The role of annexin A2 in tumorigenesis and cancer progression

Abstract

Annexin A2 is a calcium-dependent, phospholipid-binding protein found on various cell types. It is up-regulated in various tumor types and plays multiple roles in regulating cellular functions, including angiogenesis, proliferation, apoptosis, cell migration, invasion and adhesion. Annexin A2 binds with plasminogen and tissue plasminogen activator on the cell surface, which leads to the conversion of plasminogen to plasmin. Plasmin is a serine protease which plays a key role in the activation of metalloproteinases and degradation of extracellular matrix components essential for metastatic progression. We have recently found that both annexin A2 and plasmin are increased in conditioned media of co cultured ovarian cancer and peritoneal cells. Our studies suggest that annexin A2 is part of a tumor-host signal pathway between ovarian cancer and peritoneal cells which promotes ovarian cancer metastasis. Accumulating evidence suggest that interactions between annexin A2 and its binding proteins play an important role in the tumor microenvironment and act together to enhance cancer metastasis. This article reviews the current knowledge on the biological role of annexin A2 and its binding proteins in solid malignancies including ovarian cancer.

Fig. 1

Annexin A2 domain structure. The N-terminal domain consists of the p11 proteins and tissue plasminogen activator (t-PA) binding sites. The C-terminal domain consists of four repeating domains which each contains annexin A2 consensus sequence and the biding sites for calcium, phospholipids and F-actin

Fig. 2

A. 2D-gel electrophoresis of proteins in the secretome of ovarian cancer (OVCAR-5) and peritoneal cells (LP-9) cultured separately. B. 2D-gel electrophoresis gel of proteins in the secretome of OVCAR-5 and LP-9 co culture. Circled spots that were up-regulated in the ovarian cancer peritoneal co-culture but absent in the single culture were identified to be annexin A2 by mass spectrometry

Fig. 3

Annexin A2 expression in human ovarian tumor tissues. a. Benign serous cystadenoma b. Serous ovarian carcinoma. Annexin A2 immunohistochemistry using mouse anti-annexin A2 (BD Biosciences, 1: 500), with a citrate buffer microwave retrieval. Bar = 100 μm

Fig. 4

Proposed mechanism of annexin A2 promoting cancer metastasis in the plasminogen activation system. Annexin A2 heterotetramer on the cell surface binds to t-PA and activates plasminogen conversion to plasmin. Plasmin results in activation of MMPs and lead to ECM degradation. Increased annexin A2 expression results in increased plasmin generation and enhances cancer invasion and metastasis