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Oncogene Apr 2022Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of... (Review)
Review
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.
Topics: Biology; Humans; Nerve Sheath Neoplasms; Neurofibromatosis 1; Neurofibrosarcoma; Sarcoma
PubMed: 35393544
DOI: 10.1038/s41388-022-02290-1 -
The Journal of Clinical Investigation Jan 2021Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral...
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulated their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.
Topics: Animals; Cell Line; Humans; Induced Pluripotent Stem Cells; Mice; Mice, Nude; Mice, Transgenic; Mutation; Neoplasms, Experimental; Neurofibroma; Neurofibromin 1
PubMed: 33108355
DOI: 10.1172/JCI139807 -
Neuro-oncology Nov 2022Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant... (Review)
Review
Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.
Topics: Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Nerve Sheath Neoplasms; Protein Kinase Inhibitors
PubMed: 35657359
DOI: 10.1093/neuonc/noac146 -
Cell Stem Cell Aug 2021NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve...
NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve plexiform neurofibromas that originate in the embryonic neural crest cell lineage. Using reporter transgenes that label early neural crest lineage cells in multiple NF1 MPNST mouse models, we discover and characterize a rare MPNST cell population with stem-cell-like properties, including quiescence, that is essential for tumor initiation and relapse. Following isolation of these cells, we derive a cancer-stem-cell-specific gene expression signature that includes consensus embryonic neural crest genes and identify Nestin as a marker for the MPNST cell of origin. Combined targeting of cancer stem cells along with antimitotic chemotherapy yields effective tumor inhibition and prolongs survival. Enrichment of the cancer stem cell signature in cognate human tumors supports the generality and relevance of cancer stem cells to MPNST therapy development.
Topics: Animals; Disease Models, Animal; Mice; Neoplasm Recurrence, Local; Neurofibromatosis 1; Neurofibrosarcoma
PubMed: 34010628
DOI: 10.1016/j.stem.2021.04.029 -
The Annals of Pharmacotherapy Jun 2022To evaluate the safety and efficacy of selumetinib, a novel MEK inhibitor, for the treatment of plexiform neurofibromas (PN) in patients with neurofibromatosis type 1... (Review)
Review
OBJECTIVE
To evaluate the safety and efficacy of selumetinib, a novel MEK inhibitor, for the treatment of plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1).
DATA SOURCES
An English-based literature search of PubMed, EMBASE, and ClinicalTrials.gov was conducted using the terms AND from inception to August 1, 2021.
STUDY SELECTION AND DATA EXTRACTION
Relevant prescribing information, abstracts, and articles identified through the search were considered for inclusion in this review.
DATA SYNTHESIS
The open-label, multicenter, single-arm, phase II SPRINT trial demonstrated clinically significant improvements in PN-related complications. Of 50 symptomatic patients, 68% experienced a partial response, with a median change in tumor volume of -27.9% from baseline. Estimated progression-free survival at 3 years was 84%. Additionally, clinically meaningful improvements were seen on patient- and parent-reported assessments evaluating pain, range of motion, disfigurement, and quality of life. Overall, the adverse effect profile for selumetinib appears mild and manageable.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Selumetinib is the first FDA-approved treatment for inoperable PN in patients with NF1, demonstrating that MEK inhibition is a promising therapeutic strategy. Studies are ongoing to assess the effect of selumetinib on other NF1-associated tumor types and to determine the optimal dosing schedule and treatment duration. Cost and treatment burden must be considered when selecting selumetinib therapy.
CONCLUSION
Selumetinib exhibits impressive antitumor activity and sustained clinical benefit in patients lacking other viable treatment options. Further studies are warranted to determine the optimal age of initiation, treatment duration, and overall cost-effectiveness of selumetinib.
Topics: Benzimidazoles; Humans; Mitogen-Activated Protein Kinase Kinases; Multicenter Studies as Topic; Neurofibroma, Plexiform; Neurofibromatosis 1; Quality of Life
PubMed: 34541874
DOI: 10.1177/10600280211046298 -
Pediatric Radiology Aug 2022Aneurysmal bone cyst (ABC) is a benign but locally aggressive lesion that predominantly affects children and young adults. ABC, which accounts for approximately 70% of... (Review)
Review
Aneurysmal bone cyst (ABC) is a benign but locally aggressive lesion that predominantly affects children and young adults. ABC, which accounts for approximately 70% of the cases, is now recognized to be a true neoplasm, whereas ABC-like changes associated to other bone neoplasms (also referred in the literature as secondary ABC) accounts for the remaining 30%. The solid variant of ABC is also considered a true neoplasm but is rare. ABC can involve any bone in the body, and although it has a metaphyseal preference, it can involve any part of a bone and soft tissues. As with any bone tumor, the initial evaluation of ABCs should be done with radiographs followed by magnetic resonance imaging or less frequently computed tomography for further characterization. The imaging appearance of ABC is variable; however, a lytic and expansile lesion with fluid-fluid levels is the most common presentation. The main differential diagnosis of an ABC in the pediatric population is unicameral bone cyst (UBC) and telangiectatic osteosarcoma, therefore a biopsy is recommended before treatment. The therapeutic options of ABC range from curettage with or without adjuncts such as phenol, liquid nitrogen, argon laser and bone grafting or bone substitutes to more recently employed alternatives such as image-guided sclerotherapy with various sclerosing agents and monoclonal antibodies (e.g., Denosumab).
Topics: Bone Cysts; Bone Cysts, Aneurysmal; Bone Neoplasms; Child; Humans; Osteosarcoma; Tomography, X-Ray Computed; Young Adult
PubMed: 35941207
DOI: 10.1007/s00247-022-05396-6 -
Ugeskrift For Laeger Jan 2024This case report presents a 69-year-old male patient with a subcutaneous tumour in the left parietal region. Initially, the tumour was identified as a lipoma or benign...
This case report presents a 69-year-old male patient with a subcutaneous tumour in the left parietal region. Initially, the tumour was identified as a lipoma or benign cyst by the general practitioner. However, a subsequent MRI scan revealed a sarcoma metastasis with a significant intracranial component. Radical excision of the tumour was not possible due to its critical localisation. Therefore, the patient received palliative radiotherapy. This case emphasises the importance of accurate clinical assessment and highlights the clinical features that should lead to suspicion of malignancy.
Topics: Male; Humans; Aged; Sarcoma; Lipoma; Soft Tissue Neoplasms; Magnetic Resonance Imaging; Cysts
PubMed: 38327198
DOI: 10.61409/V10230622 -
ELife Mar 2022Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated...
Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs, and mouse SCPs. Mouse SCP self-renewal was reduced by genetic or pharmacological inhibition of P2ry14. In a mouse model of NF1, genetic deletion of P2ry14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2ry14 signals via G to increase intracellular cAMP, implicating P2ry14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2ry14 inhibitor diminished -/- SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identify P2ry14 as a critical regulator of SCP self-renewal, SC proliferation, and neurofibroma initiation.
Topics: Animals; Cell Self Renewal; Cell Transformation, Neoplastic; Cyclic AMP; Disease Models, Animal; Mice; Neurofibroma; Neurofibromatosis 1; Neurofibromin 1; Receptors, Purinergic P2Y; Schwann Cells
PubMed: 35311647
DOI: 10.7554/eLife.73511 -
Cancer Jan 1980Case histories of 10 patients with neurofibrosarcoma, including 14 (70%) with neurofibromatosis, evaluated over 10 years were reviewed to determine the incidence of...
Case histories of 10 patients with neurofibrosarcoma, including 14 (70%) with neurofibromatosis, evaluated over 10 years were reviewed to determine the incidence of local and systemic recurrence and the most effective means of therapy for this rare neoplasm. Initial therapy resulted in complete local disease control in only 11 (55%) patients. Local excision, or local excision plus radiation or chemotherapy resulted in local recurrence in 8 of 12 patients. Radical surgery alone, or radical surgery combined with radiation and chemotherapy resulted in local recurrence in 1 of 6. Even with complete local disease control, 7 of 16 (44%) patients died of metastases. Both A.J.C. Clinical Stage II and III patients had a similar poor prognosis. Associated neurofibromatosis did not worsen prognosis. These data suggest that both moderate and high-grade primary neurofibrosarcoma are highly malignant neoplasms and should be treated by radical resection. Preoperative intraarterial Adriamycin and radiation--found to be successful for other highly malignant sarcomas--may be of benefit. Since distant disease occurs despite local control, postoperative adjuvant chemotherapy trials are warranted.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Neoplasm Recurrence, Local; Neurofibroma; Neurofibromatosis 1; Recurrence; Remission, Spontaneous; Time Factors
PubMed: 6766081
DOI: 10.1002/1097-0142(19800101)45:1<126::aid-cncr2820450122>3.0.co;2-u -
Trends in Cell Biology Aug 2009Dissecting the early steps of tumourigenesis is key to our understanding of cancer biology. However, lack of knowledge of initiating mutations and the target 'cell of... (Review)
Review
Dissecting the early steps of tumourigenesis is key to our understanding of cancer biology. However, lack of knowledge of initiating mutations and the target 'cell of origin' has slowed progress towards this goal. Genetically engineered mouse models of the tumour-predisposition syndrome neurofibromatosis type-1 provide a rare opportunity to study tumour initiation resulting from a known genetic change in a known cell type. Recent exciting work using these models now sheds more light onto early tumourigenesis. Here, we discuss the studies that have identified mature differentiated Schwann cells as the cell of origin and revealed the molecular and cellular mechanisms of neurofibroma initiation. A novel dual and opposing role for the microenvironment, from pro-differentiative to pro-carcinogenic, has emerged.
Topics: Animals; Cell Differentiation; Genetic Engineering; Humans; Models, Biological; Mutation; Neurofibroma; Neurofibromatosis 1
PubMed: 19615906
DOI: 10.1016/j.tcb.2009.05.003