TUMOR MICROENVIRONMENT MODULATES BREAST TUMOR INVASION WITHIN 3D COLLAGEN MATRICES

63 pagesCancer metastasis is a physical process in which tumor cells break away from the primary tumor, enter and then exit the blood or lymph vessels, and establish secondary tumors in distant organs. Tumor invasion within interstitial space is a critical step in cancer metastasis. It is now indisputable that tumor cell microenvironment plays an equally important role in tumor invasion as tumor genetic makeup. Accordingly, my thesis is devoted to the studies of the tumor microenvironment. More specifically, I studied the impact of collagen matrix architecture and epidermal growth factor gradient on tumor invasion. For the first part of my thesis, I explored the roles of 3D collagen matrix architecture in tumor cell invasion and migration. I engineered collagen matrices of various architecture using a glucose glycation method. Using time-lapse images, I quantitatively compared the motility behavior of malignant breast tumor cells and co-culture spheroids embedded in glycated and non-glycated collagen matrices of various concentrations. Experimental results demonstrated that glycation increased collagen pore size, fiber diameter, and gel stiffness and promoted tumor invasion in contrast to the non-glycated gel case. For the second part of my thesis, I studied the role of EGF gradient in tumor spheroid invasion within a 3D collagen matrix using a microfluidic platform capable of generating a steady gradient over a long period of time. I found a clear chemokinesis response; tumor cells spread significantly faster in the presence of EGF gradients in contrast to no gradient. Additionally, a minor chemotactic behavior was observed, which is consistent with the existing in vivo results