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Malignant Glioma Physiology: Cellular Response to Hypoxia and Its Role in Tumor Progression

Daniel J. Brat, MD, PhD; and Timothy B. Mapstone, MD
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From Emory University School of Medicine, Atlanta, Georgia.

For definition of terms used, see Glossary.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Daniel J. Brat, MD, PhD, Department of Pathology and Laboratory Medicine, Emory University Hospital, H-176, 1364 Clifton Road NE, Atlanta, GA 30322; e-mail, dbrat@emory.edu.

Current Author Addresses: Dr. Brat: Department of Pathology and Laboratory Medicine, Emory University Hospital, H-176, 1364 Clifton Road NE, Atlanta, GA 30322.

Dr. Mapstone: Emory University, 1365B Clifton Road, Atlanta, GA 30322.

Ann Intern Med. 2003;138(8):659-668. doi:10.7326/0003-4819-138-8-200304150-00014
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It has been estimated that solid tumors cannot grow larger than 1 to 2 mm without forming new blood vessels (angiogenesis; see Glossary) (5). These estimations may not precisely apply to infiltrative astrocytomas, since neoplastic cells can migrate within the brain toward preexisting vascular supplies. However, considering the various histologic subtypes and molecular pathways of astrocytomas, the features of angiogenesis are remarkably consistent and suggest that new blood vessels are necessary for high-grade progression (6).

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Figure 1.
Axial magnetic resonance image demonstrating the features of glioblastoma multiforme.arrow

This intra-axial neoplasm located in the left frontoparietal region shows ring-like contrast enhancement, mass effect, and surrounding vasogenic edema that are typical of glioblastoma ( ).

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Figure 2.
Histopathologic and immunohistochemical features of glioblastoma multiforme.AClong arrowsACshort arrowsbottomBC

Within glioblastoma multiforme, microvascular hyperplasia ( – ; ) is often noted in regions adjacent to necrosis with pseudopalisading cells ( – ; ). In this instance, microvascular hyperplasia is in the form of glomeruloid vascular proliferation, with newly formed vessels oriented toward the hypoxic regions associated with pseudopalisading necrosis ( ). Immunohistochemistry for CD31 highlights rapidly dividing endothelial cells within glomeruloid bodies ( ), while smooth-muscle actin stains pericytes ( ).

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Figure 3.
Progression of infiltrating astrocytoma (World Health Organization [ WHO ] grade II, left ) to glioblastoma multiforme (WHO grade IV, right ).far leftblack arrowswhite arrow

In grade II infiltrating astrocytomas, individual tumor cells (black structures) percolate through central nervous system parenchyma. The vascular architecture and density are similar to normal brain ( ). Astrocytoma cells become more numerous and atypical and show occasional mitotic figures in anaplastic astrocytoma (WHO grade III). In glioblastoma multiforme, tumor cells are tightly aggregated in pseudopalisading structures around foci of necrosis ( ). Nearby, microvascular hyperplasia is present, often in the form of glomeruloid vascular proliferation ( ). The biological, genetic, and angiogenic events that occur during the progression to glioblastoma multiforme are listed below the diagram. Not all genetic events occur within an individual neoplasm. EGFR = epidermal growth factor receptor; PDGFR = platelet-derived growth factor receptor; VEGF = vascular endothelial growth factor.

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Figure 4.
Genetic changes in glioblastoma multiforme ( GBM ).

Alterations in several genetic pathways, either individually or in combination, can lead to the single histopathologic entity glioblastoma multiforme. EGFR = epidermal growth factor receptor; PDGFR = platelet-derived growth factor receptor; Rb = retinoblastoma.

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Figure 5.
Schematic representation of the effects of oxygen, tumor suppressor genes, oncogenes, and intracellular signaling pathways on hypoxia-inducible factor ( HIF )–mediated gene transcription in malignant gliomas.VHLCBPGlossaryHREPTENTP53p14 ARF EGFRPDGFREGFRPDGFRPI[3]KPTEN(3, 4, 5)PDK-1ARFARF

In the presence of oxygen, HIF-1α is hydroxylated at proline 564 and at asparagine 803. Proline 564 hydroxylation causes enhanced von Hippel–Lindau protein ( )–mediated ubiquitination and proteasomal degradation of HIF-1α. Asparagine 803 hydroxylation blocks the interaction of HIF-1α with the nuclear co-activator CREB-binding protein ( )/p300, thereby inhibiting transactivation (see ) of HIF-1 target genes. Under hypoxic conditions, HIF-1α is not hydroxylated at proline 564 or asparagine 803. In this instance, HIF-1α protein accumulates, dimerizes with HIF-1β, binds to the hypoxia-responsive element ( ) in the target gene promoter, and interacts with CBP/p300 to promote gene transcription. , , , , and genes are altered during the progression to glioblastoma multiforme in manners that may enhance HIF-induced transcription of target genes, including vascular endothelial growth factor. Increased activity of epidermal growth factor receptor ( ) and platelet-derived growth factor receptor ( ) cause elevated HIF-1α protein levels through upregulation of the phosphatidylinositol 3-kinase ( )–Akt pathway. Loss of activity leads to elevated PIP3 , which in turn activates phosphatidylinositol-dependent kinase 1 ( ) and Akt, ultimately leading to increased HIF-1α protein. Loss of p53 leads to decreased p53–MDM2-mediated degradation of HIF-1α and increased HIF-mediated transcription. Hypoxia-inducible factor activity is normally inhibited by nucleolar sequestration of HIF-1α by p14 and, therefore, loss of p14 would be expected to enhance HIF-mediated transcription. El.B = elongin B; El.C = elongin C.

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