Nuclear localization of long-VEGF is associated with hypoxia and tumor angiogenesis

Rosenbaum-Dekel, Yifat; Fuchs, Alisa; Yakirevich, Evgeny; Azriel, Aviva; Mazareb, Salam; Resnick, Murray B.; Levi, Ben‐Zion

doi:10.1016/j.bbrc.2005.04.123

Cited by 33 publications

(35 citation statements)

References 20 publications

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“…A wide range of cytokines, oncogenic proteins, or transcription factors, such as insulin-like growth factor 1, c-Src, Ras, nuclear factor-nB (NF-nB), and SP1, have been shown to regulate VEGF gene transcription (7)(8)(9). Hypoxic condition can also affect VEGF mRNA stability (10) and translation initiation (11). Extracellular cleavage of VEGF by uPA (12,13) or plasmin (14) and processing by MMPs can regulate its mitogenic effect, bioavailability, and vascular patterning in tumors (15).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Angiogenesis and Invasion by 3,3′-Diindolylmethane Is Mediated by the Nuclear Factor–κB Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer

et al. 2007

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Progression of prostate cancer is believed to be dependent on angiogenesis induced by tumor cells. 3,3 ¶-Diindolylmethane (DIM) has been shown to repress neovascularization in a Matrigel plug assay and inhibit cell proliferation, migration, invasion, and capillary tube formation of cultured human umbilical vein endothelial cells. However, the molecular mechanism, by which DIM inhibits angiogenesis and invasion, has not been fully elucidated. Therefore, we sought to explore the molecular mechanism by which DIM inhibits angiogenesis and invasion, specifically by investigating the role of angiogenic factors secreted by prostate cancer cells which control all steps of angiogenesis. We found that BioResponse DIM (B-DIM), a formulated DIM with higher bioavailability, inhibited angiogenesis and invasion by reducing the bioavailability of vascular endothelial growth factor (VEGF) via repressing extracellular matrix-degrading proteases, such as matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA), in human prostate cancer cells and reduced vascularity (angiogenesis) in vivo using Matrigel plug assay. We also found that B-DIM treatment inhibited DNA binding activity of nuclear factor-KB (NF-KB), which is known to mediate the expression of many NF-KB downstream target genes, including VEGF, IL-8, uPA, and MMP-9, all of which are involved in angiogenesis, invasion, and metastasis. Our data suggest that inhibition of NF-KB DNA binding activity by B-DIM contributes to the regulated bioavailability of VEGF by MMP-9 and uPA and, in turn, inhibits invasion and angiogenesis, which could be mechanistically linked with the antitumor activity of B-DIM as observed previously by our laboratory in a prostate cancer animal model. [Cancer Res 2007;67(7):3310-9]

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Section: Introductionmentioning

confidence: 99%

Inhibition of Angiogenesis and Invasion by 3,3′-Diindolylmethane Is Mediated by the Nuclear Factor–κB Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer

et al. 2007

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“…In addition to splice variants, a long VEGF (L-VEGF) isoform has been recently described initiating at a CUG codon, which ensures efficient translation under stress conditions such as hypoxia [11,12,19,21,35]. L-VEGF is cleaved after translocation of the protein into the endoplasmic reticulum, as has already been observed for precursor proteins of transforming growth factor b1 or insulin, which also accumulate as immature isoforms in the Golgi structures [12].…”

Section: Discussionmentioning

confidence: 95%

“…VEGF plays a major role in tumor growth and development of metastases via specific receptor tyrosine kinases that are up-regulated during angiogenesis [11,[19][20][21]. VEGF is known to play major roles in different steps of tumor development, with increase of microvascular permeability, permeabilization of blood vessels, extravasation of plasma proteins, induction of endothelial cell division and migration, promotion of endothelial cell survival, and reversal of endothelial cell senescence causing the sprouting of new blood vessels to supply the tumor with oxygen and nutrients [22][23][24][25].…”

Section: Discussionmentioning

confidence: 99%

Plasma level and tissue expression of vascular endothelial growth factor in renal cell carcinoma: a prospective study of 50 cases

et al. 2007

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“…However, these same themes are displayed by many of the cancer cells that stimulate an angiogenic response in endothelial cells. (72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87) These biological parallels give rise to the concept of ''intracrine reciprocity'' between some cancer cells and endothelial cells, meaning that the regulatory (intracrine) loops of one type of cells spill over to affect the other. These loops are to be viewed as acting in addition to any paracrine signaling occurring in the tissue and are characterized by the participation of intracrine intracellular action and the creation of self-sustaining feed-back circuits.…”

Section: Neoplasia Angiogenesis and Intracrine Reciprocitymentioning

confidence: 97%

An intracrine view of angiogenesis

Ré

Cook

2006

BioEssays

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Angiogenesis, the generation of new blood vessels from pre-existing vessels, is an integral component of wound healing, responses to inflammation and other physiologic processes. It is also an essential part of tumor growth; in the absence of new vessel formation, tumors cannot expand beyond a small volume. Although much is known about angiogenesis and its regulation, there is no overall theory that describes or explains this process. It is here suggested that the intracrine hypothesis, which ascribes to certain extracellular signaling peptides (whether hormones, growth factors, DNA-binding proteins or enzymes) a role in both intracellular biology and extracellular signaling, can contribute to a more general understanding of angiogenesis. Intracrine factors participate in angiogenesis in the following ways: (1) they can act within the cells that synthesized them (type I intracrine action), (2) they can be secreted and then taken up by their cell of synthesis to act intracellularly (type II intracrine action ), or (3) they can be secreted and internalized by a distant target cell (type III intracrine action). The parallels between the intracrine growth factor mechanisms cancer cells employ in stimulating their own growth and the mechanisms operative in endothelial cell proliferation during angiogenesis ("intracrine reciprocity") are discussed. Collectively, these explorations lead to testable hypotheses regarding the regulation of normal and pathological angiogenesis, and point to similarities between tumor-induced angiogenesis and tissue differentiation.

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Nuclear localization of long-VEGF is associated with hypoxia and tumor angiogenesis

Cited by 33 publications

References 20 publications

Inhibition of Angiogenesis and Invasion by 3,3′-Diindolylmethane Is Mediated by the Nuclear Factor–κB Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer

Inhibition of Angiogenesis and Invasion by 3,3′-Diindolylmethane Is Mediated by the Nuclear Factor–κB Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer

Plasma level and tissue expression of vascular endothelial growth factor in renal cell carcinoma: a prospective study of 50 cases

An intracrine view of angiogenesis

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