David Zagzag

Bio: David Zagzag is an academic researcher from New York University. The author has contributed to research in topics: Glioma & Angiogenesis. The author has an hindex of 75, co-authored 280 publications receiving 27272 citations. Previous affiliations of David Zagzag include University of York & Hebrew University of Jerusalem.

Prediction of central nervous system embryonal tumour outcome based on gene expression

Abstract: Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.

Overexpression of Hypoxia-inducible Factor 1α in Common Human Cancers and Their Metastases

Abstract: Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1α subunit. In this study, HIF-1α expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1α was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1α expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1α, whereas benign tumors in breast and uterus did not. HIF-1α overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1α immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1α may play an important role in human cancer progression.

Vessel Cooption, Regression, and Growth in Tumors Mediated by Angiopoietins and VEGF

Abstract: In contrast with the prevailing view that most tumors and metastases begin as avascular masses, evidence is presented here that a subset of tumors instead initially grows by coopting existing host vessels. This coopted host vasculature does not immediately undergo angiogenesis to support the tumor but instead regresses, leading to a secondarily avascular tumor and massive tumor cell loss. Ultimately, however, the remaining tumor is rescued by robust angiogenesis at the tumor margin. The expression patterns of the angiogenic antagonist angiopoietin-2 and of pro-angiogenic vascular endothelial growth factor (VEGF) suggest that these proteins may be critical regulators of this balance between vascular regression and growth.

Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging

Abstract: BACKGROUND AND PURPOSE: Sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of conventional MR imaging in predicting glioma grade are not high. Relative cerebral blood volume (rCBV) measurements derived from perfusion MR imaging and metabolite ratios from proton MR spectroscopy are useful in predicting glioma grade. We evaluated the sensitivity, specificity, PPV, and NPV of perfusion MR imaging and MR spectroscopy compared with conventional MR imaging in grading primary gliomas. METHODS: One hundred sixty patients with a primary cerebral glioma underwent conventional MR imaging, dynamic contrast-enhanced T2*-weighted perfusion MR imaging, and proton MR spectroscopy. Gliomas were graded as low or high based on conventional MR imaging findings. The rCBV measurements were obtained from regions of maximum perfusion. Metabolite ratios (choline [Cho]/creatine [Cr], Cho/N-acetylaspartate [NAA], and NAA/Cr) were measured at a TE of 144 ms. Tumor grade determined with the three methods was then compared with that from histopathologic grading. Logistic regression and receiver operating characteristic analyses were performed to determine optimum thresholds for tumor grading. Sensitivity, specificity, PPV, and NPV for identifying high-grade gliomas were also calculated. RESULTS: Sensitivity, specificity, PPV, and NPV for determining a high-grade glioma with conventional MR imaging were 72.5%, 65.0%, 86.1%, and 44.1%, respectively. Statistical analysis demonstrated a threshold value of 1.75 for rCBV to provide sensitivity, specificity, PPV, and NPV of 95.0%, 57.5%, 87.0%, and 79.3%, respectively. Threshold values of 1.08 and 1.56 for Cho/Cr and 0.75 and 1.60 for Cho/NAA provided the minimum C2 and C1 errors, respectively, for determining a high-grade glioma. The combination of rCBV, Cho/Cr, and Cho/NAA resulted in sensitivity, specificity, PPV, and NPV of 93.3%, 60.0%, 87.5%, and 75.0%, respectively. Significant differences were noted in the rCBV and Cho/Cr, Cho/NAA, and NAA/Cr ratios between low- and high-grade gliomas (P CONCLUSION: The rCBV measurements and metabolite ratios both individually and in combination can increase the sensitivity and PPV when compared with conventional MR imaging alone in determining glioma grade. The rCBV measurements had the most superior diagnostic performance (either with or without metabolite ratios) in predicting glioma grade. Threshold values can be used in a clinical setting to evaluate tumors preoperatively for histologic grade and provide a means for guiding treatment and predicting postoperative patient outcome.

Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts

Abstract: Id proteins may control cell differentiation by interfering with DNA binding of transcription factors. Here we show that targeted disruption of the dominant negative helix–loop–helix proteins Id1 and Id3 in mice results in premature withdrawal of neuroblasts from the cell cycle and expression of neural-specific differentiation markers. The Id1–Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm. As angiogenesis both in the brain and in tumours requires invasion of avascular tissue by endothelial cells, we examined the Id knockout mice for their ability to support the growth of tumour xenografts. Three different tumours failed to grow and/or metastasize in Id1+/-Id3-/- mice, and any tumour growth present showed poor vascularization and extensive necrosis. Thus, the Id genes are required to maintain the timing of neuronal differentiation in the embryo and invasiveness of the vasculature. Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design.

Targeting HIF-1 for cancer therapy

Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Repeated observation of breast tumor subtypes in independent gene expression data sets

Abstract: Characteristic patterns of gene expression measured by DNA microarrays have been used to classify tumors into clinically relevant subgroups. In this study, we have refined the previously defined subtypes of breast tumors that could be distinguished by their distinct patterns of gene expression. A total of 115 malignant breast tumors were analyzed by hierarchical clustering based on patterns of expression of 534 "intrinsic" genes and shown to subdivide into one basal-like, one ERBB2-overexpressing, two luminal-like, and one normal breast tissue-like subgroup. The genes used for classification were selected based on their similar expression levels between pairs of consecutive samples taken from the same tumor separated by 15 weeks of neoadjuvant treatment. Similar cluster analyses of two published, independent data sets representing different patient cohorts from different laboratories, uncovered some of the same breast cancer subtypes. In the one data set that included information on time to development of distant metastasis, subtypes were associated with significant differences in this clinical feature. By including a group of tumors from BRCA1 carriers in the analysis, we found that this genotype predisposes to the basal tumor subtype. Our results strongly support the idea that many of these breast tumor subtypes represent biologically distinct disease entities.

Identification of a Cancer Stem Cell in Human Brain Tumors

Abstract: Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.

Hypoxia — a key regulatory factor in tumour growth

Abstract: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.