Constitutive upregulation of hypoxia-inducible factor-1α mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure

Koshikawa, Nobuko; Iyozumi, Ayako; Gassmann, Max; Takenaga, Keizo

doi:10.1038/sj.onc.1206765

Cited by 58 publications

(47 citation statements)

References 32 publications

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“…For example, our group has recently shown that amino acid substitutions in the Spalax p53 gene are identical to known tumor-associated mutations (26,27). VEGF expression in Spalax muscle was constitutively high, a pattern similar to its expression in highly metastatic tumor cells (24,25,28). Also, erythropoietin expression levels in Spalax exhibit a higher increment under hypoxia, relative to other rodents (20).…”

Section: Discussionmentioning

confidence: 93%

“…These adaptive substitutions endow Spalax p53 with severalfold higher activation of cell arrest and DNA repair genes compared to human p53, and they also favor activation of DNA repair genes over apoptotic genes. Expression of VEGF was constitutively high in Spalax muscles, regardless of the oxygen levels, similar to its expression in highly metastatic tumor cells (28) and unlike its levels in rat muscle (25).…”

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confidence: 78%

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Adaptive evolution of heparanase in hypoxia-tolerantSpalax: Gene cloning and identification of a unique splice variant

Nasser

Nevo

Shafat

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Heparan sulfate (HS) side chains of HS proteoglycans bind to and assemble extracellular matrix proteins and play important roles in cell-cell and cell-extracellular matrix interactions. HS chains bind a multitude of bioactive molecules and thereby function in the control of multiple normal and pathological processes. Enzymatic degradation of HS by heparanase, a mammalian endoglycosidase, affects the integrity and functional state of tissues and is involved in, among other processes, inflammation, angiogenesis, and cancer metastasis. Here, we report the cloning of heparanase from four Israeli species of the blind subterranean mole rat (Spalax ehrenbergi superspecies), 85% homologous to the human enzyme. Unlike its limited expression in human tissues, heparanase is highly expressed in diverse Spalax tissues. Moreover, we have identified a unique splice variant of the Spalax enzyme lacking 16 aa encoded by exon 7. This deletion resulted in a major defect in trafficking and processing of the heparanase protein, leading to a loss of its enzymatic activity. Interspecies variation was noted in the sequence and in the expression of the splice variant of the heparanase gene in blind mole rats living under different ecogeographical stresses, indicating a possible role in adaptation to stress in Spalax evolution.alternative splicing ͉ heparan sulfate ͉ blind mole rat ͉ angiogenesis ͉ cancer H eparan sulfate (HS) proteoglycans are macromolecules associated with the cell surface and the extracellular matrix (ECM) of a wide range of cells of vertebrate and invertebrate tissues (1-3). HS binds to and assembles ECM proteins and plays important roles in the structural integrity of the ECM and in cell-cell and cell-ECM interactions. HS chains sequester a multitude of proteins and bioactive molecules and thereby function in the control of a large number of normal and pathological processes (1-4). Apart from sequestration of bioactive molecules, HS proteoglycans have a coreceptor role in which the proteoglycan, in concert with the other cell surface molecule, comprises a functional receptor complex that binds the ligand and mediates its action (3-5).Enzymatic degradation of HS by heparanase, a mammalian endoglucuronidase, affects the integrity and functional state of tissues and is involved in fundamental biological phenomena, ranging from pregnancy, morphogenesis, and development to inf lammation, angiogenesis, and cancer metastasis (6 -10). Heparanase elicits an indirect angiogenic response by releasing HS-bound angiogenic growth factors [e.g., basic fibroblast growth factor and vascular endothelial growth factor (VEGF)] from the ECM and by generating HS fragments that potentiate basic fibroblast growth factor receptor binding, dimerization, and signaling (5, 8). Despite earlier reports on the existence of several distinct mammalian HS-degrading endoglycosidases (heparanases), the cloning of the same single gene by several groups (6,7,11,12) suggests that mammalian cells express primarily a single dominant functional heparanase e...

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 78%

Adaptive evolution of heparanase in hypoxia-tolerantSpalax: Gene cloning and identification of a unique splice variant

Nasser

Nevo

Shafat

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The cell lines, P29, P34, C2, D6 and A11, established from Lewis lung carcinoma, have been characterized elsewhere (Takasu et al, 1999;Koshikawa et al, 2003). They were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum supplemented with 100 units/ml penicillin and 100 mg/ml streptomycin.…”

Section: Cell Culturementioning

confidence: 99%

Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors

et al. 2005

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Low oxygen tension (hypoxia) is a common feature of solid tumors and stimulates the expressions of a variety of genes including those related to angiogenesis, apoptosis and endoplasmic reticulum (ER) stress response. Here we show a close correlation between metastatic potential and the resistance to hypoxia-and ER stress-induced apoptosis among the cell lines with differing metastatic potential derived from Lewis lung carcinoma. An apoptosis-specific expression profiling and immunoblot analyses revealed that the expression of antiapoptotic Mcl-1 increased as the resistance to apoptosis increased. Downregulation of the Mcl-1 expression in the high-metastatic cells by Mcl-1 small interfering RNA increased the sensitivity to hypoxia-induced apoptosis and decreased the metastatic ability. The hypoxia-induced apoptosis was not associated with p53 accumulation, although at present it is not possible to conclude that apoptosis-induced apoptosis is p53-independent. There was no correlation between the expression levels of ER stress-response proteins GADD153, GRP78 and ORP150 and the resistance to hypoxia or ER stresses. In vitro, small numbers of the high-metastatic cells overtook the low-metastatic cells after exposure to several rounds of hypoxia and reoxygenation. In solid tumors initially established from equal mixtures, the proportion of the high-metastatic cells to low-metastatic cells was significantly higher in hypoxic areas. Moreover, the high-metastatic cells were overtaking the low-metastatic cells in some of the tumors. Thus, tumor hypoxia and ER stress may provide a physiological selective pressure for the expansion of the high-metastatic cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors.

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“…Furthermore, the spread of malignant tumour cells from the primary neoplasm to distant sites is influenced by the angiogenic potential and oxygenation status of the tumour (9,10). Tumour cells exposed to hypoxia show increased expression of the pro-angiogenic protein, VEGF (vascular endothelial growth factor) (11).…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

Barr

Bouchier‐Hayes²,

Harmey³

2008

Int J Oncol

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Abstract. Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti-and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy.

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Constitutive upregulation of hypoxia-inducible factor-1α mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure

Cited by 58 publications

References 32 publications

Adaptive evolution of heparanase in hypoxia-tolerantSpalax: Gene cloning and identification of a unique splice variant

Adaptive evolution of heparanase in hypoxia-tolerantSpalax: Gene cloning and identification of a unique splice variant

Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

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