Role of nerve growth factor and its receptors in non-nervous cancer growth: efficacy of a tyrosine kinase inhibitor (AG879) and neutralizing antibodies antityrosine kinase receptor A and antinerve growth factor: an in-vitro and in-vivo study

Abstract

Neurotrophins, originally identified as neuronal survival and differentiation factors, exert their actions through tyrosine kinase receptors such as TrKA, in the case of the nerve growth factor. Neurotrophins also interact with p75, a common receptor devoid of kinase activity and connected to apoptosis. Here we show that nerve growth factor, TrKA and p75 are expressed in cell lines of human cancers of various non-neuronal lineages, including a panel of muscular sarcomas, and we show that all cell lines investigated actively release nerve growth factor into the medium. Treatment by AG879 (a tyrosine kinase inhibitor that inhibits TrKA phosphorylation, but not TrKB and TrKC) or by neutralizing antibodies anti-nerve growth factor and anti-TrKA dramatically decreases their proliferation with a variable increase in apoptosis. Similarly, p75 transfection induced a significant increase in apoptosis. Furthermore, for the first time we have determined by high-performance liquid chromatography the pharmacokinetic profile of a novel preparation of AG879 and we have established an optimal plasmatic concentration for in-vivo administration. Treatment with AG879 in immunodepressed mice grafted with leiomyosarcoma or promyelocytic leukemia cells resulted in dramatic reductions in tumor sizes. In conclusion, our data have a novel preclinical potential for revealing a possible therapeutical utility in targeting in-vivo nerve growth factor/TrKA by AG879 or neutralizing antibody anti-TrKA in cancer proliferation and in muscle sarcomas, in particular.

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

“…Low in vivo tumorigenic potential of p75 expressing cells correlates well with studies that show that p75 expression induces significant increase in apoptosis of muscular sarcoma [27]. Similarly, p75 expression increases apoptosis of prostate cancer cells [8], while TrkA and TrkB expression and signaling enhances cellular malignancy.…”

“…Treatment with tyrosine kinase inhibitors or by anti-NGF antibodies that block TrkA activity decreases cell proliferation [27]. Similarly, BDNF protects neuroblastoma cells from treatment with cisplatin and doxorubicin, suggesting that it alters a common signaling pathway required for cell death initiation by DNA damaging agents [22].…”

Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons

“…Our observations, together with the proposed regulation of BRCA1 by CB 1 R activity (21,26), highlight BRCA1 as a molecular "hinge" to integrate coexistent permissive signals and outline a bidirectional signaling loop that emerges as a key component of neuronal differentiation and synaptic coupling (21). Identifying a regulatory pathway involving TrkA and CB 1 R coincidently modulating BRCA1 acting as a "feedback amplifier" is broadly relevant to the orchestration of neurotrophin/endocannabinoid interplay in cancer (19,26), pain (27), or neurodegeneration (1, 7). Understanding developmental mechanisms that allow the integration of specific neuronal subtypes into large-scale neuronal networks may be rewarding to device translational restorative strategies aimed to prevent disease-related modifications of synaptic connectivity.…”

“…S4C) accumulation at atypical locations in the proximal stem of multiple neurites. Tyrphostin (AG 879), an inhibitor of TrkA signaling (19), acutely reduced neurite outgrowth (Fig. 3G) and coincidently allowed MGL to venture into the actin-rich motile neurite tip (Fig.…”

Biologically active anti-nerve growth factor antibodies in commercial intravenous gammaglobulin

“…This appears to be particularly true for malignant melanoma, breast cancer, ovarian cancer and prostate cancer [21]. Further, activation of the NGF receptors TrkA and p75 in breast cancer is indicative of poor prognosis in early stage of the disease [22].…”