Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells.

Gladson, Candece L.; Cheresh, David A.

doi:10.1172/jci115516

Cited by 387 publications

(236 citation statements)

References 34 publications

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“…Fibronectin and vitronectin are two major components in extracellular matrix that cells bind through extracellular domain of integrin a V b 3 (Gladson and Cheresh, 1991). The key recognition motif is the amino acid triplet Arg-Gly-Asp (RGD) (Sinanan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Integrin a V b 3 signaling intensifies after JWA knockdown To elucidate the molecular mechanism involved in the increased metastasis of melanoma cells after JWA knockdown, we focused on the regulation of JWA on integrin a V b 3 for the following reasons: (1) integrin a V b 3 is a well-known key factor for tumor metastasis; (2) integrin a V b 3 is upregulated in melanoma; and (3) fibronectin and vitronectin are ligands for a V b 3 (Albelda et al, 1990;Gladson and Cheresh, 1991;Nip and Brodt, 1995;Horton, 1997). Therefore, we hypothesized that JWA may inhibit melanoma metastasis by suppressing integrin a V b 3 signaling.…”

Section: Jwa Suppresses Cell Invasion and Matrix Metalloproteinases (mentioning

confidence: 99%

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JWA regulates melanoma metastasis by integrin αVβ3 signaling

Bai

Zhang

et al. 2009

Oncogene

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JWA, a newly identified novel microtubule-associated protein (MAP), was recently demonstrated to be indispensable for the rearrangement of actin cytoskeleton and activation of MAPK cascades induced by arsenic trioxide (As 2 O 3 ) and phorbol ester (PMA). JWA depletion blocked the inhibitory effect of As 2 O 3 on HeLa cell migration, but enhanced cell migration after PMA treatment. As cancer cell migration is a hallmark of tumor metastasis and the functional role of JWA in cancer metastasis is not understood, here we show that JWA has an important role in melanoma metastasis. Our data demonstrated that JWA knockdown increased the adhesion and invasion abilities of melanoma cells. Furthermore, JWA knockdown in B16-F10 and A375 melanoma cells significantly promoted the formation and growth of metastatic colonies in vivo. Moreover, in the tumor biopsies from human melanoma patients, JWA expression was significantly decreased in malignant melanoma compared with normal nevi. In addition, we found that JWA knockdown could intensify tumor integrin a V b 3 signaling by regulating nuclear factor Sp1. These findings suggest that JWA suppresses melanoma metastasis and may serve a potential therapeutic target for human melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Jwa Suppresses Cell Invasion and Matrix Metalloproteinases (mentioning

confidence: 99%

JWA regulates melanoma metastasis by integrin αVβ3 signaling

Bai

Zhang

et al. 2009

Oncogene

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“…17,110 Some tumors that express an integrin inappropriate to their local ECM simply secrete a required ECM component that permits ligation of the integrin. 111,112 In others, tumors may activate cytosolic signaling pathways downstream of integrins that regulate apoptosis. As Figure 2 The regulation of cell survival by integrins.…”

Section: Physiological Roles For Cellular 'Dependence' On the Ecmmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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“…The presence of these integrins in capillaries and tumor cells of human brain tumors has been described. 15 Sections of snap-frozen brain tumors were examined for murine ␣v-and ␤3-integrin expression with immunofluorescence using specific monoclonal hamster anti-mouse antibodies. Intense fluorescence was documented in the invasive areas of the tumors, whereas the center of the tumors and the normal brain showed only faint background fluorescence (Fig.…”

Section: In Vivo Studiesmentioning

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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Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells.

Cited by 387 publications

References 34 publications

JWA regulates melanoma metastasis by integrin αVβ3 signaling

JWA regulates melanoma metastasis by integrin αVβ3 signaling

Integrins as a distinct subtype of dependence receptors

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

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