Breast cancer cell surface annexin II induces cell migration and neoangiogenesis via tPA dependent plasmin generation

• Published in: Experimental and molecular pathology 2010-04, Vol.88 (2), p.278-286
• Main Authors: Sharma, Meena, Ownbey, Robert T., Sharma, Mahesh C.
• Format: Article
• Language: English
• Subjects: Annexin A2 - metabolism; Annexin A2 - physiology; Annexin II; Base Sequence; Biological and medical sciences; Blotting, Western; Breast cancer; Breast Neoplasms - blood supply; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement; Female; Fibrinolysin - genetics; Gene Silencing; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Mammary gland diseases; Medical sciences; Neoangiogenesis; Neovascularization, Pathologic - prevention & control; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Plasmin; Recombinant Proteins - metabolism; Tissue Plasminogen Activator - genetics; Tissue Plasminogen Activator - metabolism; tPA; Tumors; Wound Healing
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2010.01.001

Annexin II, an abundant phospholipids binding cell surface protein, binds tPA and functions as a regulator of fibrinolysis. Annexin II also mediates angiogenesis and enhances tumor growth and metastasis. However, the mechanism supporting this role is not known. Using human breast cancer model we show that invasive human breast cancer cells (MDA-MB231) synthesize annexin II and tissue plasminogen activator (tPA). In vitro both annexin II and tPA interacts which in turn convert zymogen plasminogen to reactive enzyme plasmin. Cell surface produced plasmin inhibited the migration of MDA-MB231 cells. Silencing of annexin II gene in MDA-MB231 cells abolished tPA binding therefore inhibited tPA dependent plasmin generation. These annexin II suppressed MDA-MB231 cells showed reduced motility. Immunohistochemical analysis of prediagnosed clinical specimens showed abundant secretion of tPA and expression of annexin II on the surface of invasive human breast cancer cells which correlates with neovascularization of the tumor. Taken together, these data indicate that annexin II may regulate localized plasmin generation in breast cancer. This may be an early event switching breast cancer from the prevascular phase to the vascular phase and thus contributing to aggressive cancer with the possibility of metastasis. The data provide a mechanism explaining the role of annexin II in breast cancer progression and suggest that annexin II may be an attractive target for therapeutic strategies aimed to inhibit angiogenesis and breast cancer.