ProNGF is a potential diagnostic biomarker for thyroid cancer

Faulkner, Sam; Roselli, Séverine; Demont, Yohann; Pundavela, Jay; Choquet, Geneviève; Leissner, Philippe; Oldmeadow, Christopher; Attia, John; Walker, Marjorie M.; Hondermarck, Hubert

doi:10.18632/oncotarget.8652

Cited by 28 publications

(40 citation statements)

References 32 publications

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“…Increasing evidence points to NGF and proNGF as diagnostic markers of both thyroid and prostate cancer [38,39]. NGF and proNGF are expressed by cancer cells and mediate cancer-related phenomena, such as angiogenesis and pain.…”

Section: Discussionmentioning

confidence: 99%

ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

Ioannou

Fahnestock

2017

IJMS

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Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death. We systematically altered TrkA receptor levels by priming cells with NGF, using small interfering RNA, and using the mutagenized PC12nnr5 cell line. We found that both NGF and proNGF can support cell survival in cells expressing TrkA, even in the presence of p75NTR and sortilin. However, when TrkA is reduced, proNGF signals cell death, while NGF exhibits no activity. In the absence of TrkA, proNGF-induced cell death occurs, even when p75NTR and sortilin levels are reduced. These results show that proNGF can switch between neurotrophic and apoptotic activity in response to changes in TrkA receptor levels, whereas mature NGF cannot. These results also support the model that proNGF is neurotrophic under normal circumstances, but that a loss in TrkA in the presence of p75NTR and sortilin, as occurs in neurodegenerative disease or injury, shifts proNGF, but not NGF, signalling from cell survival to cell death.

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Section: Discussionmentioning

confidence: 99%

ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

Ioannou

Fahnestock

2017

IJMS

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“…Furthermore, detection and quantification of neurotrophic growth factors driving tumor axonogenesis may also have a diagnostic or prognostic value. In prostate cancer, the expression of proNGF by prostate cancer cells contributes to axonogenesis in the tumor microenvironment and correlates with histologic grade (26), and in thyroid cancers proNGF is increased in cancer as compared with normal thyroid tissue (70). In pancreatic (10) and gastric (28) cancers, where NGF production by cancer cells drives axonogenesis, the value of NGF as a prognostic biomarker should be investigated.…”

Section: Diagnostic and Prognostic Value Of Nerves And Neurotrophic Fmentioning

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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“…Subtyping of nerves was performed on a subgroup of thyroid cancers (n = 5) using antibodies against tyrosine hydroxylase (TH) for adrenergic (sympathetic) nerves (catalogue number #ab152, Abcam, Cambridge United Kingdom, 1:250 dilution); vesicular acetylcholine transporter (VAChT) for cholinergic (parasympathetic) nerves (catalogue number #ab62140, Abcam, 1:250 dilution) and anti-Substance P (SP) for peptidergic (sensory) nerves (catalogue number #ab14184, Abcam, 1:1000 dilution) 21 . Sections of innervated dermis and colonic mucosa were included as positive controls.…”

Section: Methodsmentioning

confidence: 99%

“…proNGF expression in thyroid cancers 21 , and given that in prostate cancer proNGF has been reported as a driver of nerve infiltration 9 , we examined whether there was an association between proNGF expression in primary thyroid tumours and nerve density. ProNGF expression was quantified in primary tumours (n = 83) using immunohistochemistry and h-score (staining intensity).…”

Section: Nerve Density In Ptc May Be Associated With Prongf Expressiomentioning

confidence: 99%

Innervation of papillary thyroid cancer and its association with extra-thyroidal invasion

Rowe

Dill

Griffin

et al. 2020

Sci Rep

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Nerves are emerging regulators of cancer progression and in several malignancies innervation of the tumour microenvironment is associated with tumour aggressiveness. However, the innervation of thyroid cancer is unclear. Here, we investigated the presence of nerves in thyroid cancers and the potential associations with clinicopathological parameters. Nerves were detected by immunohistochemistry using the pan-neuronal marker PGP9.5 in whole-slide sections of papillary thyroid cancer (ptc) (n = 75), compared to follicular thyroid cancer (FTC) (n = 13), and benign thyroid tissues (n = 26). Nerves were detected in most normal thyroid tissues and thyroid cancers, but nerve density was increased in PTC (12 nerves/cm 2 [IQR 7-21]) compared to benign thyroid (6 nerves/cm 2 [IQR: 3-10]) (p = 0.001). In contrast, no increase in nerve density was observed in FTC. In multivariate analysis, nerve density correlated positively with extrathyroidal invasion (p < 0.001), and inversely with tumour size (p < 0.001). The majority of nerves were adrenergic, although cholinergic and peptidergic innervation was detected. Perineural invasion was present in 35% of PTC, and was independently associated with extrathyroidal invasion (p = 0.008). This is the first report of infiltration of nerves into the tumour microenvironment of thyroid cancer and its association with tumour aggressiveness. The role of nerves in thyroid cancer pathogenesis should be further investigated.

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ProNGF is a potential diagnostic biomarker for thyroid cancer

Cited by 28 publications

References 32 publications

ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels

Tumor Neurobiology and the War of Nerves in Cancer

Innervation of papillary thyroid cancer and its association with extra-thyroidal invasion

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