(143 citation statements)

References 31 publications

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“…In melanoma cells, it has previously been shown that the addition of proNGF can lead to a stimulation of cell invasion through activation of p75 NTR and sortilin (28); in this model, TrkA was not found to be necessary. However, the activation of TrkA by proNGF has also been reported in other models (8), with the biological activity of proNGF dependent upon relative levels of TrkA versus p75 NTR (29).…”

Section: Discussionmentioning

confidence: 63%

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Demont

Corbet

Page

et al. 2012

Journal of Biological Chemistry

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The precursor of nerve growth factor (proNGF) has been described as a biologically active polypeptide able to induce apoptosis in neuronal cells, via the neurotrophin receptor p75 NTR and the sortilin receptor. Herein, it is shown that proNGF is produced and secreted by breast cancer cells, stimulating their invasion. Using Western blotting and mass spectrometry, proNGF was detected in a panel of breast cancer cells as well as in their conditioned media. Immunohistochemical analysis indicated an overproduction of proNGF in breast tumors, when compared with benign and normal breast biopsies, and a relationship to lymph node invasion in ductal carcinomas. Interestingly, siRNA against proNGF induced a decrease of breast cancer cell invasion that was restored by the addition of noncleavable proNGF. The activation of TrkA, Akt, and Src, but not the MAP kinases, was observed. In addition, the proNGF invasive effect was inhibited by the Trk pharmacological inhibitor K252a, a kinase-dead TrkA, and siRNA against TrkA sortilin, neurotensin, whereas siRNA against p75 NTR and the MAP kinase inhibitor PD98059 had no impact. These data reveal the existence of an autocrine loop stimulated by proNGF and mediated by TrkA and sortilin, with the activation of Akt and Src, for the stimulation of breast cancer cell invasion. Nerve growth factor (NGF),5 the prototypical member of the neurotrophin family of polypeptides, is essential for the survival and differentiation of central and peripheral neurons, and its role in the development and regeneration of the sympathetic and sensory nervous systems has been extensively described (1). NGF binds to the tropomyosin-related kinase A (TrkA) receptor, a tyrosine kinase receptor, and to the p75 neurotrophin receptor (p75 NTR ), a member of the tumor necrosis factor receptor family, to induce its neurotrophic effects. NGF is synthesized as a 25-kDa precursor protein, named proNGF, that yields the mature NGF polypeptide of 13.5 kDa and an inactive prosegment of 11.5 kDa, released from the N terminus intracellularly by furin, or extracellularly by plasmin as well as by several matrix metalloproteases (2). Importantly, proNGF can be secreted without being processed to mature NGF and can have its own biological effects (3). As more than just a source for NGF, proNGF was shown to induce neuronal death by apoptosis where mature NGF induced survival and differentiation (4, 5). For inducing its proapoptotic effect on neurons, proNGF forms a trimeric complex with two plasma membrane receptors: p75 NTR and sortilin (4). Sortilin, a 95-kDa type I receptor,

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Section: Discussionmentioning

confidence: 63%

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Demont

Corbet

Page

et al. 2012

Journal of Biological Chemistry

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“…p75NGFR is a member of the TNFR superfamily and has been shown to be a conditional tumor-suppressor gene (19). In breast cancer and melanoma, p75NGFR acts as an oncogene, increasing cell proliferation, survival, and migration (6,(20)(21)(22). In contrast, in prostate cancer and neuroblastoma, p75NGFR acts as a tumor-suppressor gene, inducing apoptosis and inhibiting cell proliferation and invasion (23)(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…The expression of p75NGFR has been observed in several human cancers, such as thyroid carcinoma, stomach cancer, and liver cancer (5)(6)(7)(8)(9)(10). p75NGFR has different functions based on the tumor type in which it is found.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Inactivation and Tumor-Suppressor Behavior of NGFR in Human Colorectal Cancer

Yang

Chen

Huo

et al. 2015

Molecular Cancer Research

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The nerve growth factor receptor (NGFR/p75) is a potential tumor suppressor, but its role in colorectal cancer is unknown. Here, the hypermethylation status, biologic function, and clinical relevance were determined for p75NGFR in colorectal cancer. The methylation status and expression of p75NGFR were assessed in colorectal cancer cell lines and clinical tissues by bisulfite genomic sequencing (BGS), qRT-PCR, and immunoblot assay. Methylation of p75NGFR was frequently found in colorectal cancer, leading to its silencing or downregulation, and it was effectively restored by a demethylation agent. The overexpression of p75NGFR in multiple colorectal cancer cell model systems significantly inhibited cell proliferation (concomitant with G 1 -phase arrest), invasion, and colony formation and induced cell apoptosis. In contrast, p75NGFR knockdown significantly promoted proliferative and invasive phenotypes. Importantly, p75NGFR methylation was observed in the majority of primary colorectal cancer specimens and was associated with histologic grade and preoperative serum CA19-9 levels. Multivariate analysis indicated that patients who lack p75NGFR have reduced overall survival (64% vs. 75%, P ¼ 0.028) and disease-free survival (61% vs. 72%, P ¼ 0.034) compared with p75NGFR-positive patients. In conclusion, p75NGFR is predominantly silenced or downregulated in colorectal cancer, and its biologic activities are consistent with it being a relevant tumor suppressor.Implications: p75NGFR is a candidate tumor suppressor and has independent prognostic potential in colorectal cancer.

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“…As melanoma could originate from melanocytes and melanocytes seem to benefit from the cutaneous neurotrophic network mainly as paracrine targets, once malignant transformation occurs, melanoma cells acquire self-renewal capabilities mediated also by autocrine NTs loops. Indeed, all NTs, particularly NT-3 and NT-4, have been detected in conditioned medium of different melanoma cell lines (Truzzi et al, 2008). Recent results show that melanoma cells proliferate through autocrine NTs stimulation.…”

Section: Nts and Melanomamentioning

confidence: 99%

Melanoma and the Nervous System – Novel Pathways Mediated by Neurotrophins and Their Receptors

Pincelli¹,

Dallaglio²,

Truzzi³

2011

Breakthroughs in Melanoma Research

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Neurotrophins and Their Receptors Stimulate Melanoma Cell Proliferation and Migration

Cited by 150 publications

References 31 publications

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Epigenetic Inactivation and Tumor-Suppressor Behavior of NGFR in Human Colorectal Cancer

Melanoma and the Nervous System – Novel Pathways Mediated by Neurotrophins and Their Receptors

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