Regulation of angiogenesis: apoptotic cues from the ECM

Cheresh, David A.; Stupack, Dwayne G.

doi:10.1038/onc.2008.304

Cited by 117 publications

(116 citation statements)

References 142 publications

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“…In the last step, the new vessel is stabilized by the recruitment of accessory cells, such as pericytes, and they form a lumen for the blood flow (Folkman, 2003). Extracellular proteolysis is an indispensable process in angiogenesis that is required for degradation of the ECM and the regulation of cytokine activity (Cheresh and Stupack, 2008).…”

Section: Discussionmentioning

confidence: 99%

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

Valapala

Thamake

Vishwanatha

2011

Journal of Cell Science

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SummaryExtracellular proteolysis is an indispensable requirement for the formation of new blood vessels during neovascularization and is implicated in the generation of several angiogenic regulatory molecules. Anti-proteolytic agents have become attractive therapeutic strategies in diseases associated with excessive neovascularization. Annexin A2 (AnxA2) is an endothelial cell-surface receptor for the generation of active proteolytic factors, such as plasmin. Here, we show that AnxA2 is abundantly expressed in the neovascular tufts in a murine model of neovascularization. Exposure to hypoxic conditions results in elevation of AnxA2 and tissue plasminogen activator (tPA) in human retinal microvascular endothelial cells (RMVECs). We show that the hexapeptide competitive inhibitor LCKLSL, which targets the N-terminal tPA-binding site of AnxA2, binds efficiently to cell-surface AnxA2 compared with binding of the control peptide LGKLSL. Treatment with the competitive peptide inhibits the generation of plasmin and suppresses the VEGFinduced activity of tPA under hypoxic conditions. Application of the competitive peptide in two in vivo models of angiogenesis demonstrated suppression of the angiogenic responses, which was also associated with significant changes in the vascular sprouting. These results suggest that AnxA2-mediated plasmin generation is an important event in angiogenesis and is inhibited by a specific competitive peptide that inhibits the binding of tPA to AnxA2.

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Section: Discussionmentioning

confidence: 99%

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

Valapala

Thamake

Vishwanatha

2011

Journal of Cell Science

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“…16 The family of matrix metalloproteinases has a major function in these processes. 17 In the extracellular matrix, the activity of matrix metalloproteinases can be inhibited by a family of natural inhibitors, which is termed as tissue inhibitors of metalloproteinase.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

Zhang

Zhao

et al. 2009

Cancer Gene Ther

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The destruction of extracellular matrix by matrix metalloproteinases is a key event in cancer progression. The tissue inhibitors of metalloproteinases can restrain tumor growth by inhibiting these enzymes. We sought to determine whether overexpression of tissue inhibitor of metalloproteinase-3 (TIMP-3) could suppress the malignant phenotype of human prostate cancer cell line PC-3M. Stable overexpression of TIMP-3 inhibited cell proliferation significantly by MTT assay. Both early and late apoptosis were observed in TIMP-3 overexpressing cells, and flow cytometry analysis showed S-phase blocking of the cell cycle. Monolayer invasion assay and transwell invasion assay showed significantly decreased invasive potential in TIMP-3 overexpressing cells compared with control cells. Cell adhesion and motility were also lower after TIMP-3 was overexpressed. In vivo, cells stably overexpressing TIMP-3 completely lost the ability to form tumors after injection into nude mice. Transfection of TIMP-3 into established tumors by electroporation also had a significant antitumor effect. TIMP-3-treated tumor tissues had significant apoptosis by TUNEL assay. These results showed that overexpression of TIMP-3 inhibits invasion and proliferation of prostate cancer cells in vitro and inhibits tumor growth in vivo. The experiments suggest a potential use for TIMP-3 in the gene therapy of prostate cancer.

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“…The cellular components are surrounded by and intermingled with a complex network of extracellular matrix (ECM) molecules that sustain and favor communication between the cells and the external milieu. One key role of the ECM that has gained prominent recognition is the regulation of tumor angiogenesis (Cheresh and Stupack, 2008;Nyberg et al, 2008). During blood vessel sprouts, endothelial cells (ECs) must not only coordinate cytoskeletal changes to move through the tissues but also secrete proteolytic enzymes to promote matrix degradation that favors invasion and affect angiogenesis (Carmeliet, 2000;Nyberg et al, 2008;Campbell et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway

et al. 2011

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MULTIMERIN2 (MMRN2), also known as Endoglyx-1, is an extracellular matrix glycoprotein whose function has so far remained elusive. Given its specific localization in tight association with the endothelium we hypothesized that this protein could modulate neo-angiogenesis. By multiple assays we showed that MMRN2 significantly impaired endothelial cell (EC) migration and organization of a functional vessel network. The interaction of ECs with MMRN2 induced a striking impairment of VEGFR1 and VEGFR2 activation. We focused our attention on VEGFR2, a chief regulator of angiogenesis, and clarified that MMRN2 interfered with the VEGF/VEGFR2 axis through a direct binding with VEGF-A. This novel interaction was assessed in several assays and the affinity was estimated (KdB50 nM). We next questioned whether the anti-angiogenic properties of MMRN2 could impair tumor growth. Although overexpression of MMRN2 by HT1080 cells did not affect their growth and apoptotic rate in vitro, it remarkably affected their growth in vivo. In fact, MMRN2-positive cells failed to efficiently grow and form well-vascularized tumors; a similar outcome was observed following treatment of established tumors with a MMRN2 adenoviral construct. Tumor-section immunostaining revealed a strong co-localization of VEGF-A with the ectopically expressed MMRN2. These novel findings suggest that VEGF may be sequestered by MMRN2 and be less available for the engagement to the receptors. Taken together these results highlight MMRN2 as a crucial player in the regulation of EC function, neoangiogenesis and hence tumor growth. We hypothesize that secreted and deposited MMRN2 may function as a homeostatic barrier halting the sprouting of novel vessels, and suggest that these studies may embody the potential for the development of novel tools for cancer treatment.

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Regulation of angiogenesis: apoptotic cues from the ECM

Cited by 117 publications

References 142 publications

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway

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