2023 |
Dowdell A, Marsland M, Faulkner S, Gedye C, Lynam J, Griffin CP, et al., 'Targeting XBP1 mRNA splicing sensitizes glioblastoma to chemotherapy', FASEB BIOADVANCES, 5 211-220 (2023) [C1]
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Nova |
2023 |
Qiao Y, Zhou Y, Zhang X, Faulkner S, Liu H, Wang L, 'Toxic effects of triphenyltin on the development of zebrafish (Danio rerio) embryos', Science of the Total Environment, 885 (2023) [C1]
Triphenyltin (TPT) is known to be an environmental endocrine disruptor and has adverse effects on aquatic animals. In this study, zebrafish embryos were treated with three differe... [more]
Triphenyltin (TPT) is known to be an environmental endocrine disruptor and has adverse effects on aquatic animals. In this study, zebrafish embryos were treated with three different concentrations (12.5, 25, 50 nmol/L) based on the LC50 value at 96 h post fertilization (96 hpf), after TPT exposure. The developmental phenotype and hatchability were observed and recorded. Reactive oxygen species (ROS) levels in zebrafish were detected at 72 hpf and 96 hpf using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) as a probe. The number of neutrophils after exposure was observed using transgenic zebrafish Tg (lyz: DsRed). RNA-seq analysis was used to compare the gene expression changes in zebrafish embryos at 96 hpf in the control group and 50 nmol/L TPT exposure group. The data revealed that TPT caused a delay in hatching of zebrafish embryos in a time- and dose-dependent manner, as well as causing pericardial edema, spinal curvature and melanin reduction. ROS levels in embryos exposed to TPT increased, and the number of neutrophils increased after TPT exposure to Tg (lyz: DsRed) in transgenic zebrafish. RNA-seq results were also analyzed, and KEGG enrichment analysis showed that significant differential genes were enriched in the PPAR signaling pathway (P < 0.05), and the PPAR signaling pathway mainly affected genes related to lipid metabolism. The RNA-seq results were verified using real-time fluorescence quantitative PCR (RT-qPCR). Oil red O and Nile red staining showed increased lipid accumulation after TPT exposure. These findings suggest that TPT affects the development of zebrafish embryos even at relatively low concentrations.
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Nova |
2023 |
Marsland M, Dowdell A, Faulkner S, Gedye C, Lynam J, Griffin CP, et al., 'The Membrane Protein Sortilin Is a Potential Biomarker and Target for Glioblastoma', Cancers, 15 2514-2514 [C1]
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Nova |
2023 |
Maddison K, Faulkner S, Graves MC, Fay M, Bowden NA, Tooney PA, 'Vasculogenic Mimicry Occurs at Low Levels in Primary and Recurrent Glioblastoma', Cancers, 15 3922-3922 [C1]
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Nova |
2023 |
Marsland M, Dowdell A, Faulkner S, Jobling P, Rush RA, Gedye C, et al., 'ProNGF Expression and Targeting in Glioblastoma Multiforme.', Int J Mol Sci, 24 (2023) [C1]
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Nova |
2022 |
Ferdoushi A, Jamaluddin MFB, Li X, Pundavela J, Faulkner S, Hondermarck H, 'Secretome analysis of human schwann cells derived from malignant peripheral nerve sheath tumor', PROTEOMICS, 22 (2022) [C1]
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Nova |
2022 |
Jiang CC, Marsland M, Wang Y, Dowdell A, Eden E, Gao F, et al., 'Tumor innervation is triggered by endoplasmic reticulum stress', ONCOGENE, 41 586-599 (2022) [C1]
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Nova |
2022 |
Li X, Liu H, Dun MD, Faulkner S, Liu X, Jiang CC, Hondermarck H, 'Proteome and secretome analysis of pancreatic cancer cells', PROTEOMICS, 22 (2022) [C1]
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Nova |
2022 |
Liu H, Sun W, Zhou Y, Griffin N, Faulkner S, Wang L, 'iTRAQ-based quantitative proteomics analysis of Sprague-Dawley rats liver reveals perfluorooctanoic acid-induced lipid metabolism and urea cycle dysfunction.', Toxicol Lett, 357 20-32 (2022) [C1]
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Nova |
2022 |
Marsland M, Dowdell A, Jiang CC, Wilmott JS, Scolyer RA, Zhang XD, et al., 'Expression of NGF/proNGF and Their Receptors TrkA, p75(NTR) and Sortilin in Melanoma', INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23 (2022) [C1]
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Nova |
2021 |
March B, Lockhart KR, Faulkner S, Smolny M, Rush R, Hondermarck H, 'ELISA-based quantification of neurotrophic growth factors in urine from prostate cancer patients', FASEB BioAdvances, 3 888-896 (2021) [C1]
Non-invasive procedures are needed for prostate cancer management, and urine represents a potential source of new biomarkers with translational value. Recent evidence has shown th... [more]
Non-invasive procedures are needed for prostate cancer management, and urine represents a potential source of new biomarkers with translational value. Recent evidence has shown that the growth of new nerves in the tumor microenvironment is essential to prostate cancer progression. Neurotrophic growth factors are expressed by prostate cancer cells and contribute to prostate tumor innervation, but their presence in urine is unclear. In the present study, we have assayed the concentration of neurotrophic factors in the urine of prostate cancer patients. Urine was collected from a prospective cohort of 45 men with prostate cancer versus 30 men without cancer and enzyme-linked immunosorbent assay was used to quantify nerve growth factor (NGF) and its precursor proNGF, brain-derived neurotrophic factor (BDNF) and proBDNF, neurotrophin-3, neurotrophin-4/5, and glia-derived neurotrophic growth factor. The results show that neurotrophic factors are detectable in various concentrations in both cancer and healthy urine, but no significant difference was found. Also, no association was observed between neurotrophic factor concentrations and prostate cancer grade. This study is the first quantification of neurotrophins in urine, and although no significant differences were observed between prostate cancer patients versus those without prostate cancer, or between prostate cancers of various grades, the potential value of neurotrophins for prostate cancer diagnosis and prognosis warrants further investigations in larger patient cohorts.
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Nova |
2021 |
Ferdoushi A, Griffin N, Marsland M, Xu X, Faulkner S, Gao F, et al., 'Tumor innervation and clinical outcome in pancreatic cancer', SCIENTIFIC REPORTS, 11 (2021) [C1]
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Nova |
2021 |
Liu H, Cheng J, Zhou Y, Liu F, Griffin N, Faulkner S, Wang L, 'Interactions of perfluorooctanoic acid with acyl-CoA thioesterase 1 (Acot1)', Comparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology, 250 (2021) [C1]
Perfluorooctanoic acid (PFOA), a typical representative of per- and polyfluoroalkyl substances (PFASs), is a widely utilized persistent organic pollutant (POP) known to induce liv... [more]
Perfluorooctanoic acid (PFOA), a typical representative of per- and polyfluoroalkyl substances (PFASs), is a widely utilized persistent organic pollutant (POP) known to induce liver toxicity in laboratory animals and wildlife. Evidence suggests that PFOA interacts with Acyl-CoA thioesterase 1 (Acot1) to modulate levels of ß-oxidation. Specifically, PFOA accelerates ß-oxidation, while Acot1 is inhibitory. Few studies have investigated the specific relationship between PFOA and Acot1 and the mechanism of their interaction remains unclear. In the following study, purified rat Acot1 protein was synthesized via bacterial recombination and the structural features that facilitate its binding to PFOA were assessed via molecular docking technology. Additionally, through use of circular dichroism spectroscopy (CD) and isothermal titration calorimetry (ITC) we demonstrate that PFOA binds to WT-Acot1 through electrostatic attraction and low strength non-covalent hydrogen bonding at a molar ratio of 1:1. Furthermore, we identify N326 and H373 amino acid residues as key regulators of the binding process. Together, these findings clarify the interaction pattern of PFOA and Acot1 proteins and provide insight into the specific molecular mechanisms that induce PFOA toxicity in humans and animals.
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Nova |
2021 |
Maddison K, Graves MC, Bowden NA, Fay M, Vilain RE, Faulkner S, Tooney PA, 'Low tumour-infiltrating lymphocyte density in primary and recurrent glioblastoma', Oncotarget, 12 2177-2187 (2021) [C1]
Immunotherapies targeting tumour-infiltrating lymphocytes (TILs) that express the immune checkpoint molecule programmed cell death-1 (PD-1) have shown promise in preclinical gliob... [more]
Immunotherapies targeting tumour-infiltrating lymphocytes (TILs) that express the immune checkpoint molecule programmed cell death-1 (PD-1) have shown promise in preclinical glioblastoma models but have had limited success in clinical trials. To assess when glioblastoma is most likely to benefit from immune checkpoint inhibitors we determined the density of TILs in primary and recurrent glioblastoma. Thirteen cases of matched primary and recurrent glioblastoma tissue were immunohistochemically labelled for CD3, CD8, CD4 and PD-1, and TIL density assessed. CD3+ TILs were observed in all cases, with the majority of both primary (69.2%) and recurrent (61.5%) tumours having low density of TILs present. CD8+ TILs were observed at higher densities than CD4+ TILs in both tumour groups. PD-1+ TILs were sparse and present in only 25% of primary and 50% of recurrent tumours. Quantitative analysis of TILs demonstrated significantly higher CD8+ TIL density at recurrence (p = 0.040). No difference was observed in CD3+ (p = 0.191), CD4+ (p = 0.607) and PD-1+ (p = 0.070) TIL density between primary and recurrent groups. This study shows that TILs are present at low densities in both primary and recurrent glioblastoma. Furthermore, PD-1+ TILs were frequently absent, which may provide evidence as to why anti-PD-1 immunotherapy trials have been largely unsuccessful in glioblastoma.
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Nova |
2021 |
Griffin N, Gao F, Jobling P, Oldmeadow C, Wills V, Walker MM, et al., 'The neurotrophic tyrosine kinase receptor 1 (TrkA) is overexpressed in oesophageal squamous cell carcinoma', Pathology, 53 470-477 (2021) [C1]
Nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA) and the common neurotrophin receptor (NGFR/p75NTR), are increasingly implicat... [more]
Nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA) and the common neurotrophin receptor (NGFR/p75NTR), are increasingly implicated in cancer progression, but their clinicopathological significance in oesophageal cancer is unclear. In this study, the expression of NGF, NTRK1 and NGFR were analysed by immunohistochemistry in a cohort of 303 oesophageal cancers versus 137 normal adjacent oesophageal tissues. Immunostaining was digitally quantified and compared to clinicopathological parameters. NGF and NGFR staining were found in epithelial cells and at similar levels between oesophageal cancers and normal oesophageal tissue. NGFR staining was slightly increased with grade (p=0.0389). Interestingly, NTRK1 staining was markedly higher in oesophageal squamous cell carcinoma (OR 2.31, 95%CI 1.13¿4.38, p<0.0001) and significantly lower in adenocarcinoma (OR 0.50, 95%CI 0.44¿0.63, p<0.0001) compared to normal oesophageal tissue. In addition, NTRK1 staining was decreased in grade 2 and grade 3 (OR 0.51, 95%CI 0.21¿1.40, p<0.0001) compared to grade 1, suggesting a preferential involvement of this receptor in the more differentiated forms of oesophageal carcinomas. Together, these data point to NTRK1 as a biomarker and a candidate therapeutic target in oesophageal squamous cell carcinoma.
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2020 |
Griffin N, Rowe CW, Gao F, Jobling P, Wills V, Walker MM, et al., 'Clinicopathological Significance of Nerves in Esophageal Cancer', American Journal of Pathology, 190 1921-1930 (2020) [C1]
Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were ana... [more]
Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were analyzed by immunohistochemistry in a cohort of 260 esophageal cancers, including 40 matched lymph node metastases and 137 normal adjacent esophageal tissues. Nerves were detected in 38% of esophageal cancers and were more associated with squamous cell carcinomas (P = 0.04). The surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with reduced survival (P = 0.04). Nerves were found to express the following receptors for nerve growth factor (NGF): neurotrophic receptor tyrosine kinase 1 and nerve growth factor receptor. An association was suggested between high production of NGF by cancer cells and the presence of nerves (P = 0.02). In vitro, NGF production in esophageal cancer cells was shown by Western blot, and esophageal cancer cells were able to induce neurite outgrowth in the PC12 neuronal cells. The neurotrophic activity of esophageal cancer cells was inhibited by anti-NGF blocking antibodies. Together, these data suggest that innervation is a feature in esophageal cancers that may be driven by cancer cell¿released NGF.
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2020 |
Faulkner S, Griffin N, Rowe CW, Jobling P, Lombard JM, Oliveira SM, et al., 'Nerve growth factor and its receptor tyrosine kinase TrkA are overexpressed in cervical squamous cell carcinoma.', FASEB bioAdvances, 2 398-408 (2020) [C1]
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Nova |
2020 |
Ferdoushi A, Li X, Griffin N, Faulkner S, Jamaluddin MFB, Gao F, et al., 'Schwann Cell Stimulation of Pancreatic Cancer Cells: A Proteomic Analysis', Frontiers in Oncology, 10 (2020) [C1]
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Nova |
2020 |
Gao F, Griffin N, Faulkner S, Li X, King SJ, Jobling P, et al., 'The Membrane Protein Sortilin Can Be Targeted to Inhibit Pancreatic Cancer Cell Invasion.', The American journal of pathology, 190 (2020) [C1]
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Nova |
2020 |
Griffin N, Marsland M, Roselli S, Oldmeadow C, Attia J, Walker MM, et al., 'The receptor tyrosine kinase trka is increased and targetable in HER2-positive breast cancer', Biomolecules, 10 1-13 (2020) [C1]
The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathologi... [more]
The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.
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Nova |
2020 |
Liu H, Li X, Dun MD, Faulkner S, Jiang CC, Hondermarck H, 'Cold Shock Domain Containing E1 (CSDE1) Protein is Overexpressed and Can be Targeted to Inhibit Invasiveness in Pancreatic Cancer Cells', PROTEOMICS, 20 (2020) [C1]
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Nova |
2020 |
Rowe CW, Dill T, Griffin N, Jobling P, Faulkner S, Paul JW, et al., 'Innervation of papillary thyroid cancer and its association with extra-thyroidal invasion', Scientific Reports, 10 (2020) [C1]
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Nova |
2020 |
Dun MD, Mannan A, Rigby CJ, Butler S, Toop HD, Beck D, et al., 'Shwachman Bodian Diamond syndrome (SBDS) protein is a direct inhibitor of protein phosphatase 2A (PP2A) activity and overexpressed in acute myeloid leukaemia', Leukemia, 34 3393-3397 (2020) [C1]
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Nova |
2020 |
March B, Faulkner S, Jobling P, Steigler A, Blatt A, Denham J, Hondermarck H, 'Tumour innervation and neurosignalling in prostate cancer', Nature Reviews Urology, 17 119-130 (2020) [C1]
Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosig... [more]
Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosignalling that is necessary in early stages of tumour progression and for initiating an angiogenic switch, whereas parasympathetic nerves activate cholinergic neurosignalling resulting in tumour dissemination and metastasis. The innervation of prostate cancer seems to be initiated by neurotrophic growth factors, such as the precursor to nerve growth factor secreted by tumour cells, and the contribution of brain-derived neural progenitor cells has also been reported. Current experimental, epidemiological and clinical evidence shows the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. Using nerves and neurosignalling could have value in the management of prostate cancer by predicting aggressive disease, treating localized disease through denervation and relieving cancer-associated pain in bone metastases.
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Nova |
2019 |
Rowe CW, Faulkner S, Paul JW, Tolosa JM, Gedye C, Bendinelli C, et al., 'The precursor for nerve growth factor (proNGF) is not a serum or biopsy-rinse biomarker for thyroid cancer diagnosis.', BMC endocrine disorders, 19 128 (2019) [C1]
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Nova |
2019 |
Rowe CW, Dill T, Faulkner S, Gedye C, Paul JW, Tolosa JM, et al., 'The precursor for nerve growth factor (ProNGF) in thyroid cancer lymph node metastases: Correlation with primary tumour and pathological variables', International Journal of Molecular Sciences, 20 1-13 (2019) [C1]
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Nova |
2019 |
Faulkner S, Jobling P, March B, Jiang CC, Hondermarck H, 'Tumor neurobiology and the war of nerves in cancer', Cancer Discovery, 9 702-710 (2019) [C1]
Nerves are emerging regulators of cancer progression. Cancer cells induce the outgrowth of nerves in the tumor microenvironment through the release of neu-rotrophic factors, and i... [more]
Nerves are emerging regulators of cancer progression. Cancer cells induce the outgrowth of nerves in the tumor microenvironment through the release of neu-rotrophic factors, and in return nerves liberate neurotransmitters that activate cancer growth and dissemination. Although sympathetic nerves drive tumor angiogenesis via the liberation of noradrena-line, 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. Significance: Nerves are emerging regulators of cancer initiation, progression, and metastasis. Here, we review the evidence to date and explore the basic and clinical ramifications of these findings.
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2018 |
Gao F, Griffin N, Faulkner S, Rowe CW, Williams L, Roselli S, et al., 'The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung', SCIENTIFIC REPORTS, 8 (2018) [C1]
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Nova |
2018 |
Griffin N, Faulkner S, Jobling P, Hondermarck H, 'Targeting neurotrophin signaling in cancer: The renaissance', Pharmacological Research, 135 12-17 (2018) [C1]
Nerve outgrowth in the tumor microenvironment (tumor neurogenesis) has recently been shown to be essential for cancer progression and the concept of nerve dependence is emerging i... [more]
Nerve outgrowth in the tumor microenvironment (tumor neurogenesis) has recently been shown to be essential for cancer progression and the concept of nerve dependence is emerging in oncology. Neurotrophins such as nerve growth factor (NGF) have long been identified as drivers of neurogenesis during development and regeneration, but intriguingly they were also known to be expressed in human tumors where they can stimulate cancer cell growth. Recent findings have unraveled that NGF released by cancer cells is also a driver of tumor neurogenesis, via the stimulation of NGF receptors on nerve endings. In return, nerves infiltrated in the tumor microenvironment secrete neurotransmitters, which can stimulate both the growth of tumor cells and angiogenesis. This neurotrophic role of NGF in cancer is likely to be relevant to a large variety of human malignancies, as well as other neurotrophins, and may have ramifications in cancer pain. Therefore, pharmacological interventions against neurotrophin signaling have the potential not only to target cancer cells directly, but also to inhibit neurogenesis and its stimulatory impact on cancer progression and pain.
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2018 |
Li X, Dun MD, Faulkner S, Hondermarck H, 'Neuroproteins in Cancer: Assumed Bystanders Become Culprits', PROTEOMICS, 18 (2018) [C1]
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Nova |
2018 |
Faulkner S, Jobling P, Rowe CW, Rodrigues Oliveira SM, Roselli S, Thorne RF, et al., 'Neurotrophin Receptors TrkA, p75
Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor k... [more]
Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75NTR, and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 found that siRNA against TrkA, p75NTR, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75NTR, and sortilin as potential therapeutic targets in thyroid cancer.
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Nova |
2017 |
Boilly B, Faulkner S, Jobling P, Hondermarck H, 'Nerve Dependence: From Regeneration to Cancer', Cancer Cell, 31 342-354 (2017) [C1]
Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in variou... [more]
Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in various species. Recent discoveries have demonstrated that denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer. Regeneration and cancer share similarities in regard to the stimulatory role of nerves, and there are indications that the stem cell compartment is a preferred target of innervation. Thus, the neurobiology of cancer is an emerging discipline that opens new perspectives in oncology.
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2016 |
Faulkner S, Roselli S, Demont Y, Pundavela J, Choquet G, Leissner P, et al., 'ProNGF is a potential diagnostic biomarker for thyroid cancer', Oncotarget, 7 28488-28497 (2016) [C1]
The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopatho... [more]
The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopathological significance of proNGF in thyroid cancer. ProNGF expression was analysed by immunohistochemistry in two cohorts of cancer versus benign tumors (adenoma) and normal thyroid tissues. In the first cohort (40 thyroid cancers, 40 thyroid adenomas and 80 normal thyroid tissues), proNGF was found overexpressed in cancers compared to adenomas and normal samples (p<0.0001). The area under the receiver-operating characteristic (ROC) curve was 0.84 (95% CI 0.75-0.93, p<0.0001) for cancers versus adenomas, and 0.99 (95% CI 0.98-1.00, p<0.0001) for cancers versus normal tissues. ProNGF overexpression was confirmed in a second cohort (127 cancers of various histological types and 55 normal thyroid tissues) and using a different antibody (p<0.0001). ProNGF staining intensity was highest in papillary carcinomas compared to other histological types (p<0.0001) and there was no significant association with age, gender, tumor size, stage and lymph node status. In conclusion, proNGF is increased in thyroid cancer and should be considered as a new potential diagnostic biomarker.
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2015 |
Dun MD, Chalkley RJ, Faulkner S, Keene S, Avery-Kiejda KA, Scott RJ, et al., 'Proteotranscriptomic profiling of 231-BR breast cancer cells: Identification of potential biomarkers and therapeutic targets for brain metastasis', Molecular and Cellular Proteomics, 14 2316-2330 (2015) [C1]
Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here ... [more]
Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and L-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation.
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2015 |
Roselli S, Pundavela J, Demont Y, Faulkner S, Keene S, Attia J, et al., 'Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion', Oncotarget, 6 10473-10486 (2015) [C1]
The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed... [more]
The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion.
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Nova |
2015 |
Faulkner S, Dun MD, Hondermarck H, 'Proteogenomics: Emergence and promise', Cellular and Molecular Life Sciences, 72 953-957 (2015) [C1]
Proteogenomics, or the integration of proteomics with genomics and transcriptomics, is emerging as the next step towards a unified understanding of cellular functions. Looking glo... [more]
Proteogenomics, or the integration of proteomics with genomics and transcriptomics, is emerging as the next step towards a unified understanding of cellular functions. Looking globally and simultaneously at gene structure, RNA expression, protein synthesis and posttranslational modifications have become technically feasible and offer a new perspective to molecular processes. Recent publications have highlighted the value of proteogenomics in oncology for defining the molecular signature of human tumors, and translation to other areas of biomedicine and life sciences is anticipated. This minireview will discuss recent developments, challenges and perspectives in proteogenomics.
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Nova |
2015 |
Pundavela J, Roselli S, Faulkner S, Attia J, Scott RJ, Thorne RF, et al., 'Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer', Molecular Oncology, 9 1626-1635 (2015) [C1]
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