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IGF-1R expression in plexiform neurofibroma. (Magnification x100, chromogen DAB, counterstain hemalum).
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Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease, characterised by the development of nerve sheath tumors. NF1 is the most frequently inherited disease associated with a predisposition for cancer (in particular malignant peripheral nerve sheath tumors: MPNST). NF1 is a progressive disease with phase-like growth spurts of de...
Citations
... First, because IGF-1R is required for Schwann cell development and response to injury through inhibition of Schwann cell apoptosis (D'Ercole et al., 1996;Ogata et al., 2006;Freude et al., 2008). Second, because IGF-1R is strongly expressed in patient samples of MPNST and PNs (Friedrich et al., 2007). ...
Plexiform neurofibromas (PNs), which may be present at birth in up to half of children with type 1 neurofibromatosis (NF1), can cause serious loss of function, such as quadriparesis, and can undergo malignant transformation. Surgery is the first line treatment although the invasive nature of these tumors often prevents complete resection. Recent clinical trials have shown promising success for some drugs, notably selumetinib, an inhibitor of MAP kinase kinase (MEK). We have developed three-dimensional (3D) cell culture models of immortalized cells from NF1 PNs and of control Schwann cells (SCs) that we believe mimic more closely the in vivo condition than conventional two-dimensional (2D) cell culture. Our goal is to facilitate pre-clinical identification of potential targeted therapeutics for these tumors. Three drugs, selumetinib (a MEK inhibitor), picropodophyllin (an IGF-1R inhibitor) and LDN-193189 (a BMP2 inhibitor) were tested with dose-response design in both 2D and 3D cultures for their abilities to block net cell growth. Cell lines grown in 3D conditions showed varying degrees of resistance to the inhibitory actions of all three drugs. For example, control SCs became resistant to growth inhibition by selumetinib in 3D culture. LDN-193189 was the most effective drug in 3D cultures, with only slightly reduced potency compared to the 2D cultures. Characterization of these models also demonstrated increased proteolysis of collagen IV in the matrix by the PN driver cells as compared to wild-type SCs. The proteolytic capacity of the PN cells in the model may be a clinically significant property that can be used for testing the ability of drugs to inhibit their invasive phenotype.
... 32,50,51 The cumulative lifetime risk of MPNST in NF1 patients has been estimated to be about 8-13%, with many patients developing this malignant tumour at around 30 years of age. [52][53][54] Although 21% of participants were not certain with regard to a prior diagnosis of MPNST, more than 50% of our patients were younger than 30. Therefore, these patients require close clinical and radiological surveillance for this malignant tumour as they approach the age of 30. ...
Neurofibromatosis Clinic: A Report on Patient Demographics and Evaluation of the Clinic – CORRIGENDUM - Volume 44 Issue 5 - Alireza Mansouri, Saber Ghadakzadeh, Talha Maqbool, Carolina Barnett, Karolyn Au, Paul Kongkham, Vera Bril, Gelareh Zadeh
... 32,50,51 The cumulative lifetime risk of MPNST in NF1 patients has been estimated to be about 8-13%, with many patients developing this malignant tumour at around 30 years of age. [52][53][54] Although 21% of participants were not certain with regard to a prior diagnosis of MPNST, more than 50% of our patients were younger than 30. Therefore, these patients require close clinical and radiological surveillance for this malignant tumour as they approach the age of 30. ...
Background:
Neurofibromatosis type 1 (NF1) is a common single-gene disorder. A multidisciplinary approach to the management of NF1 patients is necessitated by the heterogeneity of clinical manifestations. Although multidisciplinary pediatric clinics have been well-established, there is a dearth of such resources for adults with NF1. Herein we report our one-year institutional experience with a multidisciplinary adult NF1 clinic.
Methods:
A multidisciplinary team was assembled, and an NF Patient Registry Initiative questionnaire was adapted to collect patient-reported data during clinics. Multiple databases were searched to identify publications pertaining to the experience of other multidisciplinary NF1 clinics focusing on adult patients. Data on patient epidemiology and clinical staff were compared to our data.
Results:
Seventy-seven patients were seen scheduled, and 68 attended the clinic, of which 66 completed the intake questionnaire. The demographic and clinical data from this Canadian population is mostly consistent with previous reports with some exceptions. Clinical data related to immune system involvement such as asthma, airway/breathing-related difficulties or allergy were striking in our NF1 population. Six relevant published reports of other NF1 clinics were identified. Reports from these studies pertained to periods ranging from 10-38 months and the number of adults assessed ranged from 19-177 patients.
Conclusions:
The structure of our clinic and patient volume is comparable to other established centers found in the literature. Our data offer valuable cross-sectional prevalence statistics in the Canadian population. The patient-reported data concerning the involvement of the immune system contribute to an emerging recognized medical concern within the NF1 population and warrant further clinical and basic investigation.
... The lifetime risk of MPNST for patients with NF1 patients has been estimated to be about 8 to 13% and thus is more than 1000 times higher for these patients than for the general population. Moreover, many patients with NF1 develop MPNST at the unusually young age of around 30 years [10,11], compared with the median age of diagnosis of 62 years in the general population [12]. Because MPNST develop by malignant progression of pre-existing PNF, the risk to develop an MPNST increases to almost 50% in patients with NF1 and PNF [12,13]. ...
... An inverse correlation has previously been indicated between IGFBP1 levels and carcinogenesis [44,45]. The expression of IGF-I and growth-hormone receptors in PNF and MPNST in patients with NF1, and the correlation between IGF-I receptor levels and the increased mitosis index of PNFs, suggest sensitivity of these tumors to IGFBP1-regulated factors [10,46]. Taken together, IGFBP1 may modulate IGF access to PNF and MPNST, although this mechanism still needs to be elucidated. ...
Background
Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by the development of benign nerve-sheath tumors, which transform to malignant peripheral nerve-sheath tumors (MPNST) in about 8 to 13% of patients with NF1. MPNST are invasive sarcomas with extremely poor prognosis, and their development may correlate with internal tumor load of patients with NF1. Because early identification of patients with NF1 at risk for developing MPNST should improve their clinical outcome, the aim of this study was to identify serum biomarkers for tumor progression in NF1, and to analyze their correlation with tumor type and internal tumor load.
Methods
We selected candidate biomarkers for NF1 by manually mining published data sources, and conducted a systematic screen of 56 candidate serum biomarkers using customized antibody arrays. Serum from 104 patients with NF1 with and without MPNST, and from 41 healthy control subjects, was analyzed. Statistical analysis was performed using the non-parametric Mann–Whitney U-test, followed by Bonferroni correction.
Results
Our analysis identified four markers (epidermal growth factor receptor, interferon-γ, interleukin-6, and tumor necrosis factor-α) for which significantly different serum concentrations were seen in patients with NF1 compared with healthy controls. Two markers (insulin-like growth factor binding protein 1 (IGFBP1) and regulated upon activation, normal T-cell expressed and secreted (RANTES)) showed significantly higher concentrations in patients with NF1 and MPNST compared with patients with NF1 without MPNST. A correlation with internal tumor load was found for IGFBP1.
Conclusion
Our study identified two serum markers with potential for early detection of patients with NF1 at risk for developing MPNST, and four markers that could distinguish between patients with NF1 and healthy subjects. Such markers may be useful as diagnostic tools to support the diagnosis of NF1 and for timely identification of MPNST. Moreover, the data suggest that there is a systemic increase in inflammatory cytokines independently of tumor load in patients with NF1.
... A strong pro-angiogenic drive contributes to the progressive growth in MPNST. Similarly the expression of epidermal growth factor receptors (EGFR) and insulin-like growth factor1 receptors (IGF-IR) is found on tumor cells in NF1 but not in normal Schwann cells [10,11]. With the growing evidence of the role of angiogenesis in NF1 related malignancies, there have been several therapeutic trials using VEGF-inhibitors and thalidomide in NF1 patients [12,13]. ...
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive tumor especially in the patients with neurofibromatosis type 1 (NF1). Without a complete surgical excision, prognosis is guarded. We describe a 10-year-old male with NF1 with MPNST, who had a local relapse within 5 weeks of surgical excision. Chemoradiotherapy did not result in tumor regression. Initiation of palliative oral metronomic therapy resulted in complete remission after six cycles. The patient continues to be in remission, 20 months after completion of nine cycles of metronomic therapy. Metronomic therapy may be effective in MPNST where conventional chemotherapy and radiotherapy fails. Pediatr Blood Cancer 2012; 59: 1317-1319. © 2012 Wiley Periodicals, Inc.
Objective
To summarize existing biomarker data for cutaneous neurofibroma (cNF) and inform the incorporation of biomarkers into clinical trial design for cNFs.
Methods
The cNF working group, a subgroup of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) consortium, was formed to review and inform clinical trial design for cNFs. Between June 2018 and February 2020 , the cNF working group performed a review of existing data on genetic biomarkers for cNFs in the setting of Neurofibromatosis Type 1 (NF1). We also reviewed criteria for successful biomarker application in the clinic. The group then met during a series of meetings to develop a consensus report.
Results
Our systematic literature review of existing data revealed a lack of validated biomarkers for cNFs. In our report, we summarize the existing signaling, genomic, transcriptomic, histopathologic and proteomic data relevant to cNF. Finally, we make recommendations for incorporating exploratory aims for predictive biomarkers in clinical trials through biobanking samples.
Conclusion
These recommendations are intended to provide both researchers and clinicians with best practices for clinical trial design to aid in the identification of clinically validated biomarkers for cNF.
We report a case of triple cancer of the pancreas, colon, and peripheral nerve sheath. A 68-year-old woman diagnosed with type 2 diabetes at age 63 had been administered antidiabetic oral medications since then. Her HbAlc had been 6.0-7.0 % in NGSP. We found that, in the last 5 months, her HbAlc had increased by 3.5 % and she had lost 9 kg, suggesting the need to check for possibly malignant disease. Contrast-enhanced computed tomography showed 1 tumor each of the pancreas, chest wall. Preoperative colonoscopy showed a tumor of the colon. The first two tumors, diagnosed pathologically as cancer of the pancreas and of the peripheral nerve sheath, were completely resected with no significant metastasis. The third tumor, diagnosed as cancer of the colon, was removed by endoscopic mucosal resection. Symptoms in those with diabetes that include progressive weight loss and deteriorating glycemic control should thus suggest the need to check for possibly malignant disease.
One of the main clinical manifestations of Neurofibromatosis type 1 (NF1) is the development of multiple neurofibromas. It has been suggested that loss of heterozygosity (LOH) of the NF1 gene in Schwann cells represents the first step in the development of NF1-associated neurofibromas. Beyond mutations of the NF1 gene, numerous additional factors probably influence neurofibroma formation and growth. Periods of hormonal changes (puberty and pregnancy) have been correlated with an increase in number and growth rate of discrete neurofibromas, and also with malignant transformation of plexiform neurofibromas. Research advances have been made in elucidating the hormonal influence in neurofibromas of NF1. Most of the studies developed to date focused on the study of steroid hormones, mainly sex steroid hormones, on the development of neurofibromas. It seems that progesterone and androgen are responsible, at least in part, for the alterations observed in neurofibromas during periods of hormonal changes. The investigations of the influence of growth hormone (GH) in neurofibromas are still in their initial steps, but it is known that the majority of NF1-associated neurofibromas express GH receptor and also insulin-like growth factor 1 (IGF-1) receptor. Current knowledge suggests that selective hormone receptor could be useful for the treatment of NF1-associated neurofibromas.
Peripheral nerve sheath (PNS) tumors constitute a heterogeneous group of solid tumors. Neurofibroma and schwannoma are the most frequently diagnosed entities. Both tumor types occur sporadically and are associated with syndromes. Current strategies to fight PNS progression by means of pharmaceuticals aim to specifically interfere with vascular growth factors identified in PNS. Furthermore, malignant transformation of PNS tumors is known to be associated with a change in vascularization. The aim of the study was to investigate vascularization of different PNS tumors with respect to sporadic or syndromal state of the entities.
One hundred and thirty-two formalin-fixed and paraffin-embedded PNS tissue samples were retrieved from the archives of the Institute of Neuropathology, Eppendorf University Hospital. Lymphatic and blood vessels were immunohistochemically identified and morphometrically analyzed in PNS and controls.
Blood vessel density in malignant tumors was significantly higher than in benign lesions (30.8/mm(2) vs. 13.46/mm(2)). In the latter, the vessel density resembled that of control tissue. Lymphatic vessel supply was significantly higher in cutaneous neurofibroma and diffuse plexiform neurofibroma (PNF) than in intra-neural localized tumors (schwannoma, nodular PNF). Lymphatic vessels showed no marked differences with respect to tumor entity. Prevalence of mast cells differed markedly between tumor types.
Different vascularization of PNS may contribute to diverging tumor response following application of anti-neoplastic drugs. Mast cells may have an impact during formation and growth of neurofibroma but are unlikely to be involved in the process of de-differentiation.
Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
Background/aim:
Neurofibromas, benign tumors of the nerve sheaths, are the hallmark of neurofibromatosis type 1 (NF1), an autosomal-dominant inherited tumor predisposition syndrome. Malignant tumors arising from nerve sheath cells are an important factor influencing the life expectancy of NF1 patients. Expression of growth factors and growth factor receptors play a key role in the development of tumors. Therapy of peripheral nerve sheath (PNS) tumors is predominantly surgical. The outcome in malignant entities of NF1-affected patients remains poor, despite many efforts to implement pharmacological therapy into the treatment modalities. Growth of peripheral nerve sheath tumors is finely-adjusted by growth factors and PNS tumors express growth factor receptors. However, quantification of receptor expression and comparison to the expression of other related factors are not available. The aim of the present study was to determine growth factor expression relevant for growth control in neurofibromas of NF1.
Materials and methods:
Fifty-eight dermal, dermal/diffuse and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) of NF1-affected patients were analyzed immunohistochemically for the expression of growth factors relevant for angiogenesis: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and epithelial growth factor receptor (EGFR). The vessel density was also determined quantitatively by light microscopy.
Results:
Plexiform neurofibroma revealed a higher expression level for VEGF compared to dermal/diffuse neurofibroma. However, statistical significant differences for VEGF expression and of all other proteins investigated were found in comparison to MPNST only. EGFR expression was remarkably high in NF1 patients in their first decade of life. However, this result has to be interpreted with caution in view of the high number of young patients with MPNST in this age group. Vessel density correlated with tumor type. Vessel density increased significantly comparing benign nerve sheath tumors and MPNST (p<0.05).
Discussion/conclusion:
This study revealed the presence of factors and receptors involved in angiogenesis as a prerequisite for tumor development and maintenance of PNS in NF1. These factors are highly expressed in all tumors of this study. This study reveals these relevant factors in nerve sheath tumors and also described the significant increase of vessel density in MPNST compared to benign counterparts. Anti-angiogenic drugs are presently investigated for application in NF1 tumor treatment, in particular for patients with a surgically-intractable high tumor burden. Drugs capable of blocking the EGFR receptor-mediated pathway are promising tools within the pharmacological repertoires to treat these patients.
