Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors

Park, Su‐Jin; Sawitzki, Birgit; Kluwe, Lan; Mautner, Victor; Holtkamp, Nikola; Kurtz, Armin

doi:10.1186/1741-7015-11-109

Cited by 53 publications

(48 citation statements)

References 55 publications

(38 reference statements)

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“…Supporting this notion, several receptor tyrosine kinases that converge on and activate the JAK2/STAT3 pathway are known to drive tumor progression in MPNSTs, including MET (20), PDGF receptors (PDGF-R; ref. 24), ILR (25), and EGF-R (25,34). Although MET targeting has previously been shown to inhibit the migratory, invasive, and angiogenic characteristics of MPNST cells (20), we demonstrate that STAT3 is a crucial mediator of these oncogenic activities downstream of MET.…”

Section: Discussionmentioning

confidence: 52%

“…ST8814 and S462 cells have markedly different STAT3 signaling profiles in response to HGF stimulation One mechanism by which MET drives cell motility is through activation of the JAK2/STAT3 signaling pathway. The JAK2/ STAT3 pathway is also downstream of other receptor tyrosine kinases, including PDGF-R (24), ILR (21,25), and EGF-R (24, 25), which are known to promote tumorigenesis in MPNSTs. STAT3 is considered an oncogene and promotes transcription of genes linked to cancer progression, driving cell migration, invasion, and survival (26).…”

Section: Resultsmentioning

confidence: 99%

“…Cells were also stimulated with IL6 for 30 minutes as a positive control for STAT3 activation; also illustrating that signaling through multiple receptor tyrosine kinases in MPNSTs (such as ILR) can activate JAK2/STAT3 signaling. Of interest, IL6 serum levels were reportedly elevated in NF1 patients with MPNSTs (25). It is therefore likely that STAT3 is activated via multiple mechanisms in NF-1, making it an appealing therapeutic target.…”

Section: Resultsmentioning

confidence: 99%

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STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Rad

Dodd

Thomas

et al. 2015

Molecular Cancer Research

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Therapeutic options are limited for neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoral molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signaling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1, and S1507.2) were used. The data demonstrate that small-molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration, and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion, and tumor formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3 functions as a common driver of tumorigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of hypoxiainducible factor (HIF)1a, HIF2a, and VEGF-A in all four MPNST lines. Finally, the data demonstrate that wound healing, cell migration, invasion, and tumor formation through STAT3 are highly dependent on HIF signaling, where knockdown of HIF1a ablated these oncogenic facets of STAT3.Implications: This research reveals that aberrant STAT3 and HIF1a activity drives tumor progression in MPNSTs, indicating that inhibition of the STAT3/HIF1a/VEGF-A signaling axis is a viable treatment strategy.

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Section: Discussionmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Rad

Dodd

Thomas

et al. 2015

Molecular Cancer Research

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“…Cutaneous neurofi bromas are invariably benign but subcutaneous and plexiform neurofi bromas may undergo malignant transformation in about 8 -13% of patients with NF1 (33). High grade lesions herald a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Extensive Peculiar Cutaneous Form of Neurofibromatosis Type I as a New Mutation - a Case Report

Balaban

Popović

2016

Serbian Journal of Dermatology and Venereology

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Neurofi bromatosis-1 (NF1) is one of the most common hereditary multisystemic disorders. The disease manifests a variety of characteristic features that include: hyperpigmentary abnormalities of the skin (café-au-lait macules, freckles in the axillae, and iris Lisch nodules) and growth of benign peripheral nerve sheath tumors (neurofi bromas) in the skin. Associated extracutaneous clinical features include: skeletal abnormalities, neurological, cardiovascular, endocrine and other malformations. NF1 is caused by mutation in the neurofi bromatosis-1 gene, which codes for the protein neurofi bromin. The inheritance of NF1 follows an autosomal dominant trait, although about 50% of patients present with new ("de novo") mutations, and represent the fi rst member of their family. No difference in the severity of the disease can be found in patients with familial mutations versus those with new mutations. We present a 78-year-old female patient with an extreme cutaneous form of neurofi bromatosis who reported no affected family member. Apart from skin problems, she had no major health issues in childhood and adolescence, but in recent decades she had frequent headaches, occasional abdominal pain, and vision and hearing impairment. About 10 to 14 days before admission, she developed a severe cough, shortness of breath, and chest and abdominal pain. On examination, the patient of short stature (hight: 152 cm, weight: 49 kg) presented with thousands of soft nodules dispersed over the whole body, except on extensor sides of thighs and lower legs; the nodules varied in color from skin-colored, livid erythematous, to brown-grey; the nodules on the abdomen were moist, partly bleeding from the base, and accompanied by an unpleasant odor. Her feet were also densely covered by dark purple lumps, with dystrophic changes of the toe nails that were thickened, frayed, and yellowish. The skeletal abnormalities included: short stature, severe osteoporosis and osteosclerosis of the head bone structure; degenerative arthropathc-spondylotic changes of the thoracolumbar spine segment with signs of diffuse skeletal hyperostosis; pronounced degenerative changes of the lumbar spine. CT scans of the head, chest and abdomen showed the following abnormalities: fl attening of the paraventricular gyri and reduction of brain parenchyma with hypodensity of the white matter in terms of cortical atrophy; periventricular bilateral small post-ischemic microvascular brain lesions of varying chronicity; in the parenchyma of the upper left lung lobe the apical presence of small areas of pleural effusion with consequent subatelectic region; distended stomach and a small inner wall herniation; hypotrophic right kidney; atherosclerotic lesions of the abdominal aorta; low grade infrarenal kinking of the abdominal aorta. Pathohistological analysis of biopsy specimen taken from the nodule corresponded with cutaneous neurofi broma. Consultative examinations of various specialists pointed to the existence of the following comorbidities: obstructive respira...

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“…• Systematic screen of multiple serum biomarkers 14 -The authors evaluated 104 patients with NF1 and 41 healthy controls and proposed 4 candidate biomarkers that were statistically significantly different in patients with NF1 vs unaffected individuals (interleukin-6, interferon-g, epidermal growth factor receptor, tumor necrosis factor-a) and 2 biomarker candidates that were statistically significantly different in patients with NF1 with and without MPNST (insulin-like growth factor binding protein 1 and RANTES).…”

mentioning

confidence: 99%

Current status and recommendations for biomarkers and biobanking in neurofibromatosis

et al. 2016

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Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). Methods:The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. Results:We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks.Conclusions: These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN. Neurology ® 2016;87 (Suppl 1):S40-S48 GLOSSARY 5-S-CD 5 5-S-cysteinyldopa; ADM 5 adrenomedullin; MIA 5 melanoma inhibitory activity; MPNST 5 malignant peripheral nerve sheath tumors; NF1 5 neurofibromatosis 1; NF2 5 neurofibromatosis 2; PNF 5 plexiform neurofibromas; REiNS 5 Response Evaluation in Neurofibromatosis and Schwannomatosis; sAXL 5 soluble growth factor receptor Axl; SOP 5 standard operating procedure; SWN 5 schwannomatosis.

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Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors

Cited by 53 publications

References 55 publications

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Extensive Peculiar Cutaneous Form of Neurofibromatosis Type I as a New Mutation - a Case Report

Current status and recommendations for biomarkers and biobanking in neurofibromatosis

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