Targeting neurotrophin signaling in cancer: The renaissance

Griffin, Nathan; Faulkner, Sam; Jobling, Phillip; Hondermarck, Hubert

doi:10.1016/j.phrs.2018.07.019

Cited by 78 publications

(59 citation statements)

References 70 publications

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“…More and more studies support the importance of nerve-derived signals in organ development, homeostasis, regeneration, and in pathological conditions [20,68]. It is well known that most cancers are associated with pain sensation [69], and different studies have reported the expression of neurotrophic factors in many cancer types [70][71][72][73][74]. Only recently a few studies have started shedding light on the fundamental role of innervation for cancer onset and progression.…”

Section: Discussionmentioning

confidence: 97%

“…Their expression thus leads to neuroattraction and, at the same time, could induce activation of neurotrophin signaling within cancer cells themselves. Neurotrophins and their receptors are attracting increasing attention as therapeutic targets in many cancer types, as pharmacological interventions against this signaling axis have the potential to not only target cancer cells directly, but also to inhibit neurogenesis and its stimulatory effects on cancer progression and pain [73,84]. Indeed neural regulation represents an emerging targetable pathway for the treatment of cancer [75,76,78,85].…”

Section: Discussionmentioning

confidence: 99%

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Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Pagella

Catón

Meisel

et al. 2020

Cells

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Ameloblastomas are locally invasive and aggressive odontogenic tumors treated via surgical resection, which results in facial deformity and significant morbidity. Few studies have addressed the cellular and molecular events of ameloblastoma onset and progression, thus hampering the development of non-invasive therapeutic approaches. Tumorigenesis is driven by a plethora of factors, among which innervation has been long neglected. Recent findings have shown that innervation directly promotes tumor progression. On this basis, we investigated the molecular characteristics and neurotrophic properties of human ameloblastomas. Our results showed that ameloblastomas express dental epithelial stem cell markers, as well as components of the Notch signaling pathway, indicating persistence of stemness. We demonstrated that ameloblastomas express classical stem cell markers, exhibit stem cell potential, and form spheres. These tumors express also molecules of the Notch signaling pathway, fundamental for stem cells and their fate. Additionally, we showed that ameloblastomas express the neurotrophic factors NGF and BDNF, as well as their receptors TRKA, TRKB, and P75/NGFR, which are responsible for their innervation by trigeminal axons in vivo. In vitro studies using microfluidic devices showed that ameloblastoma cells attract and form connections with these nerves. Innervation of ameloblastomas might play a key role in the onset of this malignancy and might represent a promising target for non-invasive pharmacological interventions.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Pagella

Catón

Meisel

et al. 2020

Cells

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“…Animal experiments and clinical trials have already shown that systemic injections of anti-NGF antibodies have no significant impact on neuronal and cognitive activities (75). NGF has a neurotrophic effect that drives tumor axonogenesis (10,28,30); thus, targeting NGF could prevent the outgrowth of nerves in the tumor microenvironment (76). The use of anti-NGF blocking antibodies and inhibitors for TrkA (77) or NGF-targeting siRNA encapsulated into nanoparticles (78) has already demonstrated the ability to decrease cancer growth and metastasis in animal models, with further translation into clinical trials warranted.…”

Section: Targeting Neurotrophic Factorsmentioning

confidence: 99%

Tumor Neurobiology and the War of Nerves in Cancer

et al. 2019

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Nerves are emerging regulators of cancer progression. Cancer cells induce the outgrowth of nerves in the tumor microenvironment through the release of neurotrophic factors, and in return nerves liberate neurotransmitters that activate cancer growth and dissemination. Although sympathetic nerves drive tumor angiogenesis via the liberation of noradrenaline, sensory and parasympathetic nerves stimulate cancer stem cells. Interestingly, recent evidence indicates that parasympathetic nerves can eventually inhibit tumor progression, suggesting a yin-yang type of regulation of cancer by nerves. From a broader perspective, the question of a higher level of control of cancer development by the central nervous system should be raised. Signifi cance:Nerves are emerging regulators of cancer initiation, progression, and metastasis. Here, we review the evidence to date and explore the basic and clinical ramifi cations of these fi ndings.

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“…The exact linkage between neoneurogenesis and tumorigenesis of TSCC has not been uncovered, the underlying mechanisms may involve: ① Newly formed nerves can secret high level of neurotrophin family factors, such as nerve growth factor (NGF), which is contributed to the survival and proliferation of cancer cells [21,22]; ② Malignant tumors depend on angiogenesis to fuels its ability to grow and spread, endothelial β-adrenergic receptor signaling via adrenergic nerve-derived noradrenaline is critical for activation of an angiogenic switch to promote tumor angiogenesis which can facilitate rapid tumor growth [23][24][25]; ③ β2-adrenergic receptor (β2-AR) has been reported to be a potential promoter to cancer initiation and aggressiveness in various types of solid cancer [26]. Liu discovered that increased expression of β2-AR was correlated with differentiation, lymph node metastasis and reduced overall survival rate in patients with TSCC [27].…”

Section: Discussionmentioning

confidence: 99%

Neoneurogenesis in squamous cell carcinoma of tongue: a promoter to its progression and metastasis

Jie

Xiang

et al. 2020

Preprint

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Background : To explore whether neoneurogenesis is a predisposing factor to the development and metastasis of squamous cell carcinoma of tongue (TSCC) . Methods: Twenty patients diagnosed with TSCC were included. The objectives were divided into 4 groups according to WHO T-stage standard (five cases in each group) and 2 groups based on lymph node metastasis or not. Detection of neoneurogenesis in paraffin sections from primary tongue cancer tissues was stained by Neurofilament-Light chain antibody (NF-L) using immunohistochemistry method (IHC). The number of new growth nerve fiber bundles was calculated in each randomized view from 3 non-overlapping microscope fields of each tumor section under a light microscope at X 200. Differences in the density of nerve fiber bundles among the T-stage groups and lymph node metastasis groups were calculated using Chi-square test. An ɑ level of 0.05 was considered statistically significant. Results: The age of patients varied from 33 to 74 years with a mean age of 56.10±11.18 years. Males were affected predominantly with a ratio of 1.5:1 to females. IHC staining of NF-L was positive in all 20 paraffin sections of TSCC which suggested that newly growth nerves (namely neoneurogenesis) were observed in tumor mciroenvironment. The intensity of newly formed nerve bundles increased with T stage, and the difference was statistically significant between early stage (T1、T2) and late stage (T3、T4) (p=0.000). Increased prevalence of newly growth nerve bundles correlated significantly to the cervical lymph node metastasis (p=0.000). Conclusions: Neoneurogenesis in tumor microenviroment of TSCC is a predisposing factor to its aggressive development and cervical lymph node metastasis. From a therapeutic perspective, further studies on the topic may provide a new clinical opportunity through anti-neurogenesis.

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Targeting neurotrophin signaling in cancer: The renaissance

Cited by 78 publications

References 70 publications

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Tumor Neurobiology and the War of Nerves in Cancer

Neoneurogenesis in squamous cell carcinoma of tongue: a promoter to its progression and metastasis

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