Abstract
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term oncogenic plasminogen receptor to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis.
Highlights
Peyton Rous initially demonstrated that a cell-free agent isolated from chicken sarcoma was capable of infecting healthy tissues and forming sarcomas with “extreme malignancy and a tendency to wide-spread metastasis” [1]
We demonstrated that S100A10 was present on the extracellular surface of acute promyelocytic leukemia (APL) cells and was rapidly down-regulated in response to all-trans retinoic acid
These results demonstrated the upregulation of S100A10 in high-grade precursor lesions and pancreatic ductal adenocarcinoma (PDAC), which suggests that S100A10 plays a role in the progression of disease but could be discovered before pancreatic intraepithelial neoplasia (PanIN) develop into carcinoma
Summary
Peyton Rous initially demonstrated that a cell-free agent isolated from chicken sarcoma was capable of infecting healthy tissues and forming sarcomas with “extreme malignancy and a tendency to wide-spread metastasis” [1]. The discovery that the SRC gene product coded for a protein-tyrosine kinase was an exciting event because it suggested that the activity of a single enzyme and the phosphorylation of several key proteins on tyrosine residues could initiate and potentiate cancer (in chickens). A search was initiated to identify the vital cellular proteins that were phosphorylated on their tyrosine residues by pp60src and, by inference, would be responsible for converting normal cells to cancer cells. A 36-kDa protein (annexin A2, ANXA2) that underwent phosphorylation at tyrosine after transformation by RSV was identified as one of the most prominent phosphoproteins [15–17]. This protein was shown to exist in a complex with an 8-10K binding partner [18–20] in a heterotetramer form. AIIt provided a conceptual bridge between malignant cancer cells and fibrinolysis
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