Research Interests

We are interested to uncover the mechanisms by which tumor regulates neoangiogensis which are fundamental to tumor growth, survival and metastasis; role of annexin II and its dependent signaling pathways in neoangiogensis and its dependent mechanism of human breast cancer progression and metastasis.

Research Program

There is increasing evidence of a strong interrelationship between thrombosis, fibrinolysis, and angiogenesis that is controlled by synchronized cross talk between zymogens and their cleavage products. For example, during coagulation, the proteolytic activation of prothrombin produces thrombin and prothrombin fragments I and II, which triggers clotting and regulates endothelial cell (EC) growth, respectively. In fibrinolysis, fibrin-catalyzed cleavage of plasminogen produces clot-digesting enzyme plasmin, which is known to induce neoangiogensis. Autocatalytic degradation of either plasmin or elastase mediated degradation of plasminogen generate a powerful antiangiogenic molecule angiostatin. The cross talk between zymogens and their cleavage products in tumor microenvironment set the stage for neoangiogensis switching tumor to invasive and aggressive phenotype. Deregulation of fibrinolytic pathway at least in breast cancer has been well-established. For example overproduction of localized plasmin in breast cancer linked to invasive phenotype and advanced stage of breast cancer possibly via inducing neoangiogenic activity. Clinical studies have also provided strong evidence and showed that microvascular density (MVD) in breast cancer correlates with invasive and advanced stage of breast cancer. Angiostatin, an internal fragment of plasminogen, inhibited 95% of human breast cancer growth in mouse model. Angiostatin mediated inhibition of breast cancer was attributed to its ability to block neoangiogensis.

Our laboratory has uncovered a specific receptor, or target, for angiostatin and defined its mechanism of action. For the first time our laboratory has discovered that annexin II plays important role in neoangiogensis and could be a potential therapeutic target for the treatment of cancer. Because annexin II regulates plasmin production by forming an annexin II/t-PA/plasminogen complex, the binding of monoclonal antibody to annexin II on endothelial/breast cancer cells could initiate a negative feedback loop that blocks assembly of the annexin II/t-Pa/plasminogen complex, thereby precluding plasmin production and concomitant neovascularization. To test this concept, our lab is investigating the therapeutic efficacy of antibody to annexin II in breast cancer.

Selected Publications

• George P. Tuszynski, M.R Sharma, Vicki L. Rothman, and Mahesh C. Sharma (2002). Angiostatin binds tyrosine kinase substrate annexin II through lysine binding domain in endothelial cells. Microvascular Research 64: 448-462.
• Meena Sharma, George P. Tuszynski, and Mahesh C. Sharma (2004) Angiostatin-mediated inhibition of endothelial cell proliferation/apoptosis is associated with the down regulation of cell cycle regulatory protein cdk5. J. Cell. Biochemistry 91: 398-409.
• Meena Sharma, Koltowski, L., Rothman, V. L., Tuszynski, G. P., and, R. Ownbey., and Mahesh C. Sharma (2006). Angiogenesis Associated Protein Annexin II in Breast Cancer: Selective Expression in Invasive Breast Cancer and Contribution to Tumor Invasion and Progression. Exp Mol Pathol 81: 146-156.
• Mahesh C. Sharma and Sharma, M. (2007) The Role of Annexin II in Angiogenesis and Tumor Progression: A potential Therapeutic Target. Current Pharmaceutical Design, 13: 3568-3575.
• Joseph Whitten, Andrew Kiebel and Mahesh C. Sharma (2009). The Role of Fibrinolytic Proteins in Angiogenesis and Tumor Progression Arch. of Pathol. Lab. Med. A:15.