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Abbasi, Nooshin (2015) Searching for molecular mechanisms sustaining tumor formation and progression in Neurofibromatosis type 1. [Tesi di dottorato]

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Abstract (inglese)

Neurofibromatosis type 1 (NF1, OMIM # 162200), also known as von Recklinghausen, is an autosomal dominant disease caused by mutations of the NF1 gene coding a 2818 amino acid protein, neurofibromin (Nf1). More than 900 different mutations in the NF1 gene have been identified (HGMD, Human Genetic Mutation Database). Mutations of NF1 gene cause a variety of clinical manifestations such as the optic gliomas, neoplasms of the haematopoietic system and learning disabilities. However, the hallmark of NF1 is the development of multiple benign peripheral nerve sheath tumors called neurofibromas. Neurofibromas are complex tumors arising from peripheral nerve sheaths and mainly composed of Schwann Cells (SCs) homozygous for mutated NF1, mast cells (MCs) and fibroblasts (FBRs) both heterozygous for the same mutation. The plexiform variety can progress to highly malignant sarcomas termed Malignant Peripheral Nerve Sheath Tumors (MPNSTs), which are almost invariably lethal.
Up to now, any effective therapy able to either reduces neurofibroma size and its incidence or to counteract its formation, has not been developed yet. The main feature of neurofibroma is a rigid structure due to massive deposition of collagen of different types by activated FBRs. These cells, named myofibroblasts (mFBRs), are massively stimulated by mast cell-secreting Transcription Growth Factor-Beta (TGF-Beta) to produce growth factors such as Platelet Growth Factor (PDGF), Fibroblast Growth Factor (FGF) and collagen. This leads to both potent SCs proliferation and deposition of rigid extracellular matrix (ECM).
Cells’ haploinsufficient for Nf1 display hyper-activation of Rat Sarcoma (Ras), which further increases when Loss of Heterozigozyty (LOH) of NF1 occurs. Thus, the activation of Ras/ Rapidly Accelerated Fibrosarcoma (Raf) /Extracellular signal-regulated Kinase (ERK) signaling in SCs is sufficient to make them more susceptible to proliferative signals provided by a NF1+/- niche. However, the physiological response to Ras hyper-activation is cell-cycle arrest and/or senescence rather than transformation. Ras-mediated transformation of SCs probably relies on a step-wise process that integrates circuits of amplification signals from the local niche. A major component of the niche is the ECM, a complex network of macromolecules whose the elasticity (ranging from soft to stiff and rigid),contributes to development and cancer. ECM elasticity determines how a cell senses and perceives external forces and thus provides a major environmental cue that determines cell behavior. Indeed, the focal adhesion complex, which consists of integrins, multicomplex of adaptors and signaling proteins, can be viewed as a mechanosensor linking the actomyosin cytoskeleton with the ECM. How lack of Nf1 may impact on the complexity of ECM-cell dynamic and how the great rigidity of the ECM in neurofibromas influences SCs’ behavior, is still unknown. Among the three functional domains described in the Nf1 protein, a Focal Adhesion Kinas (FAK) binding domain has been identified and Nf1 has been shown to interact with FAK, paving the way for the enunciation of new hypothesis aimed to explain the route of SCs transformation toward cancer.
Rational: as in other tumors {Lu, 2012 #289}, {Yu, 2011 #292}), also in the plexiform neurofibromas, the tumorigenic phenotype of SCs is fostered by the amplification of integrated signaling pathways triggered by loss of Nf1, Ras hyper activation and deregulated ECM. Changes of the mechanical properties of ECM due to increased collagen secretion by mFBRs might actively contribute to tumor progression by influencing gene expression profile of the cells through the enhancement of Ras signaling pathway triggered by FAK. The deep investigation of these biological changes triggered in SCs by ECM formation is the goal of the present project.
Project Goals: To shed light into this issue, we intend 1) to generate a novel three-dimensional experimental model in vitro reproducing the multicellular complexity of neurofibromas with primary cells. Immortalized cells, indeed, are not suitable for our aims since the molecular oncologists consider the immortalization process as the first hit leading to tumorigenic phenotype, because of the changes which made for cell cycle control in gene expression 2) to assess the requirement ECM for SCs transformation in this new in vitro system identifying the proper ECM composition and stiffness in matrigel (structural and non structural components) required for neurofibroma’s formation.
Isolation of primary SCs and FBRs from Neurofibromas and their biological characterization:
1) We have already isolated and cultured in 2D our SCs and FBRs NF1+/- according to Serra methodology {Serra, 2000 #210}. These cells have been isolated from plexiform neurofibroma biopsies after informed consent of patients by our Milan and Rome University collaborators.
To get two populations of SCs and FBRs we have cultured cells in selective Medium (according to {Serra, 2000 #210}, and our new unpublished protocol) and characterized them biochemically by: S100B {Tucker, 2011 #321} and p75 markers specifically recognizing SCs and collagen I secretion, alpha smooth muscle actin (α-SMA) expression, Smad2/3 activation, Abl kinase activation characterizing mFBR activity {Kojima, 2010 #150}.
2) We have already obtained colonies of SCs growing in 3D in vitro system as described in step 1 and 2 (in transwell-like chambers to permit autocrine stimulation between mFBRs and SCs). Our preliminary data show that primary SCs generate colonies only when plated in an ECM/reconstituted basement membrane Collagen I-Matrigel of at list 3 mg/ml. However, we have still to set up the culture conditions to keep cells in highly proliferating state.
Preliminary indications in immortalized Mouse Embrionic Fibroblasts (MEFs)
In other cellular models as in mouse FBRs NF1-/-, we have found that the absence of Neurofibromin correlates with deregulation of FAK Y397 and Y925 phosphorylation both in absence of integrin clustering and after ligand stimulation. Further, the tumorigenesis assay showed that MEFNF1-/-ability to form colonies is affected by both MECK inhibitor and FAK inhibitor (Y15) indicating the cooperative role of FAK and PDGFBB growth factor in the tumorigenesis process mediated by Nf1. Consistently, immunoprecipitation experiments showed that in Nf1 null cells, Growth factor receptor-bound protein2 (Grb-2), the RAS pathway initiator, interacts with FAK also in absence of collagen in a PDGFBB ligand-dependent way, thus suggesting that FAK and growth factor receptors can cooperate to increase the Ras activity to a threshold required to induce tumorigenesis.

Abstract (italiano)

Neurofibromatosi tipo 1 (NF1, OMIM # 162200), nota anche come di von Recklinghausen, è una malattia autosomica dominante causata da mutazioni del gene NF1 che codifica una proteina coi 2818 aminoacidi , detta neurofibromina (Nf). Più di 900 diverse mutazioni nel gene NF1 sono state identificate (HGMD, Database di mutazione genetica umana). Mutazioni del gene NF1 causano una varietà di manifestazioni cliniche quali il glioma ottico, neoplasie del sistema ematopoietico e disabilità dell'apprendimento. Tuttavia, il segno distintivo della NF1 è lo sviluppo dei tumori benigni nella guaina dei nervi periferici, chiamati neurofibromi. I neurofibromi sono tumori complessi originati da guaine nervose periferiche e costituiti prevalentemente da cellule di Schwann omozigote mutate per NF1, mastociti e fibroblasti entrambi eterozigoti per la stessa mutazione. I plessiformi possono progredire a sarcomi altamente maligni denominati MPNSTs (schwannomi maligni), che sono quasi sempre letali.
Ad oggi non e’ ancora stata sviluppata alcuna terapia efficace in grado di ridurre la dimensione e incidenza dei neurofibromi, o atta a contrastarne la formazione. La caratteristica principale dei neurofibromi è la loro struttura rigida conseguente alla massiccia deposizione di collagene prodotto dai fibroblasti attivati. Queste cellule, denominate miofibroblasti, sono fortemente stimolate da mastociti che producono fattore di crescita trascrizionale-Beta (TGF-Beta) per produrre poi fattori di crescita, come fattore di crescita piastrinico, fattore di crescita dei fibroblasti e collagene. Ciò comporta sia la potente proliferazione di cellule di Schwann che la deposizione di matrice extracellulare rigida.
Cellule aploinsufficienti per Nf1 comportano iperattivazione di Ras, che aumenta ulteriormente con LOH. L'attivazione di vie di segnale di Ras/Raf/ERK in cellule di Schwann rende le cellule più suscettibili ai segnali proliferativi forniti dalla nicchia NF1+/-. Tuttavia, la risposta fisiologica a Ras iperattivato è l’arresto del ciclo cellulare e/o senescenza piuttosto che trasformazione. La trasformazione Ras-mediata di cellule di Schwann probabilmente si basa su un procedimento che integra diversi segnali dipendenti da circuiti di amplificazione della nicchia stessa. Uno dei più importanti componenti della nicchia è la matrice extracellulare (ECM), una rete complessa di macromolecole con plasticità variabile che contribuisce alla progressione tumorale. L’elasticità di ECM determina la modalità con cui una cellula percepisce le forze esterne e quindi fornisce un importante spunto ambientale che determina il comportamento cellulare. In effetti le adesioni focali, che consistono di integrine, adattatori multicomplesi e proteine di segnale, possono essere visti come meccano-sensori che collegano il citoscheletro con la ECM. Come la mancanza di Nf1 possa avere un impatto significativo sulla complessità di dinamismo di ECM-cellula o come la grande rigidezza dell'ECM in neurofibroma influenzi il comportamento delle cellule di Schwann, è ancora sconosciuto. Tra i tre domini funzionali descritti nella proteina, un dominio di legame, FAK, sulla proteina è stato identificato e Nf1 ha mostrato di interagire con FAK, spianando la strada per l'enunciazione di una nuova ipotesi per spiegare il percorso trasformazionale delle cellule di Schwann verso il cancro.
Razionale: come in altri tumori {Lu, 2012 #289}, {Yu, 2011 #292}), anche nei neurofibromi plessiformi il fenotipo trasformato di SCs è favorito dall'amplificazione della segnalazione di percorsi integrati attivati sia da perdita di Nf1, Ras iperattivazione che deregolamentato di matrice extracellulare (ECM). Le modifiche delle proprietà meccaniche di ECM a causa dell'aumento di secrezione di collagene dai miofibroblasti potrebbe contribuire attivamente alla progressione del tumore, influenzando profili di espressione genica delle cellule attraverso la valorizzazione di segnale di Ras pathway generato dall'adesione focale (FAK). L'indagine in profondità di queste modificazioni biologiche attivate in SCs dalla formazione di ECM è l'obiettivo del presente progetto.
Al fine di far luce su questo argomento, abbiamo intenzione di 1) generare un nuovo modello sperimentale tridimensionale in vitro che riproduce la complessità di neurofibroma pluricellulari con le cellule primarie. Cellule immortalizzate, infatti, non sono adatte per i nostri scopi poiché gli oncologi molecolari consideranno il processo di immortalizzazione come il primo colpo che conduce al fenotipo oncogenico, a causa dei cambiamenti che sono stati fatti per il controllo del ciclo cellulare di espressione genica; 2) valutare l'esigenza di ECM nella trasformazione di cellule di Schwann cell (SCs) in questo nuovo sistema in vitro identificando la corretta composizione dell'ECM e rigidità in matrigel (strutturali e non strutturali) per formazione di neurofibroma.
Isolamento delle cellule di Schwann e Fibroblasti primarie da Neurofibromi e la loro caratterizzazione biologica:
1) Abbiamo già isolato e coltivato in 2D le nostre cellule di Schwann e Fibroblasti NF1+/- secondo la metodologia di Serra {Serra, 2000 #210}. Queste cellule sono state isolate da biopsie di neurofibromi plessiformi dopo aver consenso informato dei pazienti mediante i nostri collaboratori presso Università di Milano e di Roma.
Per ottenere due popolazioni delle cellule di Schwann e Fibroblasti abbiamo coltivato le cellule in terreno selettivo (secondo {Serra, 2000 #210}, e il nostro nuovo protocollo inedito) e caratterizzato dal punto di vista biochimico: S100B {Tucker, 2011 #321} e p75 marcatori che riconoscono specificamente le cellule di Schwann e secrezione del collagene di tipo I, espressione dell’actìna alfa del muscolo liscio (α-SMA), attivazione di Smad2/3, attivazione di abl chinasi e caratterizzare l'attività di myo-fibroblasti {Kojima, 2010 #150}.
2) abbiamo già ottenuto le colonie di cellule di Schwann cresciute nel sistema 3D in vitro come descritto nella fase 1 e 2 (in transwell-like chamber per permettere la stimolazione autocrina tra myofibroblasti e le cellule di Schwann). I nostri dati preliminari mostrano che le cellule primarie di Schwann generano delle colonie solo quando piastrate in una ECM/ membrana basale ricostituita del collagene di tipo I di Matrigel di almeno 3 mg/ml. Tuttavia, dobbiamo ancora impostare le condizioni migliori di cultura per mantenere le cellule altamente proliferanti.
Indicazioni preliminari in fibroblasti Embrionali immortalati Murini (MEFs)
In altri modelli cellulari come nel fibroblasti NF1-/- murini (MEFs), abbiamo trovato che l'assenza di neurofibromina scorrela con la deregolata di fosforilazione del FAK in Y397 e Y925 sia in assenza di raggruppamento di integrine che dopo la stimolazione con ligando. Inoltre, il saggio di tumorigenesi mostrava che la capacità di cellule di MEFNf1-/- di formare colonie è influenzata sia da inibitore di MECK che inibitore FAK Y15 indicante il ruolo di cooperatzione di FAK e PDGFBB, fattore di crescita, nel processo di tumorigenesi mediato da NF1. Coerentemente, gli esperimenti di immunoprecipitazione hanno mostrato che in cellule null NF1, il recettore del fattore di crescita di proteina legata2 (Grb-2), l’iniziatore di via di segnale di RAS, interagisce con FAK anche in assenza di collagene in un modo PDGFBB ligando-dipendente, suggerendo così che FAK e recettori di fattori di crescita possono cooperare per aumentare l'attività di Ras con un valore di soglia necessario per indurre la tumorigenesi.

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Tipo di EPrint:Tesi di dottorato
Relatore:Trevisan, Andrea - Chiara, Federica
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > BIOMEDICINA > MEDICINA MOLECOLARE
Data di deposito della tesi:20 Gennaio 2016
Anno di Pubblicazione:20 Gennaio 2015
Parole chiave (italiano / inglese):Neurofibromatosis type 1 (NF1), Extra Cellular Matrix (ECM), Focal Adhesion Kinase (FAK), Schwann Cells (SCs), Fibroblasts (FBRs), myoFibroblasts (mFBRs), Collagne I
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:9048
Depositato il:21 Ott 2016 09:53
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REFERENCES Cerca con Google

 A.O., Cancelas, J.A., and Ratner, N. (2008). Plexiform and dermal neurofibromas Cerca con Google

 Aragona M1, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo SCell. 2013 Aug 29;154(5):1047-59. doi: 10.1016/j.cell.2013.07.042. Epub 2013 Aug 15.A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors.Aragona M et al, 2013 Cerca con Google

 Aravind L, Neuwald AF, Ponting CP. Curr Biol. 1999 Mar 25;9(6):R195-7.Sec14p-like domains in NF1 and Dbl-like proteins indicate lipid regulation of Ras and Rho signaling. Cerca con Google

 Ballester R1, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F. Cell. 1990 Nov 16;63(4):851-9.The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cerca con Google

 Bernards A: Neurofibromatosis type 1 and Ras-mediated signaling: filling in the GAPs. Biochim Biophys Acta 1242:43– 59, 1995 Cerca con Google

 Bhola P, Banerjee S, Mukherjee J, Balasubramanium A, Arun V, Karim Z, et al: Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft. Int J Cancer [epub ahead of print], 2009 Cerca con Google

 Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P, et al: Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 12:144–148, 1996 Cerca con Google

 Brannan CI1, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, Buchberg AM, Jenkins NA, Parada LF, Copeland NG. Genes Dev. 1994 May 1;8(9):1019-29.Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Brannan et al., 1994 Cerca con Google

 Brems H, Beert E, de Ravel T, Legius E.Lancet Oncol. 2009 May;10(5):508-15. doi: 10.1016/S1470-2045(09)70033-6. Review.PMID:19410195[PubMed - indexed for MEDLINE]Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Cerca con Google

 Brossier NM1, Carroll SL. Brain Res Bull. 2012 May 1;88(1):58-71. doi: 10.1016/j.brainresbull.2011.08.005. Epub 2011 Aug 10.Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system.Brossier and Carroll, 2012 Cerca con Google

 Butcher DT, Alliston T, Weaver VM.Nat Rev Cancer. 2009 Feb;9(2):108-22. doi:10.1038/nrc2544. Review. A tense situation: forcing tumour progression. Cerca con Google

 Carroll SL1, Ratner N. Glia. 2008 Nov 1;56(14):1590-605. doi: 10.1002/glia.20776.How does the Schwann cell lineage form tumors in NF1? Carroll SL, Ratner N. Glia 2008; 56: 1590–605 Cerca con Google

 Chan, J.R. et al. (2006) The polarity protein Par-3 directly interacts with p75NTR to regulate myelination. Science 314, 832–836 Cerca con Google

 Chen, S. et al. (2003) Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nat. Neurosci. 6, 1186–1193 Cerca con Google

 Chen, Z.L. et al. (2007) Peripheral regeneration. Annu. Rev. Neurosci. 30, 209–233 Cerca con Google

 Chernousov MA1, Yu WM, Chen ZL, Carey DJ, Strickland S. Glia. 2008 Nov 1;56(14):1498-507. doi: 10.1002/glia.20740.Regulation of Schwann cell function by the extracellular matrix. Michael A. Cherousov et al,GLIA 56:1498–1507 (2008)) Cerca con Google

 Cichowski K1, Jacks T Cell. 2001 Feb 23;104(4):593-604.NF1 tumor suppressor gene function: narrowing the GAP. Cichowski K and Jacks T, 2001 Cerca con Google

 Cichowski K1, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME, Bronson RT, Jacks T. Science. 1999 Dec 10;286(5447):2172-6.Mouse models of tumor development in neurofibromatosis type 1. Cerca con Google

 Clementi M1, Barbujani G, Turolla L, Tenconi R. Hum Genet. 1990 Jan;84(2):116-8 Neurofibromatosis-1: a maximum likelihood estimation of mutation rate Cerca con Google

 Corfas, G. et al. (2004) Mechanisms and roles of axon-Schwann cellinteractions. J. Neurosci. 24, 9250–9260. Cerca con Google

 Cutts BA, Sjogren AK, Andersson KM, Wahlstrom AM, Karlsson C, Swolin B, Bergo MO.Wallenberg Laboratory, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.Blood. 2009 Oct 22;114(17):3629-32. doi: 10.1182/blood-2009-02-205146. Epub 2009 Aug 26.Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice. Cerca con Google

 Daston MM1, Scrable H, Nordlund M, Sturbaum AK, Nissen LM, Ratner N. Neuron. 1992 Mar;8(3):415-28.The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Daston et al., 1992 Cerca con Google

 De Luca, A. et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum. Mutat. 23, 629 (2004)). Cerca con Google

 Denayer E, de Ravel T, Legius E: Clinical and molecular aspects of RAS related disorders. J Med Genet 45:695–703, 2008 Cerca con Google

Differ. 6, 315-323. Cerca con Google

 Dilworth JT1, Kraniak JM, Wojtkowiak JW, Gibbs RA, Borch RF, Tainsky MA, Reiners JJ Jr, Mattingly RR. Biochem Pharmacol. 2006 Nov 30;72(11):1485-92. Epub 2006 Apr 28.Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Dilworth et al., 2006). Cerca con Google

 Downward J: Ras signalling and apoptosis. Curr Opin Genet Dev 8:49–54, 1998 Cerca con Google

 Ehninger D, de Vries PJ, Silva AJ: From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis. J Intellect Disabil Res 53:838–851, 2009 Cerca con Google

 Encinas, J.A. et al. (1999) Cloning, expression, and genetic mapping of SemaW, a member of the semaphorin family. Proc. Natl. Acad. Sci. U. S. A. 96, 2491–2496. Cerca con Google

 Evans, D. G. et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am. J. Med. Genet. A 152A, 327–332 (2010)) Cerca con Google

 Fawcett, J.W. and Keynes, R.J. (1990) Peripheral nerve regeneration. Annu. Rev. Neurosci. 13, 43–60 Cerca con Google

 Feng Chun-Yang DOI 10.1016/j.cell.2008.08.041).Cell. 2008 Oct 31;135(3):437-48. doi: 10.1016/j.cell.2008.08.041. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cerca con Google

 Feng-Chun Yang et al, Dermatology 2000;201:10–14 Cerca con Google

 Feng-Chun Yang et al. Human Molecular Genetics, 2006, Vol. 15, No. 16 2421–2437, doi:10.1093/hmg/ddl165)Hum Mol Genet. 2006 Aug 15;15(16):2421-37. Epub 2006 Jul 11. Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling.. Cerca con Google

 Firszt R1, Francisco D, Church TD, Thomas JM, Ingram JL, Kraft M. Eur Respir J. 2014 Feb;43(2):464-73. doi: 10.1183/09031936.00068712. Epub 2013 May 16.Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma.Firszt, R., Eur.Respir.J.43,464–473 Cerca con Google

 Fricker FR1, Bennett DL. Future Neurol. 2011 Nov;6(6):809-822.The role of neuregulin-1 in the response to nerve injury. Fricker and Bennett, Future Neurol 2011;6:809–82;) Cerca con Google

 Gavrilovic J, Brennan A, Mirsky R, Jessen KR: Fibroblast growth factors and insulin growth factors combine to promote survival of rat Schwann cell precursors without induction of DNA synthesis. Eur J Neurosci 7:77–85, 1995 Cerca con Google

 Gomez-Sanchez JA, et al.. tumorigenesis. J Neurosci 2009; 29: 11304–15J Neurosci. 2009 Sep 9;29(36):11304-15. doi: 10.1523/JNEUROSCI.1753-09.2009.Sustained axon-glial signaling induces Schwann cell hyperproliferation, Remak bundle myelination, and tumorigenesis. Cerca con Google

 Gomez-Sanchez JA1, Gomis-Coloma C, Morenilla-Palao C, Peiro G, Serra E, Serrano M, Cabedo H. Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge. Brain. 2013 Jul;136(Pt 7):2262-78. doi: 10.1093/brain/awt130. Epub 2013 Jun 6. Cerca con Google

 Gottfried ON1, Viskochil DH, Couldwell WT Neurosurg Focus. 2010 Jan;28(1):E8. doi: 10.3171/2009.11.FOCUS09221.Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications. Gottfried, 2010 Cerca con Google

 Gottfried ON1, Viskochil DH, Fults DW, Couldwell WT. Neurosurgery. 2006 Jan;58(1):1-16; discussion 1-16.Molecular, genetic, and cellular pathogenesis of neurofibromas and surgical implications. Gottfried et al., 2006 Cerca con Google

 Grove M1, Komiyama NH, Nave KA, Grant SG, Sherman DL, Brophy PJ. J Cell Biol. 2007 Jan 29;176(3):277-82. Epub 2007 Jan 22. FAK is required for axonal sorting by Schwann cells. Cerca con Google

 Gutmann DH1, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. JAMA. 1997 Jul 2;278(1):51-7.The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Gutmann et al., 1997 Cerca con Google

 Gutmann DH1, Geist RT, Wright DE, Snider WD. Cell Growth Differ. 1995 Mar;6(3):315-23. Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues.Cell Growth Neurosurgery 58, 1-16; discussion 1-16. Cerca con Google

 Gutmann DH1, Wood DL, Collins FS Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9658-62.Identification of the neurofibromatosis type 1 gene product. Gutmann et al., 1991  Hahn SA, Hoque AT, Moskaluk CA, da Costa LT, Schutte M, Rozenblum E, Seymour AB, Weinstein CL, Yeo CJ, Hruban RH, Kern SE.Cancer Res. 1996 Feb 1;56(3):490-4.Homozygous deletion map at 18q21.1 in pancreatic cancer. Cerca con Google

 Harrisingh MC1, Lloyd ACCell Cycle. 2004 Oct;3(10):1255-8. Epub 2004 Oct 17.Ras/Raf/ERK signalling and NF1.Harrisingh MC and Lloyd AC, 2004 Cerca con Google

 Hersh JH; American Academy of Pediatrics Committee on Genetics. Pediatrics. 2008 Mar;121(3):633-42. doi: 10.1542/peds.2007-3364.Health supervision for children with neurofibromatosis. Cerca con Google

 Hewett SJ1, Choi DW, Gutmann DH. Neuroreport. 1995 Jul 31;6(11):1565-8.Expression of the neurofibromatosis 1 (NF1) gene in reactive astrocytes in vitro. Gutmann et al., 1995 Cerca con Google

 Hiatt KK, Ingram DA, Zhang Y, Bollag G, Clapp DW. J Biol Chem. 2001 Mar 9;276(10):7240-5. Epub 2000 Nov 15. Neurofibromin GTPase-activating protein-related domains restore normal growth in Nf1-/- cells. Hiatt et al., 2001 Cerca con Google

 Hirata, K. and Kawabuchi, M. (2002) Myelin phagocytosis by macrophages and nonmacrophages during Wallerian degeneration. Microsc. Res. Tech. 57, 541–547. Cerca con Google

 Huang J, Wu S, Wu CL, Manning BD: Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res 69:6107–6114, 2009 Cerca con Google

 Hwang SL1, Lu Y2, Li X1, Kim YD1, Cho YS3, Jahng Y1, Son JK1, Lee YJ4, Kang W5, Taketomi Y6, Murakami M6, Moon TC7, Chang HW8. J Allergy Clin Immunol. 2014 Sep;134(3):714-721.e7. doi: 10.1016/j.jaci.2014.05.001. Epub 2014 Jun 17.ERK1/2 antagonize AMPK-dependent regulation of FcεRI-mediated mast cell activation and anaphylaxis. Seung-Lark Hwang, et al, J ALLERGY CLIN IMMUNOL, Vol. 134, 3, 2006) Cerca con Google

 Ingram JL1, Antao-Menezes A, Mangum JB, Lyght O, Lee PJ, Elias JA, Bonner JC. J Immunol. 2006 Sep 15;177(6):4141-8.Opposing actions of Stat1 and Stat6 on IL-13-induced up-regulation of early growth response-1 and platelet-derived growth factor ligands in pulmonary fibroblasts.Ingram J et al. J.Immunol.177,4141–4148;  Irby RB1, Yeatman TJ. Oncogene. 2000 Nov 20;19(49):5636-42.Role of Src expression and activation in human cancer. Cerca con Google

 Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA.Nat Genet. 1994 Jul;7(3):353-61 Tumour predisposition in mice heterozygous for a targeted mutation in Nf1.  Johannessen CM1, Reczek EE, James MF, Brems H, Legius E, Cichowski K. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8573-8. Epub 2005 Jun 3.The NF1 tumor suppressor critically regulates TSC2 and mTOR. Cerca con Google

 Joseph NM1, Mukouyama YS, Mosher JT, Jaegle M, Crone SA, Dormand EL, Lee KF, Meijer D, Anderson DJ, Morrison SJ. Development. 2004 Nov;131(22):5599-612. Epub 2004 Oct 20. Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. Cerca con Google

 Joseph, N.M., Mosher, J.T., Buchstaller, J., Snider, P., McKeever, P.E., Lim, M., Conway, SJ, Parada LF, Zhu Y, Morrison SJ. Cancer Cell. 2008 Feb;13(2):129-40. doi: 10.1016/j.ccr.2008.01.003. The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells.  Kalluri R, Zeisberg M.Nat Rev Cancer. 2006 May;6(5):392-401. Review.Fibroblasts in cancer. Cerca con Google

 Khalaf WF1, Yang FC, Chen S, White H, Bessler W, Ingram DA, Clapp DW. J Immunol. 2007 Feb 15;178(4):2527-34.K-ras is critical for modulating multiple c-kit-mediated cellular functions in wild-type and Nf1+/- mast cells. Khalaf WF et al, J Immunol. 2007 Feb 15;178(4):2527-34). Cerca con Google

 Kim et al., 1997Hum Genet. 1997 Jan;99(1):88-92. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene.  Koenig A, Mueller C, Hasel C, Adler G, Menke A.Cancer Res. 2006 May 1;66(9):4662-71Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. Cerca con Google

 Kojima Y, et al. (2010) Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proceedings of the National Academy of Sciences of the United States of America 107(46):20009-20014. Kojima, 2010 #150 Cerca con Google

 Kruger, R.P. et al. (2005) Semaphorins command cells to move. Nat. Rev. Mol. Cell Biol. 6, 789–800 Cerca con Google

 Kweh F1, Zheng M, Kurenova E, Wallace M, Golubovskaya V, Cance WG Mol Carcinog. 2009 Nov;48(11):1005-17. doi: 10.1002/mc.20552.Neurofibromin physically interacts with the N-terminal domain of focal adhesion kinase.Kweh F. et al, 2009 Cerca con Google

 Le and Parada, 2007.Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Cerca con Google

 Le et al., 2009 4, 453-463. Cerca con Google

 Le LQ1, Parada LF. Oncogene. 2007 Jul 12;26(32):4609-16. Epub 2007 Feb 12.Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Le LQ and Parada LF,2007 Cerca con Google

 Le, L.Q., Shipman, T., Burns, D.K., and Parada, L.F. (2009). Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cerca con Google

 Levental KR1, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM. Cell. 2009 Nov 25;139(5):891-906. doi: 10.1016/j.cell.2009.10.027.Matrix crosslinking forces tumor progression by enhancing integrin signaling. Levental KR, et al, 2009 Cerca con Google

 Levine, S. M., Levine, E., Taub, P. J. & Weinberg, H. Electrosurgical excision technique for the treatment of multiple cutaneous lesions in neurofibromatosis type I. J. Plast. Reconstr. Aesthet. Surg. 61, 958–962 (2008) Cerca con Google

 Lu P1, Weaver VM, Werb Z. J Cell Biol. 2012 Feb 20;196(4):395-406. doi: 10.1083/jcb.201102147. The extracellular matrix: a dynamic niche in cancer progression. Cerca con Google

 Mangoura D1, Sun Y, Li C, Singh D, Gutmann DH, Flores A, Ahmed M, Vallianatos G Oncogene. 2006 Feb 2;25(5):735-45.Phosphorylation of neurofibromin by PKC is a possible molecular switch in EGF receptor signaling in neural cells. Mangoura et al., 2006 Cerca con Google

 Mashour GA, Ratner N, Khan GA, Wang HL, Martuza RL, Kurtz A: The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells. Oncogene 20:97–105, 2001  Menke A, Philippi C, Vogelmann R, Seidel B, Lutz MP, Adler G, Wedlich D.Cancer Res. 2001 Apr 15;61(8):3508-17.Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cerca con Google

 Mi R, Ma J, Zhang D, Li L, Zhang H: Efficacy of combined inhibition of mTOR and ERK/MAPK pathways in treating a tuberous sclerosis complex cell model. J Genet Genomics 36:355–361, 2009 Cerca con Google

 Michailov, G.V. et al. (2004) Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703) microenvironment contribution for NF1-associated dermal neurofibromas. Cell. Stem Cell.  Miles FL, Sikes RA.Mol Cancer Res. 2014 Mar;12(3):297-312. doi: 10.1158/1541-7786.MCR-13-0535. Epub 2014 Jan 22. Review. Insidious changes in stromal matrix fuel cancer progression. Cerca con Google

 Mirsky R, Woodhoo A, Parkinson DB, Arthur-Farraj P, Bhaskaran A, Jessen KR. J Peripher Nerv Syst. 2008 Jun;13(2):122-35. doi: 10.1111/j.1529-8027.2008.00168.x. Review. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. Cerca con Google

 Mozaffari M, Hoogeveen-Westerveld M, Kwiatkowski D, Sampson J, Ekong R, Povey S, et al: Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex. BMC Med Genet 10:88, 2009 Cerca con Google

 Muir D, Neubauer D, Lim IT, Yachnis AT, Wallace MR: Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells. Am J Pathol 158:501–513, 2001 Cerca con Google

 Muir D: Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression. Clin Exp Metastasis 13:303–314, 1995 Cerca con Google

 Parrinello S, Lloyd AC.MRC Laboratory for Molecular Cell Biology and the UCL Cancer Institute, University College London, Gower Street, London WC1E 6BT, UK. Trends Cell Biol. 2009 Aug;19(8):395-403. doi: 10.1016/j.tcb.2009.05.003. Epub 2009 Jul 15.Neurofibroma development in NF1--insights into tumour initiation. Cerca con Google

 Parrinello S1, Noon LA, Harrisingh MC, Wingfield Digby P, Rosenberg LH, Cremona CA, Echave P, Flanagan AM, Parada LF, Lloyd AC. Genes Dev. 2008 Dec 1;22(23):3335-48. doi: 10.1101/gad.490608.NF1 loss disrupts Schwann cell-axonal interactions: a novel role for semaphorin 4F.Parrinello S et al.,2008 Cerca con Google

 Parrinello, S., and Lloyd, A.C. (2009). Neurofibroma development in NF1--insights into tumour initiation. Trends Cell Biol. 19, 395-403.  Pasca di Magliano M, Biankin AV, Heiser PW, Cano DA, Gutierrez PJ, Deramaudt T, Segara D, Dawson AC, Kench JG, Henshall SM, Sutherland RL, Dlugosz A, Rustgi AK, Hebrok M.PLoS One. 2007 Nov 7;2(11):e1155.Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. Cerca con Google

 Peter J. Amos*,1, Alexander M. Bailey*,1, Hulan Shang, Ph.D.2, Adam J. Katz, M.D.2, MichaelB. Lawrence, Ph.D.1, and Shayn M. Peirce, Ph.D Functional Binding of Human Adipose-Derived Stromal Cells:Effects of Extraction Method & Hypoxia Pretreatment..1 1Department of Biomedical Engineering University of Virginia PO Box 800759, Health System Charlottesville, VA 22908 2Department of Plastic and Reconstructive Surgery University of Virginia PO Box 800376 Charlottesville, VA 22908 Cerca con Google

 Poulikakos PI1, Xiao GH, Gallagher R, Jablonski S, Jhanwar SC, Testa JR. Oncogene. 2006 Sep 28;25(44):5960-8. Epub 2006 May 1. Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Cerca con Google

 Prada, C. E. et al. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J. Pediatr. 160, 461–467 (2012). Cerca con Google

 Rasmussen SA, Friedman JM.Am J Epidemiol. 2000 Jan 1;151(1):33-40. Review.PMID:10625171[PubMed - indexed for MEDLINE]).NF1 gene and neurofibromatosis 1. Cerca con Google

 Rasmussen, S. A., Yang, Q. & Friedman, J. M. Mortality in neurofibromatosis 1: an analysis using U. S. death certificates. Am. J. Hum. Genet. 68, 1110–1118 (2001)). Cerca con Google

 Ratner N, Lieberman MA, Riccardi VM, Hong DM: Mitogen accumulation in von Recklinghausen neurofibromatosis. Ann Neurol 27:298–303, 1990 Cerca con Google

 Riccardi, V.M. (1981) Cutaneous manifestation of neurofibromatosis: cellular interaction, pigmentation, and mast cells. Birth Defects Orig. Artic. Ser. 17, 129–145 . Cerca con Google

 Riccardi, V.M. (1992) Neurofibromatosis: Phenotype, Natural History and Pathogenesis. The John Hopkins University Press, (Baltimore and London) Cerca con Google

 Robert L (2014) Tumors perturbing extracellular matrix biosynthesis. The case of von Recklinghausen's disease. Pathologie-biologie 62(2):118-122. Robert, 2014 #300} Cerca con Google

 Rubin JB1, Gutmann DH Nat Rev Cancer. 2005 Jul;5(7):557-64.Neurofibromatosis type 1 - a model for nervous system tumour formation? Rubin, J.B. and Gutmann, D.H. 2005  Ruggeri B, Zhang SY, Caamano J, DiRado M, Flynn SD, Klein-Szanto AJ.Oncogene. 1992 Aug;7(8):1503-11.Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumor-suppressor genes. Cerca con Google

 Ruggieri M, Iannetti P, Clementi M, Polizzi A, Incorpora G, Spalice A, Pavone P, Praticò AD, Elia M, Gabriele AL, Tenconi R, Pavone L Neurofibromatosis type 1 and infantile spasms. Cerca con Google

 S.J., Parada, L.F., Zhu, Y., and Morrison, S.J. (2008). The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells.  Scarpa A, Capelli P, Mukai K, Zamboni G, Oda T, Iacono C, Hirohashi S.Am J Pathol. 1993 May;142(5):1534-43.Pancreatic adenocarcinomas frequently show p53 gene mutations. Cerca con Google

 Scherer, S. a.S., J. L. (2001) Axon-Schwann cell interactions during peripheral nerve degeneration and regeneration. Oxford: Oxford University Press Cerca con Google

 Serra E, et al. (2000) Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Human molecular genetics 9(20):3055-3064. Serra, 2000 #210 Cerca con Google

 Shin YK1, Jang SY, Park JY, Park SY, Lee HJ, Suh DJ, Park HT. Glia. 2013 Jun;61(6):892-904. doi: 10.1002/glia.22482. Epub 2013 Mar 15.The Neuregulin-Rac-MKK7 pathway regulates antagonistic c-jun/Krox20 expression in Schwann cell dedifferentiation.Yoon Kyung Shin, GLIA 2013 Cerca con Google

 Staser K, Yang FC, Clapp DW. Curr Opin Hematol. 2010 Jul;17(4):287-93. doi: 10.1097/MOH.0b013e328339511b. Review. Plexiform neurofibroma genesis: questions of Nf1 gene dose and hyperactive mast cells. Cerca con Google

 Staser K1, Yang FC, Clapp DW. Blood. 2010 Jul 15;116(2):157-64. doi: 10.1182/blood-2009-09-242875. Epub 2010 Mar 16.Mast cells and the neurofibroma microenvironment. Karl Staser et al. Blood First Edition paper, March 16, 2010; DOI 10.1182/blood-2009-09-242875.). Cerca con Google

 Sternberg PW, Alberola-Ila J: Conspiracy theory: RAS and RAF do not act alone. Cell 95:447–450, 1998 Cerca con Google

 Stumpf, D. A. et al. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch. Neurol. 45, 575–578 (1987)).  Talamonti MS, Roh MS, Curley SA, Gallick GE. J Clin Invest. 1993 Jan;91(1):53-60. Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer.  Tatsuka M1, Ota T, Yamagishi N, Kashihara Y, Wada M, Matsuda N, Mitsui H, Seiki M, Odashima S. Mol Carcinog. 1996 Apr;15(4):300-8. Different metastatic potentials of ras- and src-transformed BALB/c 3T3 A31 variant cells. Cerca con Google

 Tidyman WE, Rauen KA: The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19:230–236, 2009  Tucker T1, Riccardi VM, Sutcliffe M, Vielkind J, Wechsler J, Wolkenstein P, Friedman JM J Histochem Cytochem. 2011 Jun;59(6):584-90. doi: 10.1369/0022155411407340. Epub 2011 Apr 27.Different patterns of mast cells distinguish diffuse from encapsulated neurofibromas in patients with neurofibromatosis 1. Cerca con Google

 Upadhyaya M, Osborn MJ, Maynard J, Kim MR, Tamanoi F, Cooper DN. Hum Genet. 1997 Jan;99(1):88-92. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Cerca con Google

 Vandenbroucke I, van Doorn R, Callens T, Cobben JM, Starink TM, Messiaen L. Hum Genet. 2004 Feb;114(3):284-90. Epub 2003 Nov 6. Genetic and clinical mosaicism in a patient with neurofibromatosis type 1. Cerca con Google

 Vandenbroucke I, Van Oostveldt P, Coene E, De Paepe A, Messiaen L. FEBS Lett. 2004 Feb 27;560(1-3):98-102. Neurofibromin is actively transported to the nucleus. Cerca con Google

 Viskochil DH: The structure and function of the NF1 gene: molecular pathophysiology, in Friedman JM, Gutmann DH, MacCollin M, Riccardi VM (eds): Neurofibromatosis: Phenotype, Natural History, and Pathogenesis, ed 3. Baltimore: Johns Hopkins University Press, 1999, pp 119–141 Cerca con Google

 Wallace MR1, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, et al. Science. 1990 Jul 13;249(4965):181-6 Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients Cerca con Google

 Wu et al., 2008105-116 Cerca con Google

 Wu J1, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA, Ratner N. Cancer Cell. 2008 Feb;13(2):105-16. doi: 10.1016/j.ccr.2007.12.027. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cerca con Google

 Wu, M. et al. (2005) Tumorigenic properties of neurofibromin-deficient Schwann cells in culture and as syngrafts in Nf1 knockout mice. J. Neurosci. Res. 82, 357–367 Cerca con Google

 Xu et al., 1990Cell. 1990 Nov 16;63(4):835-41. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cerca con Google

 Xu GF1, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R, Tamanoi F. Cell. 1990 Nov 16;63(4):835-41.The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cerca con Google

 Xu GF1, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R, et al. Cell. 1990 Aug 10;62(3):599-608.The neurofibromatosis type 1 gene encodes a protein related to GAP.Xu et al., 1990 Cerca con Google

 Yang FC, Chen S, Clegg T, Li X, Morgan T, Estwick SA, Yuan J, Khalaf W, Burgin S, Travers J, Parada LF, Ingram DA, Clapp DW. Hum Mol Genet. 2006 Aug 15;15(16):2421-37. Epub 2006 Jul 11. Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling. Cerca con Google

 Yang FC, Chen S, Robling AG, Yu X, Nebesio TD, Yan J, Morgan T, Li X, Yuan J, Hock J, Ingram DA, Clapp DW. J Clin Invest. 2006 Nov;116(11):2880-91. Epub 2006 Oct 19. Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. Cerca con Google

 Yang FC, Ingram DA, Chen S, Hingtgen CM, Ratner N, Monk KR, Clegg T, White H, Mead L, Wenning MJ, Williams DA, Kapur R, Atkinson SJ, Clapp DW. J Clin Invest. 2003 Dec;112(12):1851-61. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. Cerca con Google

 Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW. Cell. 2008 Oct 31;135(3):437-48. doi: 10.1016/j.cell.2008.08.041. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cerca con Google

 Yang FC1, Chen S, Clegg T, Li X, Morgan T, Estwick SA, Yuan J, Khalaf W, Burgin S, Travers J, Parada LF, Ingram DA, Clapp DW Hum Mol Genet. 2006 Aug 15;15(16):2421-37. Epub 2006 Jul 11.Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling. Cerca con Google

 Yu H, Mouw JK, & Weaver VM (2011) Forcing form and function: biomechanical regulation of tumor evolution. Trends in cell biology 21(1):47-56. Yu, 2011 #292 Cerca con Google

 Zheng et al., 2008formation. Cancer. Cell. 13, 117-128. Zheng H1, Chang L, Patel N, Yang J, Lowe L, Burns DK, Zhu Y. Cancer Cell. 2008 Feb;13(2):117-28. doi: 10.1016/j.ccr.2008.01.002. Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation. Cerca con Google

 Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF. Zhu, Y. et al. (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920–922 Cerca con Google

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