Annexin A2 (ANX A2): An emerging biomarker and potential therapeutic target for aggressive cancers

Abstract

ANX A2 is an important member of annexin family of proteins expressed on surface of endothelial cells (ECs), macrophages, mononuclear cells and various types of cancer cells. It exhibits high affinity binding for calcium (Ca ) and phospholipids. ANX A2 plays an important role in many biological processes such as endocytosis, exocytosis, autophagy, cell-cell communications and biochemical activation of plasminogen. On the cell surface ANX A2 organizes the assembly of plasminogen (PLG) and tissue plasminogen activator (tPA) for efficient conversion of PLG to plasmin, a serine protease. Proteolytic activity of plasmin is required for activation of inactive pro-metalloproteases (pro-MMPs) and latent growth factors for their biological actions. These activation steps are critical for degradation of extracellular matrix (ECM) and basement proteins (BM) for cancer cell invasion and metastasis. Increased expression of ANX A2 protein/gene has been correlated with invasion and metastasis in a variety of human cancers. Moreover, clinical studies have positively correlated ANX A2 protein expression with aggressive cancers and with resistance to anticancer drugs, shorter disease-free survival (DFS), and worse overall survival (OS). The mechanism(s) by which ANX A2 regulates cancer invasion and metastasis are beginning to emerge. Investigators used various technologies to target ANX A2 in preclinical model of human cancers and demonstrated exciting results. In this review article, we analyzed existing literature concurrent with our own findings and provided a critical overview of ANX A2-dependent mechanism(s) of cancer invasion and metastasis.

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

“…One molecule is Annexin A2 (Anxa2), a calcium-dependent phospholipid-binding protein [2,[12][13][14]. Anxa2 has been shown as a multifunctional protein implicated in many biological processes [13][14][15]. Its abnormal expression is associated with a variety of diseases, especially cancer [13][14][15].…”

“…Anxa2 has been shown as a multifunctional protein implicated in many biological processes [13][14][15]. Its abnormal expression is associated with a variety of diseases, especially cancer [13][14][15]. Anxa2 overexpression promotes proliferation, migration, invasion, angiogenesis, and metastasis in various types of tumors [13][14][15].…”

“…Its abnormal expression is associated with a variety of diseases, especially cancer [13][14][15]. Anxa2 overexpression promotes proliferation, migration, invasion, angiogenesis, and metastasis in various types of tumors [13][14][15]. In addition, a high Anxa2 level has been observed in many types of drug-resistant cells [16][17][18][19][20].…”

Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer

“…For the xenograft experiments reported here, SKOV3 was used as a model of heterogeneous ANXA2 expression. In this case, the target ANXA2 is known to promote neovasculature via plasmin generation [17]. As such, the depletion of ANXA2+ cells from the tumour could potentially inhibit tumour growth via the removal of an angiogenic pathway.…”

“…Surface-expressed ANXA2 mediates extracellular matrix degradation and neovascularisation via the production of plasmin, and has been found to correlate with invasion and metastasis in a range of cancers, including breast cancer, pancreatic ductal adenocarcinoma, renal cell carcinoma, colorectal cancer, and nasopharyngeal cancer [16]. In particular, ANXA2 overexpression correlates with poor prognosis in ovarian and breast cancer [17]. These features suggest the potential of annexin A2 as a target for immunotherapy.…”