Engineering Approaches To Analyze And Target Cancer Invasion And Metastasis

Abstract

Metastasis of primary tumor accounts for 90% of all deaths in cancer patients. Interaction between cells in the primary tumor is known to play an important role in determining the metastatic potential of cancer cells that leave the primary site. Cancer cells that metastasize through the bloodstream invade through the basement membrane surrounding the primary tumor to enter the adjacent blood capillaries. Then, they can evade the host immune response in the circulation and interact with E-selectin on endothelial cells lining the blood vessel wall to exit the circulation and establish at a secondary site. The first focus of my project was to study the effect of homotypic and heterotypic cell-cell interactions on the metastatic potential of cancer cells using a 3D tumor spheroid model. 3D spheroids generated by culturing breast cancer cell lines on polydimethylsiloxane had stronger interaction with E-selectin, increased invasiveness and resistance to apoptosis inducing signals in the circulation when compared to their respective 2D monolayer grown counterparts on tissue culture plate. Cancer cells entering the lymphatic system get lodged within the tumor draining lymph nodes (TDLN), thus contributing to the lymphatic spread of cancer. Natural killer (NK) cells in the TDLN elicit an anti-tumor response by expressing Tumor necrosis factor-[alpha] Related Apoptosis Inducing Ligand (TRAIL) on their surface. TRAIL can bind to death receptors on cancer cells and induce apoptosis. Despite the presence of immunoregulatory NK cells, lymph node metastases are prevalent in several types of cancers. This is because of the abnormalities of NK cells in the TDLN, including reduced count and decreased cytotoxicity. Given the coexistence of cancer cells and NK cells within the TDLN, the second part of this dissertation was focused on demonstrating a nanomedicine-based approach to enhance the therapeutic efficacy of endogenous NK cells by coating them with liposomes functionalized with TRAIL. Human NK cells coated with TRAIL liposomes were able to induce apoptosis in cancer cells cultured in engineered lymph node microenvironments. Liposomes functionalized with TRAIL and an antibody against mouse NK cells were carried to the TDLN and prevented the lymphatic spread of a subcutaneous tumor in mice.