DOCSLIB.ORG

MGEA6 Is Tumor-Specific Overexpressed and Frequently

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
MGEA6 Is Tumor-Specific Overexpressed and Frequently Oncogene (2002) 21, 239 ± 247 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc MGEA6 is tumor-speci®c overexpressed and frequently recognized by patient-serum antibodies Nicole Comtesse1, Isolde Niedermayer2, Brenda Glass1, Dirk Heckel1, Esther Maldener1, Wolfgang Nastainczyk3, Wolfgang Feiden2 and Eckart Meese*,1 1Institut fuÈr Humangenetik, UniversitaÈtskliniken des Saarlandes, 66421 Homburg/Saar, Germany; 2Abteilung fuÈr Neuropathologie, UniversitaÈtskliniken des Saarlandes, 66421 Homburg/Saar, Germany; 3Institut fuÈr Medizinische Biochemie, UniversitaÈtskliniken des Saarlandes, 66421 Homburg/Saar, Germany Tumorigenesis of meningioma has been associated with 40% of the meningiomas show no mutation in the NF2 chromosome 22, most notably the NF2 gene, but gene, indicating that other genes are involved in the additional genes have also been implicated in meningioma tumorigenesis (Ruttledge et al., 1994; Akagi et al., development. Previously, we have cloned the cDNAs for 1995). the meningioma expressed antigen 6 (MGEA6) and its A variety of tumors are known to elicit immune splice variant MGEA11. Here, we show that antibodies responses in patients bearing the tumor. Immunogenic against recombinantly expressed MGEA6/11 are found in tumor-associated antigens have been described pri- 41.7% (10/24) of the sera from meningioma patients and marily for malignant tumors including melanoma, in 2/8 sera of glioblastoma patients, whereas no response breast cancer, colon cancer, ovarian cancer (Real et was seen in 12 sera from healthy persons. Western-blot al., 1988; Ben-Mahrez et al., 1990; Gallagher et al., analyses using generated polyclonal antibodies, revealed 1991; Disis et al., 1994; Disis and Cheever, 1996; overexpression in meningioma and glioma tumor samples Boon and Lloyd, 1997). However, dierent studies compared to normal brain. Immunohistochemical staining have indicated that meningiomas are also capable of of tissue sections con®rms reactivity in meningioma tumor inducing an immune response in the host. In 1976, cells and tumor cells of glial origin. We found no Pees and Seidel already described a cellular immune reactivity to normal astrocytes and only faint reactivity response against autologous and heterologous menin- to normal leptomeninges. Sequence analysis predicted gioma cells in the serum of patients (Pees and Seidel, membranic localization of MGEA6/11, that was con- 1976). Another study concerning a cytotoxic immune ®rmed by cell fractionation. The immune response to response presents data suggesting that meningiomas MGEA6/11 is frequent in both meningioma and glioma can induce complex immunological responses in the patients and may likely be attributed to overexpression of host (Pees, 1979). The presence of IgG in meningioma the MGEA6/11 protein in the tumor cells. was shown by Tabuchi et al. (1979). Expression of Oncogene (2002) 21, 239 ± 247. DOI: 10.1038/sj/onc/ MHC class II and MHC class I molecules have also 1205005 been detected in meningioma tissue (Becker and Roggendorf, 1989). Keywords: tumor antigen; overexpression; central- Previously, we reported cloning of immunoreactive nervous-system neoplasm; meningioma; glioma antigens expressed in meningioma, providing the ®rst evidence for the expression of immunogenic antigens in this tumor type (Heckel et al., 1997, 1998; Comtesse et Introduction al., 1999). The meningioma expressed antigens 6/11 (MGEA6/11; previously called MEA6/11) induced an Meningiomas are neoplasms of the leptomeninges immune response in the patient bearing the meningioma covering the brain and the spinal cord. With *20% (Heckel et al., 1997). Expression analysis on the mRNA of all primary intracranial tumors, they are among the level revealed constitutive expression of the MGEA6/11 most common tumors of the human nervous system in all human tissues tested. MGEA6 belongs to a (Kleihues and Cavenee, 2000). Although there is a multigene family with an active locus on chromosome large amount of evidence for involvement of the 14q and at least nine pseudogenes on dierent neuro®bromatosis type 2 (NF2) gene in tumor growth, chromosomes. The smaller MGEA11 is generated by alternative splicing of exon 19 of the MGEA6 gene (Comtesse et al., 2001). In this study we report that the immune response *Correspondence: E Meese, Department of Human Genetics, against MGEA6/11 is found in 41.7% (10/24) of University of Saarland, Building 60, 66421 Homburg/Saar, meningioma and in 2/8 of glioblastoma patients, with Germany; E-mail: [email protected] Received 19 June 2001; revised 28 September 2001; accepted 1 no antibodies present in 12 sera of healthy persons, October 2001 indicating that MGEA6/11 probably acts as a tumor MGEA6 is overexpressed and immunogenic N Comtesse et al 240 antigen in these tumor types. We report that on the protein level, MGEA6/11 is overexpressed in menin- gioma and glioma tumor cells compared to the normal tissue. Immunohistochemical staining of tissue sections revealed reactivity of meningioma cells and tumor cells of glial origin, whereas no reactivity was found in the cellular elements of the normal control brain and only faint reactivity in normal leptomeninges. No expression was found in tumor cells of cerebral carcinoma metastases. Sequence analysis purported a membranic localization of the protein, which was con®rmed by Western-blot analysis of cellular fractions of MGEA6/ 11 expressing cells. Our ®ndings suggest that the immune response in glioma and meningioma patients may likely be attributed to overexpression of this gene at the protein level. Results Recombinant expression of MGEA6/11 in a eukaryotic expression system To further characterize the meningioma expressed antigens 6 and 11 (MGEA6/11), we expressed the two variants in a recombinant eukaryotic expression system. As shown previously, cDNA for MGEA6 shows an open reading frame (ORF) of 2415 bp and cDNA for MGEA11 an ORF of 2286 bp, with the coding regions diering only in a 129 bp sequence (Heckel et al., 1997). As most recently described, Figure 1 Western-blot analyses using recombinantly expressed mRNA for MGEA11 probably results from alternative MGEA6/11. (a) Serum of meningioma patient H4 detects a 110 kDa and a 105 kDa protein corresponding to MGEA6 and splicing of exon 19 of the MGEA6 gene on chromo- MGEA11. (b) Detection of MGEA6 and MGEA11 with serum some 14q (Comtesse et al., 2001). Sequence analysis of from glioblastoma patient H57. (c, left) Western blot with three the cDNA clones revealed a high number of codons pooled normal sera. Reactivity of the sera was shown using a rarely used in bacteria. Therefore, we used the positive control (data not shown). (Right) Same blot as left, stripped and incubated with meningioma serum H4 detecting baculovirus expression system to facilitate complete MGEA6 and 11. NR: not recombinant clone translation of the clones. After recombinant expression, the proteins were visualized by Western blot analysis using the serum of the autologous patient for detection. We determined molecular masses for MGEA6 of subtype of meningiomas (Tables 1 and 2). In detail, we 110 kDa and for MGEA11 of 105 kDa (Figure 1a). found antibodies against MGEA6/11 in 4/10 sera from Deducting the fusion portion of 34AA (about 4 kDa), WHO grade I meningiomas including arachnothelial, results in a molecular mass of 106 kDa for MGEA6 transitional and secretory subtypes, in 5/12 sera from and of 101 kDa for MGEA11. This is in good atypical meningiomas, and in one of two sera from accordance with the predicted theoretical molecular anaplastic meningioma. masses of 91 kDa for MGEA6 and 89 kDa for We further tested sera from patients with primary MGEA11. The minimal mass dierences can be brain tumors of glial origin (Table 2). We detected attributed to post-translational modi®cation. antibodies against MGEA6 in 2/8 sera from glioblas- toma (WHO grade IV) patients (Figure 1b) and in one of two patients with WHO grade II astrocytomas. Humural immune response against MGEA6/11 is found in Sera derived from two patients with WHO grade III meningioma and glioma patients, not in healthy persons astrocytomas and from three patients with pilocytic We also used the baculovirus-expressed recombinant astrocytomas did not react with MGEA6/11. When proteins to examine the immune response against using 12 sera from healthy, tumor-free persons, in no MGEA6/11 in other patients bearing meningiomas. case was an antibody response detected against We tested 24 sera derived from patients with MGEA6/11 (Figure 1c). Additionally, for testing meningioma of dierent grading and histological tumors derived from other embryonic origin, we tested subtype. An antibody reaction was detected with 10 six sera of patients with squamous cell lung of 24 (41.7%) meningioma sera. The immune response carcinoma. In no case were antibodies against was not correlated with tumor grading or histological MGEA6/11 found. Oncogene MGEA6 is overexpressed and immunogenic N Comtesse et al 241 Table 1 Summary of sera from meningioma-patients examined for C-terminal region is characterized by a high percentage antibody-response against MGEA6 (22%) of proline residues including several polyproline Meningioma Immune stretches. Notably, the insertion found in MGEA6 also No WHO grading Subtype response possesses a high amount of proline residues and shows H 4 WHO I Arachnothelial + high hydrophobicity. H 19 WHO I Transitional + H 28 WHO I Arachnothelial 7 H 52 WHO I Secretory 7 Generation of polyclonal antibodies against MGEA6/11 H 53 WHO I Arachnothelial 7 via peptide immunization H 63 WHO I Transitional, regressive + H 64 WHO I Angiomatous, regressive 7 To investigate the MGEA6/11 expression at the protein H 71 WHO I Secretory 7 level, we generated polyclonal rabbit antibodies against H 78 WHO I Fibroblastic 7 MGEA6/11. We synthesized a peptide from the C- H 81 WHO I Secretory + terminus of MGEA6/11. For immunization, the H 15 WHO II Atypical 7 peptide was coupled with an additional N-terminal H 60 WHO II Atypical + cysteine residue to keyhole limpet hemocyanine.
Load more

Recommended publications
  • Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies
    cancers Review Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies Nga T. H. Truong 1, Tessa Gargett 1,2,3, Michael P. Brown 1,2,3,† and Lisa M. Ebert 1,2,3,*,† 1 Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, North Terrace, Adelaide, SA 5000, Australia; [email protected] (N.T.H.T.); [email protected] (T.G.); [email protected] (M.P.B.) 2 Cancer Clinical Trials Unit, Royal Adelaide Hospital, Port Rd, Adelaide, SA 5000, Australia 3 Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia * Correspondence: [email protected] † These authors contributed equally. Simple Summary: CAR-T cell therapy is a new approach to cancer treatment that is based on manipulating a patient’s own T cells such that they become able to seek and destroy cancer cells in a highly specific manner. This approach is showing remarkable efficacy in treating some types of blood cancers but so far has been much less effective against solid cancers. Here, we review the diverse effects of chemotherapy agents on circulating leukocyte populations and find that, despite some negative effects over the short term, chemotherapy can favourably modulate the immune systems of cancer patients over the longer term. Since blood is the starting material for CAR-T cell Citation: Truong, N.T.H.; Gargett, T.; production, we propose that these effects could significantly influence the success of manufacturing, Brown, M.P.; Ebert, L.M.
    [Show full text]
  • Ambient Mass Spectrometry for the Intraoperative Molecular Diagnosis of Human Brain Tumors
    Ambient mass spectrometry for the intraoperative molecular diagnosis of human brain tumors Livia S. Eberlina, Isaiah Nortonb, Daniel Orringerb, Ian F. Dunnb, Xiaohui Liub, Jennifer L. Ideb, Alan K. Jarmuscha, Keith L. Ligonc, Ferenc A. Joleszd, Alexandra J. Golbyb,d, Sandro Santagatac, Nathalie Y. R. Agarb,d,1, and R. Graham Cooksa,1 aDepartment of Chemistry and Center for Analytical Instrumentation Development, Purdue University, West Lafayette, IN 47907; and Departments of bNeurosurgery, cPathology, and dRadiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 Edited by Jack Halpern, The University of Chicago, Chicago, IL, and approved December 5, 2012 (received for review September 11, 2012) The main goal of brain tumor surgery is to maximize tumor resection at Brigham and Women’s Hospital (BWH), created an opportu- while preserving brain function. However, existing imaging and nity for collecting information about the extent of tumor resection surgical techniques do not offer the molecular information needed during surgery (5, 6). Although brain tumor resection typically to delineate tumor boundaries. We have developed a system to requires multiple hours, intraoperative MRI can be completed rapidly analyze and classify brain tumors based on lipid information and information evaluated within an hour. However, MRI has acquired by desorption electrospray ionization mass spectrometry limited ability to distinguish residual tumor from surrounding (DESI-MS). In this study, a classifier was built to discriminate gliomas normal brain (9). In consequence, there is a need for more de- and meningiomas based on 36 glioma and 19 meningioma samples. tailed molecular information to be acquired on a timescale closer The classifier was tested and results were validated for intraoper- to real time than can be supplied by MRI.
    [Show full text]
  • Monoclonal Antibody Therapeutics and Apoptosis
    Oncogene (2003) 22, 9097–9106 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Monoclonal antibody therapeutics and apoptosis Dale L Ludwig*,1, Daniel S Pereira1, Zhenping Zhu1, Daniel J Hicklin1 and Peter Bohlen1 1ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA The potential for disease-specific targeting and low including the generation of human antibody phage toxicity profiles have made monoclonal antibodies attrac- display libraries, human immunoglobulin-producing tive therapeutic drug candidates. Antibody-mediated transgenic mice, and directed affinity maturation meth- target cell killing is frequently associated with immune odologies, have further improved on the efficiency, effector mechanisms such as antibody-directed cellular specificity, and reactivity of monoclonal antibodies for cytotoxicity, but they can also be induced by apoptotic their target antigens (Schier et al., 1996; Mendez et al., processes. Antibody-directed mechanisms, including anti- 1997; de Haard et al., 1999; Hoogenboom and Chames, gen crosslinking, activation of death receptors, and 2000; Knappik et al., 2000). As a result, the isolation of blockade of ligand-receptor growth or survival pathways, high-affinity fully human monoclonal antibodies is now can elicit the induction of apoptosis in targeted cells. commonplace. Owing to their inherent specificity for a Depending on their mechanism of action, monoclonal particular target antigen, monoclonal antibodies pro- antibodies can induce targeted cell-specific killing alone or mise precise selectivity for target cells, avoiding non- can enhance target cell susceptibility to chemo- or reacting normal cells. radiotherapeutics by effecting the modulation of anti- To be effective as therapeutics for cancer, antibodies apoptotic pathways.
    [Show full text]
  • UCSD Moores Cancer Center Neuro-Oncology Program
    UCSD Moores Cancer Center Neuro-Oncology Program Recent Progress in Brain Tumors 6DQWRVK.HVDUL0'3K' 'LUHFWRU1HXUR2QFRORJ\ 3URIHVVRURI1HXURVFLHQFHV 0RRUHV&DQFHU&HQWHU 8QLYHUVLW\RI&DOLIRUQLD6DQ'LHJR “Brain Cancer for Life” Juvenile Pilocytic Astrocytoma Metastatic Brain Cancer Glioblastoma Multiforme Glioblastoma Multiforme Desmoplastic Infantile Ganglioglioma Desmoplastic Variant Astrocytoma Medulloblastoma Atypical Teratoid Rhabdoid Tumor Diffuse Intrinsic Pontine Glioma -Mutational analysis, microarray expression, epigenetic phenomenology -Age-specific biology of brain cancer -Is there an overlap? ? Neuroimmunology ? Stem cell hypothesis Courtesy of Dr. John Crawford Late Effects Long term effect of chemotherapy and radiation on neurocognition Risks of secondary malignancy secondary to chemotherapy and/or radiation Neurovascular long term effects: stroke, moya moya Courtesy of Dr. John Crawford Importance Increase in aging population with increased incidence of cancer Patients with cancer living longer and developing neurologic disorders due to nervous system relapse or toxicity from treatments Overview Introduction Clinical Presentation Primary Brain Tumors Metastatic Brain Tumors Leptomeningeal Metastases Primary CNS Lymphoma Paraneoplastic Syndromes Classification of Brain Tumors Tumors of Neuroepithelial Tissue Glial tumors (astrocytic, oligodendroglial, mixed) Neuronal and mixed neuronal-glial tumors Neuroblastic tumors Pineal parenchymal tumors Embryonal tumors Tumors of Peripheral Nerves Shwannoma Neurofibroma
    [Show full text]
  • The New WHO Classification of Brain Tumors and Molecular Profiling in the Diagnosis of Gliomas
    The New WHO Classification of Brain Tumors and Molecular Profiling in the Diagnosis of Gliomas Aivi Nguyen, MD Neuropathology Fellow Division of Neuropathology Center for Personalized Diagnosis (CPD) Glial neoplasms – infiltrating gliomas Astrocytic tumors • Diffuse astrocytoma II • Anaplastic astrocytoma III • Glioblastoma • Giant cell glioblastoma IV • Gliosarcoma Oligodendroglial tumors • Oligodendroglioma II • Anaplastic oligodendroglioma III Oligoastrocytic tumors • Oligoastrocytoma II • Anaplastic oligoastrocytoma III Courtesy of Dr. Maria Martinez-Lage 2 2016 3 The 2016 WHO classification of tumours of the central nervous system Louis et al., Acta Neuropathologica 2016 4 Talk Outline Genetic, epigenetic and metabolic changes in gliomas • Mechanisms/tumor biology • Incorporation into daily practice and WHO classification Penn’s Center for Personalized Diagnostics • Tests performed • Results and observations to date Summary 5 The 2016 WHO classification of tumours of the central nervous system Louis et al., Acta Neuropathologica 2016 6 Mechanism of concurrent 1p and 19q chromosome loss in oligodendroglioma lost FUBP1 CIC Whole-arm translocation Griffin et al., Journal of Neuropathology and Experimental Neurology 2006 7 Oligodendroglioma: 1p19q co-deletion Since the 1990s Diagnostic Prognostic Predictive Li et al., Int J Clin Exp Pathol 2014 8 Mutations of Selected Genes in Glioma Subtypes GBM Astrocytoma Oligodendroglioma Oligoastrocytoma Killela et al., PNAS 2013 9 Escaping Senescence Telomerase reverse transcriptase gene
    [Show full text]
  • Malignant CNS Solid Tumor Rules
    Malignant CNS and Peripheral Nerves Equivalent Terms and Definitions C470-C479, C700, C701, C709, C710-C719, C720-C725, C728, C729, C751-C753 (Excludes lymphoma and leukemia M9590 – M9992 and Kaposi sarcoma M9140) Introduction Note 1: This section includes the following primary sites: Peripheral nerves C470-C479; cerebral meninges C700; spinal meninges C701; meninges NOS C709; brain C710-C719; spinal cord C720; cauda equina C721; olfactory nerve C722; optic nerve C723; acoustic nerve C724; cranial nerve NOS C725; overlapping lesion of brain and central nervous system C728; nervous system NOS C729; pituitary gland C751; craniopharyngeal duct C752; pineal gland C753. Note 2: Non-malignant intracranial and CNS tumors have a separate set of rules. Note 3: 2007 MPH Rules and 2018 Solid Tumor Rules are used based on date of diagnosis. • Tumors diagnosed 01/01/2007 through 12/31/2017: Use 2007 MPH Rules • Tumors diagnosed 01/01/2018 and later: Use 2018 Solid Tumor Rules • The original tumor diagnosed before 1/1/2018 and a subsequent tumor diagnosed 1/1/2018 or later in the same primary site: Use the 2018 Solid Tumor Rules. Note 4: There must be a histologic, cytologic, radiographic, or clinical diagnosis of a malignant neoplasm /3. Note 5: Tumors from a number of primary sites metastasize to the brain. Do not use these rules for tumors described as metastases; report metastatic tumors using the rules for that primary site. Note 6: Pilocytic astrocytoma/juvenile pilocytic astrocytoma is reportable in North America as a malignant neoplasm 9421/3. • See the Non-malignant CNS Rules when the primary site is optic nerve and the diagnosis is either optic glioma or pilocytic astrocytoma.
    [Show full text]
  • Meningioma ACKNOWLEDGEMENTS
    AMERICAN BRAIN TUMOR ASSOCIATION Meningioma ACKNOWLEDGEMENTS ABOUT THE AMERICAN BRAIN TUMOR ASSOCIATION Meningioma Founded in 1973, the American Brain Tumor Association (ABTA) was the first national nonprofit advocacy organization dedicated solely to brain tumor research. For nearly 45 years, the ABTA has been providing comprehensive resources that support the complex needs of brain tumor patients and caregivers, as well as the critical funding of research in the pursuit of breakthroughs in brain tumor diagnosis, treatment and care. To learn more about the ABTA, visit www.abta.org. We gratefully acknowledge Santosh Kesari, MD, PhD, FANA, FAAN chair of department of translational neuro- oncology and neurotherapeutics, and Marlon Saria, MSN, RN, AOCNS®, FAAN clinical nurse specialist, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA; and Albert Lai, MD, PhD, assistant clinical professor, Adult Brain Tumors, UCLA Neuro-Oncology Program, for their review of this edition of this publication. This publication is not intended as a substitute for professional medical advice and does not provide advice on treatments or conditions for individual patients. All health and treatment decisions must be made in consultation with your physician(s), utilizing your specific medical information. Inclusion in this publication is not a recommendation of any product, treatment, physician or hospital. COPYRIGHT © 2017 ABTA REPRODUCTION WITHOUT PRIOR WRITTEN PERMISSION IS PROHIBITED AMERICAN BRAIN TUMOR ASSOCIATION Meningioma INTRODUCTION Although meningiomas are considered a type of primary brain tumor, they do not grow from brain tissue itself, but instead arise from the meninges, three thin layers of tissue covering the brain and spinal cord.
    [Show full text]
  • SEREX Analysis for Tumor Antigen Identification in a Mouse Model Of
    © 2000 Nature America, Inc. 0929-1903/00/$15.00/ϩ0 www.nature.com/cgt SEREX analysis for tumor antigen identification in a mouse model of adenocarcinoma Tracy A. Hampton,1–3 Robert M. Conry,2 M. B. Khazaeli,2 Denise R. Shaw,2 David T. Curiel,1,2 Albert F. LoBuglio,2 and Theresa V. Strong1–3 1Gene Therapy Center, 2Division of Hematology/Oncology, Department of Medicine, and 3Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294. Evaluation of immunotherapy strategies in mouse models of carcinoma is hampered by the limited number of known murine tumor antigens (Ags). Although tumor Ags can be identified based on cytotoxic T-cell activation, this approach is not readily accomplished for many tumor types. We applied an alternative strategy based on a humoral immune response, SEREX, to the identification of tumor Ags in the murine colon adenocarcinoma cell line MC38. Immunization of syngeneic C57BL/6 mice with MC38 cells by three different methods induced a protective immune response with concomitant production of anti-MC38 antibodies. Immunoscreening of an MC38-derived expression library resulted in the identification of the endogenous ecotropic leukemia virus envelope (env) protein and the murine ATRX protein as candidate tumor Ags. Northern blot analysis demonstrated high levels of expression of the env transcript in MC38 cells and in several other murine tumor cell lines, whereas expression in normal colonic epithelium was absent. ATRX was found to be variably expressed in tumor cell lines and in normal tissue. Further analysis of the expressed env sequence indicated that it represents a nonmutated tumor Ag.
    [Show full text]
  • Current Diagnosis and Treatment of Oligodendroglioma
    Neurosurg Focus 12 (2):Article 2, 2002, Click here to return to Table of Contents Current diagnosis and treatment of oligodendroglioma HERBERT H. ENGELHARD, M.D., PH.D. Departments of Neurosurgery, Bioengineering, and Molecular Genetics, The University of Illinois at Chicago, Illinois Object. The strategies used to diagnose and treat oligodendroglial tumors have changed significantly over the past decade. The purpose of this paper is to review the topic of oligodendroglioma, emphasizing the new developments. Methods. Information was obtained by conducting a Medline search in which the term oligodendroglioma was used. Recent editions of standard textbooks were also studied. Because of tools such as magnetic resonance imaging, oligodendrogliomas are being diagnosed earlier, and they are being recognized more frequently histologically than in the past. Seizures are common in these patients. Functional mapping and image-guided surgery may now allow for a safer and more complete resection, especially when tumors are located in difficult areas. Genetic analysis and positron emission tomography may provide data that supplement the standard diagnostic tools. Unlike other low-grade gliomas, patients in whom residual or recurrent oligodendroglioma (World Health Organization Grade II) is present may respond to chemotherapy. Although postoperative radiotherapy prolongs survival of the patient, increasingly this therapeutic modality is being delayed until tumor recurrence, espe- cially if a gross-total tumor resection has been achieved. Oligodendrogliomas are the first type of brain tumor for which “molecular” characterization gives important information. The most significant finding is that allelic losses on chro- mosomes 1p and 19q indicate a favorable response to chemotherapy. Conclusions. Whereas surgery continues to be the primary treatment for oligodendroglioma, the scheme for post- operative therapy has shifted, primarily because of the lesion’s relative chemosensitivity.
    [Show full text]
  • Immune Escape Mechanisms As a Guide for Cancer Immunotherapy Gregory L
    Published OnlineFirst December 12, 2014; DOI: 10.1158/1078-0432.CCR-14-1860 Perspectives Clinical Cancer Research Immune Escape Mechanisms as a Guide for Cancer Immunotherapy Gregory L. Beatty and Whitney L. Gladney Abstract Immunotherapy has demonstrated impressive outcomes for exploited by cancer and present strategies for applying this some patients with cancer. However, selecting patients who are knowledge to improving the efficacy of cancer immunotherapy. most likely to respond to immunotherapy remains a clinical Clin Cancer Res; 21(4); 1–6. Ó2014 AACR. challenge. Here, we discuss immune escape mechanisms Introduction fore, promote tumor outgrowth. In this process termed "cancer immunoediting," cancer clones evolve to avoid immune-medi- The immune system is a critical regulator of tumor biology with ated elimination by leukocytes that have antitumor properties the capacity to support or inhibit tumor development, growth, (6). However, some tumors may also escape elimination by invasion, and metastasis. Strategies designed to harness the recruiting immunosuppressive leukocytes, which orchestrate a immune system are the focus of several recent promising thera- microenvironment that spoils the productivity of an antitumor peutic approaches for patients with cancer. For example, adoptive immune response (7). Thus, although the immune system can be T-cell therapy has produced impressive remissions in patients harnessed, in some cases, for its antitumor potential, clinically with advanced malignancies (1). In addition, therapeutic mono- relevant tumors appear to be marked by an immune system that clonal antibodies designed to disrupt inhibitory signals received actively selects for poorly immunogenic tumor clones and/or by T cells through the cytotoxic T-lymphocyte–associated antigen establishes a microenvironment that suppresses productive anti- 4 (CTLA-4; also known as CD152) and programmed cell death-1 tumor immunity (Fig.
    [Show full text]
  • Tumor Immunology 101 for the Non-Immunologist
    Tumor Immunology 101 For the Non-Immunologist Louis M. Weiner, MD Director, Lombardi Comprehensive Cancer Center Francis L. and Charlotte G. Gragnani Chair Professor and Chairman, Department of Oncology Georgetown University Medical Center Disclosure Consulting Fees Ownership Interest Abbvie Pharmaceuticals Celldex Novartis Jounce Merck Merrimack Genetech Symphogen Cytomax Immunovative Therapies, Ltd. Contracted Research Symphogen We Have Been at War Against Cancer Throughout Human History Tumor President Nixon declares a “War on Cancer” in 1971 Medieval Saxon man with a large tumor of the left femur Which Target? Hanahan, Weinberg, Cell 2000 The “War on Cancer” is fought one person at a time… • Primary Combatants: – Malignant cell population – Host immune system • The host immune system is the dominant active enemy faced by a developing cancer • All “successful” cancers must solve the challenges of overcoming defenses erected by host immune systems Which System? Hanahan, Weinberg, Cell 2011 The Case for Cancer Immunotherapy • Surprisingly few new truly curative anti- cancer cytotoxic drugs or targeted therapies in 20+ years – Tumor heterogeneity – Too many escape routes? • The immune response is designed to identify and disable “escape routes ” that cancers employ • Immunotherapy can cure cancers Immunotherapy • Treatment of disease by inducing, enhancing, or suppressing an immune response • “Treating the immune system so it can treat the cancer” (J. Wolchok) Some Examples of Successful Cancer Immunotherapy • Type 1 interferons – bladder
    [Show full text]
  • Molecular Subtypes of Anaplastic Oligodendroglioma: Implications for Patient Management at Diagnosis1
    Vol. 7, 839–845, April 2001 Clinical Cancer Research 839 Molecular Subtypes of Anaplastic Oligodendroglioma: Implications for Patient Management at Diagnosis1 Yasushi Ino, Rebecca A. Betensky, without TP53 mutations, which are poorly responsive, ag- Magdalena C. Zlatescu, Hikaru Sasaki, gressive tumors that are clinically and genotypically similar David R. Macdonald, to glioblastomas. Conclusions: These data raise the possibility, for the Anat O. Stemmer-Rachamimov, first time, that therapeutic decisions at the time of diagnosis 2 David A. Ramsay, J. Gregory Cairncross, and might be tailored to particular genetic subtypes of anaplastic David N. Louis oligodendroglioma. Molecular Neuro-Oncology Laboratory, Department of Pathology and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School [Y. I., H. S., A. O. S-R., D. N. L.] and Department of INTRODUCTION Biostatistics, Harvard School of Public Health, Boston, Massachusetts Malignant gliomas are the most common type of primary 02114 [R. A. B.], and Departments of Clinical Neurological Sciences, ϳ Oncology, and Pathology, University of Western Ontario and London brain tumor, with 12,000 new cases diagnosed each year in the Regional Cancer Centre, London, Ontario N6A 4L6, Canada United States (1). For nearly a century, malignant gliomas have [M. C. Z., D. R. M., D. A. R., J. G. C.] been classified on the basis of their histological appearance as astrocytomas (including glioblastomas), oligodendrogliomas, ependymomas, or mixed gliomas. For each type, surgical resec- ABSTRACT tion and radiation therapy have been the mainstays of treatment. Purpose: In a prior study of anaplastic oligodendrogli- Cytotoxic drugs have had a relatively minor therapeutic role omas treated with chemotherapy at diagnosis or at recur- because responses to chemotherapy generally have been infre- rence after radiotherapy, allelic loss of chromosome 1p cor- quent, brief, and unpredictable.
    [Show full text]