The Role of Annexin II in Angiogenesis and Tumor Progression: A Potential Therapeutic Target

Abstract

It is well established that human tumors overproduce plasmin a serine protease that is known to promote angiogenesis, tumor growth and metastasis. However, the mechanism by which endothelial or tumor cells regulate the proteolytic activity of plasmin is not well understood. Cell surface receptors regulate activation of plasminogen to plasmin and its proteolytic activity. Annexin II is one of the well studied receptors for plasminogen and tPA, which binds to plasminogen and converts it to plasmin. Plasmin is a highly reactive enzyme which is physiologically involved in fibrinolysis. Since the proteolytic activity of plasmin is very tightly regulated, uncontrolled production of plasmin can degrade extracellular matrix (ECM) and basement membrane (BM) of the surrounding blood vessels. Thus plasmin plays an important role in neoangiogenesis and cancer invasion and metastasis. Therefore, the receptor which regulates plasmin generation may be an attractive target for the development of anti-cancer/anti-metastatic agents. Angiostatin (AS), internal fragment of plasminogen, has been reported to inhibit human tumor growth and metastasis. We have shown that AS binds to endothelial/cancer cell surface annexin II with high affinity and interferes with plasmin generation suggesting that the role of plasmin/plasminogen system may be more complex than we previously thought. In this review we provide a comprehensive analysis of the literature in context of the role of annexin II in angiogenesis, tumor progression and metastasis. Compelling evidence from the literature and our own findings suggest that annexin II may be a potential target for the development of effective therapeutic strategies for the treatment of cancer and its induced metastasis.

Cell Surface Translocation of Annexin A2 Facilitates Glutamate-induced Extracellular Proteolysis

“…Dysregulation in the cell surface expression levels of AnxA2 has been shown to manifest as bleeding diseases, conferring on the cells the ability to generate increased levels of plasmin (45). Many cancer cells have also been shown to abundantly express cell surface AnxA2, which confers on them the invasive and metastatic behavior by the generation of plasmin or by the plasmin-mediated activation of matrix metalloproteinases (46). Therefore, modulating the activity of a potent plasmin-generating recep- LGKLSL) at the indicated concentrations for 1 h at 37°C.…”

Efficacy of the EGFr inhibitor Iressa on development of chemically-induced urinary bladder cancers: Dose dependency and modulation of biomarkers

“…3). Annexin II is a tumor associated protein with a potential role in tumor progression and angiogenesis (21). the decrease in expression of MApK kinase, a protein associated with angiogeneis (22), suggests downstream effects of egFr inhibitors.…”

S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility

“…However, we cannot rule out the possibility that the relationship between membranous expression of annexin 2 and S100A6 level is a consequence, rather than a cause, of the effect of S100A6 on motility. In addition, the interaction between annexin 2 and S100A6 may contribute to increased tPA activity, which could lead to a variety of effects, potentially including increased cell motility (Ortiz-Zapater et al, 2007;Sharma and Sharma, 2007).…”