The role of αv integrins during angiogenesis: insights into potential mechanisms of action and clinical development

Eliceiri, Brian P.; Cheresh, David A.

doi:10.1172/jci6869

Cited by 604 publications

(379 citation statements)

References 18 publications

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“…Integrin ␣ v␤3 was not only found on capillaries but also in the walls of larger vessels and in tumor stroma. These findings are consistent with ␣ v␤3 expression on vascular and intestinal smooth muscle cells (13).…”

Section: Discussionsupporting

confidence: 88%

Integrin αvβ3 Expression in Colon Carcinoma Correlates with Survival

Vonlaufen¹,

Wiedle²,

Borisch³

et al. 2001

Modern Pathology

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Integrin ␣ v ␤ 3 is expressed by newly formed blood vessels in diseased and neoplastic tissue and can therefore be used as a marker for angiogenesis. We investigated its expression on the vasculature of 40 colon carcinomas using the anti-␣ v ␤ 3 -specific monoclonal antibody LM609. The average relapsefree interval and overall survival in patients suffering from colon carcinomas with high vascular expression of ␣ v ␤ 3 integrin was significantly reduced compared with that in patients with low ␣ v ␤ 3 integrin expressing tumor vasculature. Moreover, the expression level of ␣ v ␤ 3 integrin correlated with the presence of liver metastases. In conclusion, we propose vascular expression of ␣ v ␤ 3 integrin as a prognostic indicator for colon carcinoma.

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Section: Discussionsupporting

confidence: 88%

Integrin αvβ3 Expression in Colon Carcinoma Correlates with Survival

Vonlaufen¹,

Wiedle²,

Borisch³

et al. 2001

Modern Pathology

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“…14,15,17,19 Extracellular matrix proteins are important adhesion ligands for anchoragedependent cells supporting survival, migration, proliferation and differentiation. 3 Cell adhesion to matrix proteins is mediated by specific cell surface receptors, among which integrins play an important role. The main cell-associated receptors for vitronectin are ␣v␤3 and ␣v␤5 and for tenascin ␣v␤3 and other ␣v-integrins.…”

Section: Discussionmentioning

confidence: 99%

αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

Taga

Suzuki

González-Gómez

et al. 2002

Intl Journal of Cancer

182

110

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Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the ␣v-integrin antagonist EMD 121974. This compound, a cyclic RGDpenta-peptide, is a potent inhibitor of angiogenesis, which induces apoptosis of growing endothelial cells through inhibition of their ␣v-integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the ␣v-integrin-expressing tumor cell lines U87 MG and DAOY by detaching them from vitronectin and tenascin, matrix proteins known to be essential for brain tumor growth and invasion. These matrix proteins are shown to be produced by the brain tumor cells in vitro and in vivo. Key words: brain tumor; xenograft; anti-angiogenesis; ␣v-integrins; apoptosisAngiogenesis, the recruitment of new blood vessels from existing capillaries, is essential for tumor growth and progression. 1 This complex process is characterized by proliferation, migration and invasion of capillary endothelial cells, as well as functional features that depend on their interactions with the surrounding extracellular matrix components. The expression of the integrin adhesion molecules ␣v␤3 and ␣v␤5 on sprouting capillary cells and their interaction with specific matrix ligands has been shown to play a key role in angiogenesis. [2][3][4] Although vitronectin is the only matrix ligand for ␣v␤5, the promiscuous ␣v␤3 receptor interacts with various matrix proteins including vitronectin, tenascin, fibronectin, fibrinogen, etc. 5 Ligand binding to these receptors through specific RGD motifs leads to complex intracellular signaling resulting in endothelial cell survival. 3,6,7 Consequently, blocking of these receptors with specific antibodies or RGD peptides results in endothelial cell apoptosis in vitro and suppression of angiogenesis in vivo, with subsequent suppression of tumor growth. 2,4 We have recently shown that the cyclic RGD pentapeptide EMD 121974, a specific ␣v-integrin antagonist, inhibited growth of brain tumor cell lines xenotransplanted into the forebrain of nu/nu mice, resulting in long-term survival. 8 In the present study, we investigated in more detail the mechanisms responsible for this growthinhibitory effect. Our data demonstrate that EMD 121974 detaches both the ␣v-integrin-expressing brain capillary and brain tumor cells from the matrix proteins vitronectin and tenascin, resulting in significant apoptosis of both cell types. We also show that the brain tumor cells produce these matrix proteins in vitro and in vivo. Furthermore, we found that only ␣v-integrin-expressing tumor cells responded in vivo to the treatment with EMD 121974. Taken together, these data suggest that EMD 121974 not only inhibits angiogenesis but is also cytotoxic for brain tumor cells. MATERIAL AND METHODS Cell linesThe human brain tumor cell lines DAOY (medulloblastoma) and U87MG (glioblastoma) were purchased from ATCC (Manassas, VA) and grown in RPMI-1640 medium with 10% FBS in 5% CO 2 at 37°C. Primary human and mouse brain capillar...

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“…Integrins are involved in a direct interaction of cells with matrix and each combination of ␣␤-subunit has its own binding specificity. Next to regulation of cell migration by providing cell-matrix interactions integrins are also thought to regulate degradation of ECM [63,66].…”

Section: Cell-matrix Interactionmentioning

confidence: 99%

“…This integrin can bind vitronectin and fibronectin and various other proteins with an arginine-glycine-aspartic acid (RGD) (Arg-Gly-Asp) sequence, like fibrinogen, von Willebrand factor and denatured collagen [62,66]. Different reports have correlated expression of integrins with more invasive phenotypes of tumor cells and activation of MT1-MMP and MMP-2 [67,[69][70][71].…”

Section: Cell-matrix Interactionmentioning

confidence: 99%