Intratumoral histologic heterogeneity of gliomas. A quantitative study

Paulus, Werner; Peiffer, J.

doi:10.1002/1097-0142(19890715)64:2<442::aid-cncr2820640217>3.0.co;2-s

Cited by 188 publications

(89 citation statements)

References 19 publications

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“…In gliomas there are large variations in the activities of enzymes involved in both purine and pyrimidine metabolism. Tlhis is in agreement with the well-documented heterogeneity of these neoplasms in terms of morphological and immunochemical properties and metabolic behaviour (Bigner et al, 1981;Paulus & Pfeiffer, 1989;Shapiro, 1986). Despite these variations, our results show that glial tumours exhibit a characteristic profile of purine and pyrimidine metabolism compared with non-glial neoplasms (Figure 4).…”

Section: Disc-ssiomsupporting

confidence: 86%

Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations

Bardot

Dutrillaux²,

Delattre³

et al. 1994

Br J Cancer

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3Clinique Neurologique, H6pital de la Salptriere, 47 boulevard de l'Hopital, 75 651 Paris cedex 13, France. SmaryChromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occasionally an excess of chromosome 7 and a loss of sex chromosome are observed. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losses or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromosomes 19 and 20. To understand the meaning of these chromosome imblances, the relationships between chromosome abnormalities and metabolic disturbances were studied. The losses or deletions observed affected principally chromosomes carrying genes encoding enzymes involved in punne metabolism. The activities of ten enzymes were measured: adenosine kinase, adenine phosphoribosyltransferase, adenylate kinase, methylthioadenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adenylosuccinate lyase, inosine monophosphate dehydrogenase, adenosine deaminase, nuckoside phosphorylase and adenosine monophosphate deaminase. In paralkle, two enzymes involved in pyrimidine metabolism, thymidine kinase and thymidylate synthase (TS), were studied. The activities of all these enzymes were measured on samples from 30 human primary glial tumours with low or high malignancy, six xenografted tumours at different passages, four portions of normal brain tissue and four non-gal brain neoplasms. As suggested by cytogenetic data, the enzymatic results showed a relatively low activity of puine metabolism in ghal tumours when compared with normal brain and non-glial brain neoplasms. Considering the two enzymes involved in pyrimidine metabolism, only T'S had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balanc between salvage and de novo pathways changes in gliomas, and even more in grafted tumours, in favour of de novo synthesis. The relation between chromosomes and metabolic imbalancs does not correspond to a simple gene dosage effect in these tumours.These data suggest that the dcrease of adenosine metabolism ocus before chromosomal aberrations appear, since it is observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progression.

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Section: Disc-ssiomsupporting

confidence: 86%

Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations

Bardot

Dutrillaux²,

Delattre³

et al. 1994

Br J Cancer

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“…Heterogeneity is a prominent feature of high-grade astrocytomas (36). This heterogeneity is multifaceted and is considered, for example, with respect to the proliferative capacity of cells within a tumor, invasion and motility, mutations in tumor-suppressor genes and oncogenes, altered gene expression due to factors in the tumor microenvironment, such as hypoxia or neovascularization, and altered expression of plasma membrane receptors.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-13 Receptor α2, EphA2, and Fos-Related Antigen 1 as Molecular Denominators of High-Grade Astrocytomas and Specific Targets for Combinatorial Therapy

Wykosky¹,

Gibo²,

Stanton

et al. 2008

Clinical Cancer Research

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Purpose: We investigated the expression of interleukin-13 receptor a2 (IL-13Ra2), EphA2, and Fos-related antigen 1 (Fra-1) in astrocytomas and normal brain.We sought to document whether the expression of the three factors changed with progression to higher grade malignancy and whether two or three targets in combination might be sufficient to target all patients with highgrade astrocytomas. Experimental Design: Immunohistochemistry was done for IL-13Ra2, EphA2, and Fra-1using human brain tumor tissue microarrays containing 30 specimens of WHO grades II and III astrocytomas, 46 glioblastoma multiformes (GBM), and 9 normal brain samples. Sections were scored based on frequency and intensity of expression. Western blotting was done for all three markers using GBM tumor specimens and xenograft cell lines. Two cytotoxins, IL-13.E13K.PE38QQR and ephrinA1-PE38QQR, which target IL-13Ra2 or EphA2, respectively, were tested for cytotoxicity against human GBM primary explant cells and established cells. Results: Expression of all three proteins was significantly higher in GBM compared with normal brain, low-grade, and anaplastic astrocytomas. Greater than 95% of GBM overexpressed at least two of the three markers. Importantly, every GBM overexpressed at least one marker. Human GBM primary explant cells and cell lines were potently killed by IL-13.E13K.PE38QQR and ephrinA1-PE38QQR, in accordance with their level of expression of IL-13Ra2 and EphA2, respectively. Conclusions: IL-13Ra2, EphA2, and Fra-1 are attractive therapeutic targets representing molecular denominators of high-grade astrocytomas. One hundred percent of GBM tumors overexpress at least one of these proteins, providing the basis for rational combinatorial targeted therapies/diagnostics suitable for all patients with this disease.High-grade astrocytomas, including WHO grade IV glioblastoma multiforme (GBM), are the most common adult primary malignant brain tumor and respond poorly to the current standard treatments of surgery, radiation, and chemotherapy. The mean survival rate of patients with GBM is f14 months and has improved only slightly over the past several decades. GBM tumors are highly infiltrative, resulting in residual invasive tumor cells after surgical resection and leading, in part, to the high rate of recurrence that contributes to the poor clinical outcome (1). Moreover, these tumors are often resistant to radiotherapy and chemotherapy (1, 2), the former of which is known to cause radiation-induced damage to the normal brain tissue, resulting in acute and chronic cognitive impairment (3). Molecularly targeted therapies have thus emerged as a way to increase the specificity and efficacy of antibrain tumor therapy. High-grade astrocytomas, in general, and GBM, in particular, are very heterogenous tumors, within which the tumor cells themselves often display different molecular profiles based on variables, such as the tumor microenvironment (4). Thus, a rational therapeutic approach may require more than one molecular target, which, in c...

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“…The system of the World Health Organization (WHO) classifies the most frequent brain tumors, the gliomas, into 4 grades (Table 1), with grades I and II being benign; grade III being anaplastic; and grade IV, glioblastoma multiforme, being the most malignant tumor with the worst prognosis (4). Histologic grading is based on tissue biopsies, which may not be representative since gliomas are frequently heterogeneous (5). Thus, imaging indicators of tumor grade and prognosis may be of additional value.…”

Section: Diagnosis and Gradingmentioning

confidence: 99%

Multimodality Assessment of Brain Tumors and Tumor Recurrence

Heiss¹,

Raab²,

Lanfermann³

2011

J Nucl Med

124

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Learning Objectives: On successful completion of this activity, participants should be able to describe (1) the differences in the information obtained by various MRI and PET modalities and (2) the best combination of imaging procedures to detect brain tumors, to define the biologic activity or malignancy of a tumor, to validate therapeutic effects, and to differentiate between recurrent tumor and tissue necrosis.Financial Disclosure: The authors of this article have indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNM is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNM designates each JNM continuing education article for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only credit commensurate with the extent of their participation in the activity.For CE credit, participants can access this activity through the SNM Web site (http://www.snm.org/ce_online) through October 2012.Neuroimaging plays a significant role in the diagnosis of intracranial tumors, especially brain gliomas, and must consist of an assessment of location and extent of the tumor and of its biologic activity. Therefore, morphologic imaging modalities and functional, metabolic, or molecular imaging modalities should be combined for primary diagnosis and for following the course and evaluating therapeutic effects. MRI is the gold standard for providing detailed morphologic information and can supply some additional insights into metabolism (MR spectroscopy) and perfusion (perfusion-weighted imaging) but still has limitations in identifying tumor grade, invasive growth into neighboring tissue, and treatment-induced changes, as well as recurrences. These insights can be obtained by various PET modalities, including imaging of glucose metabolism, amino acid uptake, nucleoside uptake, and hypoxia. Diagnostic accuracy can benefit from coregistration of PET results and MRI, combining the high-resolution morphologic images with the biologic information. These procedures are optimized by the newly developed combination of PET and MRI modalities, permitting the simultaneous assessment of morphologic, functional, metabolic, and molecular information on the human brain. Brai n tumors are newly formed alterations of morphology, and for their diagnosis, therefore, CT or MRI is mandatory. These imaging modalities are essential for delineating the normal and pathologic anatomy and also for assessing vascular supply and impairment of the blood-brain barrier (BBB) (perfusion-weighted imaging; contrast enhancement). Additionally, MRI is capable of giving functional information on microstructural (diffusion-weighted imaging [DWI]), physiologic, and metabolic (MR spectroscopy [MRS]) changes of tumor tissues. PET and MRI provide physiologic, biochemical, and molecular information related to tumor metabolism, proliferation rate, invasiveness, and interaction with surrounding and remote areas-informati...

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Intratumoral histologic heterogeneity of gliomas. A quantitative study

Cited by 188 publications

References 19 publications

Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations

Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations

Interleukin-13 Receptor α2, EphA2, and Fos-Related Antigen 1 as Molecular Denominators of High-Grade Astrocytomas and Specific Targets for Combinatorial Therapy

Multimodality Assessment of Brain Tumors and Tumor Recurrence

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