Neuregulin-1 and ErbB4 Immunoreactivity is Associated with Neuritic Plaques in Alzheimer Disease Brain and in a Transgenic Model of Alzheimer Disease

Journal of Neuropathology and Experimental Neurology. Jan, 2003  |  Pubmed ID: 12528817

Neuregulin-1 (NRG-1) regulates developmental neuronal survival and synaptogenesis, astrocytic differentiation, and microglial activation. Given these NRG-1 actions, we hypothesized that the synaptic loss, gliosis, inflammation, and neuronal death occurring in Alzheimer disease (AD) is associated with altered expression of NRG-1 and its receptors (the erbB2, erbB3, and erbB4 membrane tyrosine kinases). We examined the expression and distribution of NRG-1 and the erbB kinases in the hippocampus of AD patients and cognitively normal controls and in transgenic mice that coexpress AD-associated mutations of the beta amyloid precursor protein (APP(K670N,M671L)) and presenilin-1 (PS1(M146L)). In the hippocampi of both control humans and wild type mice, NRG-1 and the 3 erbB receptors are expressed in distinct cellular compartments of hippocampal neurons. All 4 molecules are associated with neuronal cell bodies, but only NRG-1, erbB2, and erbB4 are present in synapse-rich regions. In AD and in the doubly transgenic mouse, erbB4 is expressed by reactive astrocytes and microglia surrounding neuritic plaques. In AD brains, microglia and, to a lesser extent, dystrophic neurites, also upregulate NRG-1 in neuritic plaques, suggesting that autocrine and/or paracrine interactions regulate NRG-1 action within these lesions. NRG-1 and erbB4, as well as erbB2, are similarly associated with neuritic plaques in the doubly transgenic mice. Thus, in AD the hippocampal distribution of NRG-1 and erbB4 is altered. The similarities between the alterations in the expression of NRG-1 and its receptors in human AD and in APP(K670N;M671L)/PS1(M146L) mutant mice suggests that this animal model may be very informative in deciphering the potential role of these molecules in AD.

The Antitumor Effects of IFN-alpha Are Abrogated in a STAT1-deficient Mouse

The Journal of Clinical Investigation. Jul, 2003  |  Pubmed ID: 12865406

IFN-alpha activates the signal transducer and activator of transcription (STAT) family of proteins; however, it is unknown whether IFN-alpha exerts its antitumor actions primarily through a direct effect on malignant cells or by stimulating the immune system. To investigate the contribution of STAT1 signaling within the tumor, we generated a STAT1-deficient melanoma cell line, AGS-1. We reconstituted STAT1 into AGS-1 cells by retroviral gene transfer. The resulting cell line (AGS-1STAT1) showed normal regulation of IFN-alpha-stimulated genes (e.g., H2k, ISG-54) as compared with AGS-1 cells infected with the empty vector (AGS-1MSCV). However, mice challenged with the AGS-1, AGS-1STAT1, and AGS-1MSCV cell lines exhibited nearly identical survival in response to IFN-alpha treatment, indicating that restored STAT1 signaling within the tumor did not augment the antitumor activity of IFN-alpha. In contrast, STAT1-/- mice could not utilize exogenous IFN-alpha to inhibit the growth of STAT1+/+ melanoma cells in either an intraperitoneal tumor model or in the adjuvant setting. The survival of tumor-bearing STAT1-/- mice was identical regardless of treatment (IFN-alpha or PBS). Additional cell depletion studies demonstrated that NK cells mediated the antitumor effects of IFN-alpha. Thus, STAT1-mediated gene regulation within immune effectors was necessary for mediating the antitumor effects of IFN-alpha in this experimental system.

Expression of STAT1 and STAT2 in Malignant Melanoma Does Not Correlate with Response to Interferon-alpha Adjuvant Therapy

Cancer Immunology, Immunotherapy : CII. Sep, 2005  |  Pubmed ID: 15668815

Interferon-alpha (IFN-alpha) is used as an adjuvant therapy in patients with malignant melanoma and who have undergone surgical resection of high-risk lesions. Defective expression or activation of STAT1 or STAT2 has been shown to correlate with IFN-alpha or resistance in vitro; however, recent data from our laboratory suggest that the anti-tumor effects of IFN-alpha are dependent on STAT1 signaling within host immune cells. We measured STAT1 and STAT2 expression in 28 melanoma biopsies (8 cutaneous lesions; 1 lung metastasis; 19 nodal metastases) obtained from patients prior to the initiation of adjuvant IFN-alpha therapy. Disease recurrence following IFN-alpha treatment did not correlate with the staining intensity of either STAT1 (P = 0.61) or STAT2 (P = 0.52). Tumors with minimal STAT1 or STAT2 expression (< 20% positive) were present in four patients with tumor-positive lymph nodes, who exhibited prolonged relapse-free survival (> 44 months) following adjuvant therapy. Conversely, high levels of STAT1 were present in a patient who recurred during the course of IFN-alpha therapy. A case study of one patient who experienced recurrent disease during IFN-alpha treatment revealed that STAT1 levels were greater in the recurrent tumor when compared to the original lesion. These studies provide direct evidence to suggest that levels of STAT1 and STAT2 within the tumor do not influence a patient's response to adjuvant IFN-alpha.

Neuregulin Growth Factors and Their ErbB Receptors Form a Potential Signaling Network for Schwannoma Tumorigenesis

Journal of Neuropathology and Experimental Neurology. Feb, 2006  |  Pubmed ID: 16462207

Sporadic and neurofibromatosis type 2-associated schwannomas contain a glial growth factor (GGF)-like activity that has been hypothesized to promote neoplastic Schwann cell mitogenesis. It is not known whether this GGF-like activity is neuregulin-1 (NRG-1), an epidermal growth factor (EGF)-related molecule that regulates the proliferation, survival, and differentiation of developing Schwann cells, the related factor NRG-2, or another NRG/EGF ligand. We report that neoplastic Schwann cells within schwannomas overexpress multiple alpha and beta transmembrane precursors from the class II and class III NRG-1 subfamilies. NRG-2 alpha and beta transcripts are similarly overexpressed in some tumors. Of the other 8 known NRG/EGF ligands, only heparin-binding EGF, epiregulin, and TGFalpha are detectable in schwannomas. Neoplastic Schwann cells almost uniformly express erbB2 and erbB3, 2 membrane receptor tyrosine kinases mediating NRG-1 and NRG-2 action. Expression of the NRG receptor erbB4 and EGF receptor is also evident in schwannomas, but is more limited, occurring in only a subset of these tumors. ErbB2, the preferred dimerization partner for all erbB kinases, is constitutively phosphorylated in schwannomas. These observations suggest that autocrine, paracrine, and/or juxtacrine NRG-1/NRG-2 signaling promotes schwannoma pathogenesis and that this signaling pathway may be an important therapeutic target in schwannomas.

Gerstmann-Sträussler-Scheinker: a New Phenotype with 'curly' PrP Deposits

Journal of Neuropathology and Experimental Neurology. Jul, 2006  |  Pubmed ID: 16825951

Gerstmann-Sträussler-Scheinker (GSS) is a hereditary prion disease typically associated with prion protein (PrP)-containing plaques. The protease-resistant, scrapie PrP (PrPSc) is represented by internal fragments, whereas the C-terminal fragments associated with the other prion diseases are generally underrepresented. Different histopathologic and PrPSc features associated with at least 13 PrP gene (PRNP) mutations have been described in GSS. We report the histopathology and PrP characteristics in a father and son carrying a mutation at PRNP codon 187 that substitutes histidine (H) with arginine (R) and is coupled with valine (V) at position 129 (H187R-129V). The PrP plaques were present in both cases but with different structure and topography and minimal spongiform degeneration. A distinctive, "curly" PrP immunostaining was prominent in one case. The protease-resistant PrPSc differed in amount in the 2 cases, possibly depending on whether plaques or the curly immunostain was present. Two protease-resistant PrP fragments of 14 kDa and 7 kDa with, in at least one case, N-terminus between residues 90-99 and 82-90, respectively, codistributed with the plaques, whereas only very small amounts of the PK-resistant PrP were present in the curly staining regions. PK-resistant PrP recovered from the plaque and curly staining regions appeared to be full length.

Interferon Alpha and CPG Oligodeoxynucleotides Elicit Additive Immunostimulatory and Antitumor Effects

Surgery. Aug, 2006  |  Pubmed ID: 16904983

We hypothesized that interferon alpha (IFN-alpha) and unmethylated cytosine-phosphothioate-guanine (CpG)-rich oligodexoynucleotides (CpG ODNs) would elicit potent antitumor activity due to the ability of this treatment combination to activate complimentary signal transduction intermediates.

Brain Tumor Imaging and Cancer Management: the Neuro-oncologists Perspective

Topics in Magnetic Resonance Imaging : TMRI. Apr, 2006  |  Pubmed ID: 17198229

Brain tumors remain a significant cause of morbidity and mortality and are often refractory to treatment. Neuroimaging, in particular magnetic resonance imaging (MRI) and associated techniques, has become an important tool for the neuro-oncologist in the management of brain tumors. Magnetic resonance imaging is the most sensitive method to demonstrate the presence of a mass in the brain and can often narrow the differential diagnosis with nonneoplastic lesions such as cerebral abscess and subacute infarction. Once the diagnosis has been confirmed, MRI is essential for initial treatment planning, including surgical resection and radiation therapy. In selected patients, serial MRI will also be necessary to evaluate for response during adjuvant chemotherapy and to monitor for treatment-induced toxicity. New magnetic resonance techniques such as magnetic resonance spectroscopy, diffusion-weighted imaging, and perfusion-based imaging methods will also be discussed where applicable.

Extradural Dermoid Tumor of the Petrous Apex. Case Report

Journal of Neurosurgery. Aug, 2007  |  Pubmed ID: 17695401

Dermoid cysts are rare, benign, congenital tumors. Most case series thus far have featured intradural tumors. The authors report on a case of an extradural dermoid tumor of the middle cranial fossa with osseous invasion, successfully removed using a left subtemporal extradural approach. The clinical presentation, histological features, radiological findings, and management of this unique case are described.

Melanoma Cells Exhibit Variable Signal Transducer and Activator of Transcription 1 Phosphorylation and a Reduced Response to IFN-alpha Compared with Immune Effector Cells

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Sep, 2007  |  Pubmed ID: 17785551

IFN-alpha is administered to melanoma patients and its endogenous production is essential for immune-mediated tumor recognition. We hypothesized that a reduced capacity for signal transducer and activator of transcription (STAT) 1 activation allows melanoma cells to evade the direct actions of IFN-alpha.

Solitary Pituitary Sarcoidosis with Normal Endocrine Function: Case Report

Journal of Neurosurgery. Mar, 2008  |  Pubmed ID: 18312108

Sarcoidosis is a multisystemic granulomatous disease characterized by noncaseating epithelioid granulomata that affects the lung in over 90% of patients and the central nervous system (CNS) in 5-9%. Neurosarcoidosis often occurs as multifocal meningeal and parenchymal lesions, and its diagnosis is particularly difficult in the absence of concomitant systemic disease. Hypothalamic-pituitary sarcoidosis occurs in fewer than 10% of patients with neurosarcoidosis and has been previously reported in association with profound endocrinological dysfunction. The authors report the case of a patient with isolated pituitary sarcoidosis who was first evaluated for visual symptoms and showed no preoperative endocrinological dysfunction or evidence of multisystemic or other CNS involvement. To the authors' knowledge, only 1 other such presentation is previously reported in the English literature. Such presentations are diagnostically and therapeutically challenging, and definitive diagnosis requires obtaining a biopsy specimen of the lesion with histological proof of noncaseating epithelioid granuloma, as well as the exclusion of other possible entities.

Spinal Myxopapillary Ependymoma Metastatic to Bilateral Internal Auditory Canals

The Annals of Otology, Rhinology, and Laryngology. Feb, 2008  |  Pubmed ID: 18357830

We report a rare case of spinal myxopapillary ependymoma metastatic to both internal auditory canals (IACs) and its implications for diagnosing neurofibromatosis type 2 (NF2).

Primary Meningeal CNS Lymphoma Treated with Intra-arterial Chemotherapy and Blood-brain Barrier Disruption

Journal of Neuro-oncology. Dec, 2008  |  Pubmed ID: 18758913

Diffuse large B-cell lymphoma of the meninges is a particularly rare form of primary CNS lymphoma. We report a case of a 63-year-old woman found to have primary meningeal lymphoma (PML) with dural and leptomeningeal involvement whom we treated with multiple cycles of intra-arterial (IA) methotrexate, intravenous (IV) etoposide phosphate, and IV cyclophosphamide after reversible osmotic blood-brain barrier disruption (BBBD). Improvement was evident on gadolinium-enhanced brain MRI one month into therapy. At 67 months post-diagnosis there is no evidence of CNS disease. After completing her therapy regimen, she remained disease-free for 34 months, when stage IV diffuse large B-cell lymphoma was discovered in her left adrenal gland and right thigh. Following six cycles of rituximab and CHOP treatment, she is presently in complete remission. IA methotrexate and reversible osmotic BBBD without radiation therapy may be an effective therapy for treating PML.

IFN-alpha and Bortezomib Overcome Bcl-2 and Mcl-1 Overexpression in Melanoma Cells by Stimulating the Extrinsic Pathway of Apoptosis

Cancer Research. Oct, 2008  |  Pubmed ID: 18922907

We hypothesized that IFN-alpha would enhance the apoptotic activity of bortezomib on melanoma cells. Combined treatment with bortezomib and IFN-alpha induced synergistic apoptosis in melanoma and other solid tumor cell lines. Apoptosis was associated with processing of procaspase-3, procaspase-7, procaspase-8, and procaspase-9 and with cleavage of Bid and poly(ADP-ribose) polymerase. Bortezomib plus IFN-alpha was effective at inducing apoptosis in melanoma cells that overexpressed Bcl-2 or Mcl-1, suggesting that this treatment combination can overcome mitochondrial pathways of cell survival and resistance to apoptosis. The proapoptotic effects of this treatment combination were abrogated by a caspase-8 inhibitor, led to increased association of Fas and FADD before the onset of cell death, and were significantly reduced in cells transfected with a dominant-negative FADD construct or small interfering RNA targeting Fas. These data suggest that bortezomib and IFN-alpha act through the extrinsic pathway of apoptosis via FADD-induced caspase-8 activation to initiate cell death. Finally, bortezomib and IFN-alpha displayed statistically significant antitumor activity compared with either agent alone in both the B16 murine model of melanoma and in athymic mice bearing human A375 xenografts. These data support the future clinical development of bortezomib and IFN-alpha for malignant melanoma.

Advances in Oncolytic Virus Therapy for Glioma

Recent Patents on CNS Drug Discovery. Jan, 2009  |  Pubmed ID: 19149710

The World Health Organization grossly classifies the various types of astrocytomas using a grade system with grade IV gliomas having the worst prognosis. Oncolytic virus therapy is a novel treatment option for GBM patients. Several patents describe various oncolytic viruses used in preclinical and clinical trials to evaluate safety and efficacy. These viruses are natural or genetically engineered from different viruses such as HSV-1, Adenovirus, Reovirus, and New Castle Disease Virus. While several anecdotal studies have indicated therapeutic advantage, recent clinical trials have revealed the safety of their usage, but demonstration of significant efficacy remains to be established. Oncolytic viruses are being redesigned with an interest in combating the tumor microenvironment in addition to defeating the cancerous cells. Several patents describe the inclusion of tumor microenvironment modulating genes within the viral backbone and in particular those which attack the tumor angiotome. The very innovative approaches being used to improve therapeutic efficacy include: design of viruses which can express cytokines to activate a systemic antitumor immune response, inclusion of angiostatic genes to combat tumor vasculature, and also enzymes capable of digesting tumor extra cellular matrix (ECM) to enhance viral spread through solid tumors. As increasingly more novel viruses are being tested and patented, the future battle against glioma looks promising.

Primary Central Nervous System Lymphomatoid Granulomatosis in a Patient Receiving Azathioprine Therapy

Clinical Advances in Hematology & Oncology : H&O. Jan, 2009  |  Pubmed ID: 19274043

High Resolution Ultra High Field Magnetic Resonance Imaging of Glioma Microvascularity and Hypoxia Using Ultra-small Particles of Iron Oxide

Investigative Radiology. Jul, 2009  |  Pubmed ID: 19448552

This study assessed whether ultra-small particles of iron oxide (USPIO) intravascular contrast agent could enhance visualization of tumor microvascularity in F98 glioma bearing rats by means of ultra high field (UHF) high-resolution gradient echo (GRE) magnetic resonance imaging (MRI). In an effort to explain differences in visualization of microvascularity before and after USPIO administration, hypoxia and vessel diameters were assessed on corresponding histopathologic sections.

Metastasis Development at the Site of Cervical Spine Arthrodesis

Acta Neurochirurgica. Mar, 2010  |  Pubmed ID: 19551339

Biologically, the site of arthrodesis provides a microenvironment replete of growth factors and active remodeling, which is propitious for bone regrowth. There is a theoretical possibility though that this microenvironment would also provide a fertile site for metastatic deposits to occur. Although spinal fusion with various types of instrumentation is commonly used to treat various disorders, development of tumors at the site of spinal arthrodesis has not been previously reported. We present the clinical, radiographic, and pathological features of a case of previously undiagnosed metastatic adenocarcinoma, occurring 1 year following anterior arthrodesis and fusion for cervical spondylotic myelopathy at the C3-C4 level. The patient's initial radiologic presentation suggested an epidural abscess with osteomyelitic destruction of C3 and C4. Our report alerts surgeons to the possibility that metastasis may occur at the site of a previous spinal arthrodesis.

Pathologic Complete Response of a Solitary Melanoma Brain Metastasis After Local Ablative Radiation Therapy: Case Report

Medical Oncology (Northwood, London, England). Dec, 2010  |  Pubmed ID: 19921550

A 73-year-old female with malignant melanoma metastatic to her left frontal lobe status post-gross total resection of the metastasis, whole brain radiotherapy, and Gamma Knife-based stereotactic radiosurgery for local recurrence presented with an area of increasing enhancement on follow-up magnetic resonance imaging (MRI) and hypermetabolic lesions on 18-fluorodeoxyglucose positron emission tomography/computerized tomography (18FDG PET/CT) of the brain suspicious for tumor recurrence. Surgical resection of the lesion was performed showing radiation necrosis with no evidence of tumor. The patient was alive 1 year after her second craniotomy. This case illustrates that despite being perceived as a radioresistant histology, complete local eradication of melanoma is possible with ablative dose regimens. Prolonged survival is possible in patients with limited metastatic melanoma if local tumor control is achieved.

Increased Expression of Cholesterol 24S-hydroxylase Results in Disruption of Glial Glutamate Transporter EAAT2 Association with Lipid Rafts: a Potential Role in Alzheimer's Disease

Journal of Neurochemistry. May, 2010  |  Pubmed ID: 20193040

The glial glutamate transporter EAAT2 (excitatory amino acid transporter 2) is the major mediator of glutamate clearance that terminates glutamate-mediated neurotransmission. Loss of EAAT2 and associated glutamate uptake function has been reported in the brains of patients with Alzheimer's disease (AD). We previously reported that EAAT2 is associated with lipid raft microdomains of the plasma membrane. In the present study, we demonstrated that association of EAAT2 with lipid rafts is disrupted in AD brains. This abnormality is not a consequence of neuron degeneration, oxidative stress, or amyloid beta toxicity. In AD brains, cholesterol 24S-hydroxylase (CYP46), a key enzyme in maintenance of cholesterol homeostasis in the brain, is markedly increased in astrocytes but decreased in neurons. We demonstrated that increased expression of CYP46 in primary astrocytes results in a reduction of membrane cholesterol levels and leads to the dissociation of EAAT2 from lipid rafts and the loss of EAAT2 and associated glutamate uptake function. These results suggest that a disturbance of cholesterol metabolism may contribute to loss of EAAT2 in AD.

Hemangioblastoma of the Cerebellopontine Angle

Archives of Otolaryngology--head & Neck Surgery. Jul, 2010  |  Pubmed ID: 20644074

The Role of Sphingosine Kinase-1 in EGFRvIII-regulated Growth and Survival of Glioblastoma Cells

Journal of Neuro-oncology. May, 2011  |  Pubmed ID: 20938717

We have previously shown that high expression levels of the lipid kinase sphingosine kinase-1 (SphK1) correlate with poor survival of glioblastoma (GBM) patients. In this study we examined the regulation of SphK1 expression by epidermal growth factor receptor (EGFR) signaling in GBM cells. As the EGFR gene is often overexpressed and mutated in GBM, and EGFR has been shown to regulate SphK1 in some cell types, we examined the effect of EGF signaling and the constitutively active EGFRvIII mutant on SphK1 in GBM cells. Treatment of glioma cell lines with EGF led to increased expression and activity of SphK1. Expression of EGFRvIII in glioma cells also activated and induced SphK1. In addition, siRNA to SphK1 partially inhibited EGFRvIII-induced growth and survival of glioma cells as well as ERK MAP kinase activation. To further evaluate the connection between EGFR and SphK1 in GBM we examined primary neurosphere cells isolated from fresh human GBM tissue. The GBM-derived neurosphere cell line GBM9, which forms GBM-like tumors intracranially in nude mice, maintained expression of EGFRvIII in culture and had high levels of SphK1 activity. EGFR inhibitors modestly decreased SphK1 activity and proliferation of GBM9 cells. More extensive blockage of SphK1 activity by a SphK inhibitor, potently blocked cell proliferation and induced apoptotic cell death of GBM9 cells. Thus, SphK1 activity is necessary for survival of GBM-derived neurosphere cells, and EGFRvIII partially utilizes SphK1 to further enhance cell proliferation.

IL-12 Enhances the Antitumor Actions of Trastuzumab Via NK Cell IFN-γ Production

Journal of Immunology (Baltimore, Md. : 1950). Mar, 2011  |  Pubmed ID: 21321106

The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-γ production from NK cells and T cells. We hypothesized that coadministration of IL-12 with a murine anti-HER2/neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 μg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26(HER2/neu)) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN-γ, monokine induced by IFN-γ, and RANTES. Experiments with IFN-γ-deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4(+) or CD8(+) T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26(HER2/neu) tumor cells revealed that IFN-γ induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-γ production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs.

Frequency, Molecular Pathology and Potential Clinical Significance of Partial Chromosome 3 Aberrations in Uveal Melanoma

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. Jul, 2011  |  Pubmed ID: 21499235

The clinical significance of partial chromosome 3 alteration in uveal melanoma is still not clear. Also, the reported frequencies vary considerably in the published literature from 0 to 48%. The aims of the following study were to identify the frequency, molecular pathology and potential clinical significance of partial chromosome 3 alteration in uveal melanoma. We studied 47 uveal melanomas with an average follow-up of 36 months. Of these, 14 had confirmed metastasis. Allelic imbalance/loss of heterozygosity was studied using microsatellite markers on chromosome 3 enriched in markers located in the previously reported smallest regions of deletion overlap. Chromosomal alterations were assessed by conventional cytogenetics or comparative genomic hybridization (CGH) in a subset of patients. Utilizing genotyping, partial chromosome 3 alteration was detected in 14/47 tumors (30%). In the 23 tumors with available cytogenetic/CGH, partial chromosome 3 alteration was detected in 8/23 (38%) and was caused by both gains (4/8) and losses (4/8) of chromosome 3 with high frequency of complex chromosome 3 aberrations detected by cytogenetics. Out of the 14 tumors with confirmed metastasis, only 1 showed partial chromosome 3 alteration and the remaining showed monosomy 3. By limiting the aggressive disease marker to monosomy 3, genotyping showed 93% sensitivity and 67% specificity for detection of aggressive uveal melanoma. In conclusion, partial chromosome 3 alterations are common in uveal melanoma and mostly caused by complex cytogenetic changes leading to partial gains and/or partial losses of chromosome 3. Partial chromosome 3 alteration is not likely to be associated with highly aggressive uveal melanoma that metastasizes within the first 3 years after treatment. Microsatellite-based genotyping of chromosome 3 is highly sensitive for detection of aggressive uveal melanoma.

Myeloid-derived Suppressor Cell Inhibition of the IFN Response in Tumor-bearing Mice

Cancer Research. Aug, 2011  |  Pubmed ID: 21680779

Our group and others have determined that immune effector cells from patients with advanced cancers exhibit reduced activation of IFN signaling pathways. We hypothesized that increases in immune regulatory cells termed myeloid-derived suppressor cells (MDSC) could interfere with the host immune response to tumors by inhibiting immune cell responsiveness to IFNs. The C26 murine adenocarcinoma model was employed to study immune function in advanced malignancy. C26-bearing mice had significantly elevated levels of GR1(+)CD11b(+) MDSC as compared with control mice, and splenocytes from tumor-bearing mice exhibited reduced phosphorylation of STAT1 (P-STAT1) on Tyr(701) in response to IFN-α or IFN-γ. This inhibition was seen in splenic CD4(+) and CD8(+) T cells as well as natural killer cells. In vitro coculture experiments revealed that MDSC inhibited the IFN responsiveness of splenocytes from normal mice. Treatment of C26-bearing mice with gemcitabine or an anti-GR1 antibody led to depletion of MDSC and restored splenocyte IFN responsiveness. Spleens from C26-bearing animals displayed elevated levels of iNOS protein and nitric oxide. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. The elevation in nitric oxide in C26-bearing mice was associated with increased levels of nitration on STAT1. Finally, splenocytes from iNOS knockout mice bearing C26 tumors exhibited a significantly elevated IFN response as compared with control C26 tumor-bearing mice. These data suggest that nitric oxide produced by MDSC can lead to reduced IFN responsiveness in immune cells.