Metastasis is the major cause of morbidity and mortality associated with breast carcinoma, the most commonly diagnosed neoplastic disease and the second leading cause of cancer-related death among women in North America and worldwide. However, the development of efficient therapeutic modalities targeting specifically metastatic breast disease has been hindered by a limited knowledge of the molecular mechanisms governing hematogenous spread of cancer. This project outlines a multidisciplinary research effort to identify and investigate major molecular and cellular mechanisms underpinning the process of hematogenous breast cancer metastasis, when blood borne tumor cells interact with distant organ vasculature. The underlying hypothesis posits that the initial, transient metastatic cell arrest in target organ microvessels [mediated by cancer-associated Thomsen- Friedenreich antigen expressed on tumor cells and carbohydrate-binding protein galectin-3 (Gal-3) expressed on endothelial cells (EC) lining blood vessel walls] is further stabilized by the endothelial integrin ?31 inducing downstream Src/RhoA/ROCK-dependent signaling pathways, prompting EC contraction and retraction, neoplastic cell extravasation and ultimately the establishment of new metastatic deposits. An innovative integrated approach is proposed involving the use of modified parallel flow chamber techniques and atomic force microscopy to identify integrin molecules stabilizing breast cancer cell/EC adhesion in Aim 1; advanced immunofluorescence and confocal microscopy approaches coupled with cell biology experiments to investigate spatiotemporal dynamics and biological consequences of ?31/Src/RhoA activation in EC on tight junction disassembly, EC contraction, and tumor cell transendothelial migration in Aim 2; sophisticated animal experimentation utilizing transgenic Gal-3-/- and human breast carcinoma xenograft models for in vivo validation in Aim 3. Completing the aims of this study will significantly enhance our knowledge of the molecular mechanisms underpinning hematogenous spread of cancer, enable generation of a newly integrated molecular model of breast cancer metastasis, and provide rationale for developing new therapeutic strategies targeting several rate-limiting metastasis-associated processes simultaneously to control more efficiently and, perhaps, even prevent hematogenous breast cancer metastasis.
Breast carcinoma is the most commonly diagnosed neoplastic malignant disease and the second leading cause of cancer-related death among women in the U.S. and worldwide. Metastasis is the major cause of morbidity and mortality associated with breast cancer. While primary breast tumors most often could be efficiently treated, the advanced metastatic breast cancer is presently incurable and as such represents a massive clinical problem. This application outlines a multidisciplinary research effort to identify and investigate major molecular and cellular mechanisms associated with breast cancer metastasis, which could be subsequently targeted for therapeutic purposes.
