With the increased capabilities of early detection and treatment of breast cancer, mortality rates due to the primary tumor have decreased, and currently 90% of cancer mortality is a result of metastatic events. In the process of metastasis tumor cells must pass through the tumor extracellular matrix, and matrix structure has been shown to predict metastatic outcome. Consequently, we are interested in understanding the structure and function of the tumor extracellular matrix with the ultimate goal of improving our ability to predict and prevent breast tumor metastasis. Second Harmonic Generation (SHG) is a scattering phenomenon in which two photons are combined into one emission photon by a non-centrosymmetric scattering material such as collagen fibrils. It has been shown that qualitative morphological analysis of collagen SHG images can be used to predict metastatic potential of a primary breast tumor. In ovarian cancer the scattering directionality, as defined by the ratio of forward-scattered to backward-scattered SHG emission (the "F/B ratio") was used to differentiate between healthy and cancerous tissue by directly capturing forward and backward propagating photons. Our work has previously shown from human tumor biopsies that the F/B ratio can be used to distinguish breast tumors that are more metastatic to the lymph nodes. This research proposal will be composed of two parts, which will utilize methods of quantitatively monitoring of the F/B ratio to increase our understanding of the role of extracellular matrix changes in the stroma throughout metastatic progression. The first specific Aim of this proposal is to evaluate the relationship between collagen F/B and tumor locomotion through collagen gel manipulation. The focus of Aim 2 is to investigate the temporal behavior of the F/B ratio.
Both aims will also incorporate electron microscopy and to identify the physical collagen changes that correspond to the observed F/B progression. Breast cancer forms highly diverse tumors characterized by their location in the tissue, their receptors, and other histological features. Th goal of this work is to utilize the capabilities of SHG F/B measurements to improve our understanding of the role extracellular matrix changes play in the tumor metastasis and thereby improve treatment and diagnostic capabilities.
Breast cancer is the second leading cause of cancer related deaths in women and patient survival is highly dependent upon tumor cell spreading to secondary tissue, where spread of the tumor to the mammary lymph nodes or distant secondary tissues significantly decreases 5-year survival rates. During tumor progression the structure of the surrounding matrix is altered, with the result that tumor cells can travel through it more securely and efficiently to a secondary tissue. An increased understanding of these changes this could increase the ability to diagnose patients with more aggressive tumors and aid in the creation of new treatments that prevent or hinder tumor spreading.