Breast cancer is the most common cancer in women and usually originates from the epithelial cells of the mammary duct. During the earliest stage, the tumor cells remain trapped inside the duct, generating an indolent “Ductal Carcinoma In Situ” (DCIS). However, DCIS cells can break the wall of the mammary duct, invade the surrounding stromal tissue, and metastasize to other organs. Unfortunately, the mechanisms that trigger this invasion remain elusive. One hypothesis is that the harsh microenvironment (i.e., hypoxia, nutrient-starvation) of DCIS leads to epithelial cell invasion into the stroma. In this work, a microfluidic DCIS model was developed including DCIS and normal epithelial cells, fibroblasts, and blood vessel-like structures. Optical metabolic imaging (OMI) of the metabolic co-factors NAD(P)H and FAD was used to assess spatial gradients in metabolism within the microfluidic model. We observed that the epithelial cells hindered the penetration of nutrients inside the lumen, and led to severe hypoxia. This hypoxia exerted OMI-measured metabolic changes in both normal and DCIS cells. Nuclear magnetic resonance (NMR) metabolomics analysis showed DCIS-specific metabolic differences compared with normal cells, in agreement with OMI results. Metabolic changes included an increase in glycolysis products and production of cancer-associated metabolites. A hypoxia-activated prodrug (Tirapazamine) selectively destroyed the hypoxic tumor cells inside the lumen, without affecting cells at the lumen surface or the fibroblasts in the matrix. In the future, OMI of this microfluidic model will be used to test metabolic therapies that prevent the growth of DCIS into an invasive tumor.
Jose Ayuso, Karina Lugo-Cintron, Suehelay Acevedo, Amani Gillette, Patrick N. Ingram, Tiffany M. Heaster, Kari B. Wisinski, Sean P. Palecek, David J. Beebe, and Melissa C. Skala, "Microfluidic models and optical imaging to monitor microenvironmental stimuli for breast cancer invasion (Conference Presentation)," Proc. SPIE 10472, Diagnosis and Treatment of Diseases in the Breast and Reproductive System IV, 104720A (Presented at SPIE BiOS: January 27, 2018; Published: 14 March 2018); https://doi.org/10.1117/12.2287981.5751477424001.
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