Nf1 haploinsufficiency augments angiogenesis

Wu, Min; Wallace, Margaret R.; Muir, David

doi:10.1038/sj.onc.1209264

Cited by 53 publications

(45 citation statements)

References 31 publications

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“…48 In addition, the highly vascular nature of plexiform neurofibromas is thought to be the result of hyperactive Rasdependent increases in angiogenesis found in Nf1 ϩ/Ϫ endothelial cells. 49,50 If molecular therapeutics designed for correcting hyperactive pathways in Nf1 ϩ/Ϫ cells located in the tumor microenvironment are developed, plexiform neurofibroma formation may be delayed or even prevented. For example, in recently submitted studies using the Krox20Cre;Nf1 flox/Ϫ murine tumor model, we have effectively used the small molecule imatinib (which inhibits c-kit and other RTKs) to reduce plexiform neurofibroma mass and significantly extend survival.…”

Section: Discussionmentioning

confidence: 99%

Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/− mast cells

McDaniel¹,

Allen

Park

et al. 2008

Blood

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Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutations in the NF1 locus, which encodes neurofibromin, a negative regulator of Ras. Patients with NF1 develop numerous neurofibromas, which contain many inflammatory mast cells that contribute to tumor formation. Subsequent to c-Kit stimulation, signaling from Ras to Rac1/2 to the MAPK pathway appears to be responsible for multiple hyperactive mast cell phenotypes; however, the specific effectors that mediate these functions remain uncertain. p21-activated kinase 1 (Pak1) is a downstream mediator of Rac1/2 that has been implicated as a positive regulator of MAPK pathway members and is a modulator of cell growth and cytoskeletal dynamics. Using an intercross of Pak 1 Ϫ/Ϫ mice with Nf1 ϩ/Ϫ mice, we determined that Pak1 regulates hyperactive Ras-dependent proliferation via a Pak1/ Erk pathway, whereas a Pak1/p38 pathway is required for the increased migration in Nf1 ϩ/Ϫ mast cells. Furthermore, we confirmed that loss of Pak1 corrects the dermal accumulation of Nf1 ϩ/Ϫ mast cells in vivo to levels found in wild-type mice. Thus, Pak1 is a novel mast cell mediator that functions as a key node in the MAPK signaling network and potential therapeutic target in NF1 patients. (Blood. 2008; 112:4646-4654) IntroductionMutations at the NF1 locus cause neurofibromatosis type 1 (NF1), a common human genetic disorder that affects approximately 1 in 3500 live births. 1 The NF1 gene encodes neurofibromin, a tumor suppressor that functions at least in part as a GTPase-activating protein (GAP) for p21 ras (Ras) 2 and accelerates the hydrolysis of active Ras-GTP to inactive NF1 is characterized by the development of tumors called neurofibromas, 4 which are composed of Schwann cells, fibroblasts, endothelial cells, and large numbers of degranulating mast cells. 5 Previous work in a genetically engineered murine model of NF1 that closely recapitulates the spontaneous tumor progression observed in patients has established that nullizygosity of Nf1 in tumorigenic Schwann cells is necessary but not sufficient for plexiform neurofibroma formation. 6 Furthermore, haploinsufficiency of Nf1 in at least a subset of lineages within the tumor microenvironment is required to promote neurofibroma development. 6 Besides mediating innate immune responses and allergic hypersensitivity, there is an emerging understanding that mast cells in the tumor microenvironment have relevance in the promotion of neoplastic development in multiple murine disease models. [7][8][9][10][11][12] We have previously shown that bone marrow-derived mast cells (BMMCs) haploinsufficient at Nf1 have hyperactivated Ras-GTP, as well as increases in Ras-dependent functions such as proliferation and migration after stem cell factor (SCF) stimulation. 13 Previous work has established that the excess proliferation in Nf1 ϩ/Ϫ BMMCs is the result of Ras activation of the class1A-PI-3 kinase (PI-3K) pathway. 14 Genetic and pharmacologic blockade of PI-3K activity in Nf1 ϩ/Ϫ cells leads to reduction of phosp...

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Section: Discussionmentioning

confidence: 99%

Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/− mast cells

McDaniel¹,

Allen

Park

et al. 2008

Blood

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“…Ras is believed to serve as an essential component of intracellular signalling downstream from endothelial receptor tyrosine kinases. Previous studies using knockout mice have revealed that the regulators for Ras GTPases and Ras effectors -Nf1, p120 Ras-GAP (also known as Rasa1), Rasip1 and Braf -play important roles in normal blood vessel development (Henkemeyer et al, 1995;Wojnowski et al, 1997;Wu et al, 2006;Xu et al, 2009). In addition, mice homozygous for a mutated Pi3kca gene encoding the catalytic p110a isoform of PI3 kinase that does not interact with Ras exhibit lymphatic vessel hypoplasia (Gupta et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice

2010

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SUMMARYMammalian Ras, which is encoded by three independent genes, has been thought to be a versatile component of intracellular signalling. However, when, where and how Ras signalling plays essential roles in development and whether the three Ras genes have overlapping functions in particular cells remain unclear. Here, we show that the three Ras proteins dose-dependently regulate lymphatic vessel growth in mice. We find that lymphatic vessel hypoplasia is a common phenotype in Ras compound knockout mice and that overexpressed normal Ras in an endothelial cell lineage selectively causes lymphatic vessel hyperplasia in vivo. Overexpression of normal Ras in lymphatic endothelial cells leads to sustained MAPK activation, cellular viability and enhanced endothelial network formation under serum-depleted culture conditions in vitro, and knockdown of endogenous Ras in lymphatic endothelial cells impairs cell proliferation, MAPK activation, cell migration and endothelial network formation. Ras overexpression and knockdown result in up-and downregulation of vascular endothelial growth factor receptor (VEGFR) 3 expression, respectively, in lymphatic endothelial cells in vitro. The close link between Ras and VEGFR3 in vitro is consistent with the result that Ras knockout and transgenic alleles are genetic modifiers in lymphatic vessel hypoplasia caused by Vegfr3 haploinsufficiency. Our findings demonstrate a cooperative function of the three Ras proteins in normal development, and also provide a novel aspect of VEGFR3 signalling modulated by Ras in lymphangiogenesis.

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“…These findings indicate that Nf1 heterozygous endothelial cells have an exaggerated mitogenic response. These findings were described in detail in a published report (Wu et al, 2006;appended). In addition proliferation response, we also tested the effects of pro-angiogenic factors on endothelial cell migration in vitro.…”

Section: Body Technical Objective 1: Examine the Response Of Nf1 Endomentioning

confidence: 80%

MicroRNA Inhibitors as Anticancer Therapies

Hammond¹

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) REPORT DATE (DD-MM-YYYY) 01-04-2007 REPORT TYPE Revised Final DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUniversity of Florida Gainesville, FL 32610 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe goal of this project is to specify how anti-angiogenic approaches can be effectively applied to NF1 tumors. Invivo and in vitro models were used to firmly conclude that Nf1 haploinsufficiency in endothelial cells results inexaggerated proliferation and angiogenesis in response to key pro-angiogenic factors. Results implicate these growthfactor pathways as potential targets for therapeutic agents. In addition, endostatin was found to be a potent inhibitorof Nf1+/-endothelial cell migration in vitro, suggesting endostatin may be an effective antiangiogenic agent forreducing NF1 tumor growth. Two intraneural xenograft models of NF1 peripheral nerve sheath tumors weredeveloped and characterized. Tumor growth and vascularity of NF1 tumor xenografts was quantified by advancedMRI, gadolinium permeability and dynamic contrast enhancement that match results obtained by conventionalhistological measurements. Several methods to deliver endostatin in vivo were tested and several difficulties wereencountered. Finally, cell factories made by alginate-encapsulation of 293 cells transfected with AAV-endostatinwere developed and are being refined to deliver consistent, high-dose systemic levels of endostatin. The effects ofsystemic endostatin on NF1 xenograft tumor growth will be completed in a no-cost extension of this project. SUBJECT TERMSCancer biology, angiogenesis, xenograft, gene therapy, anti-angiogenic therapy, MRI INTRODUCTIONNeurofibromatosis type 1 (NF1) is a common genetic disease with a wide variety of features which primarily involve the nervous system and related tissues. NF...

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Nf1 haploinsufficiency augments angiogenesis

Cited by 53 publications

References 31 publications

Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/− mast cells

Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/− mast cells

H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice

MicroRNA Inhibitors as Anticancer Therapies

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