Abstract
Triple (ER/PR/HER2) negative breast cancer (TNBC) accounts for approximately 20% of all breast cancer diagnoses and is characterized by metastasis that is refractory to treatment. We and others have demonstrated that cyclooxygenase-2 (COX-2) products are important mediators of increased invasion and metastasis in the MDA-MB-231 human xenograft model of TNBC. Increasing evidence suggest that high density of collagen I fibers in the extracellular matrix (ECM) is predictive of increased metastasis and cancer cells have been observed to migrate along these fibers during the metastatic journey. We previously observed that downregulation of COX-2 significantly reduced the expression of degradative enzymes such as matrix metalloproteinase 1 and altered the expression of ECM components such as hyaluronan and lumican that play a role in intra-fibrillar collagen spacing. Tumor growth of MDA-MB-231 and Clone 13 (a MDA-MB-231-derived COX-2 shRNA-expressing clone secreting less than 10% of PGE2 compared to parental) xenografts, studied following Matrigel-supported orthotopic implantation in SCID mice, showed a 3-week delay in tumor growth. Here, we have used non-Matrigel tumors derived from Clone 13 cells were used to investigate the relationship between COX-2 expression, interstitial fluid transport using MRI and collagen fiber density and volume using second harmonic generation (SHG) microscopy. MRI was performed once tumor volumes were approximately 400-500 mm3. Interstitial fluid transport parameters were measured from quantitative T1 maps obtained before and following intravenous administration of the contrast agent albumin-GdDTPA. Interstitial fluid transport parameters calculated included number of draining and pooling voxels, draining and pooling rates, and volumes. SHG microscopy of tissue slices was performed using a 25x lens on a Zeiss 710 LSM NLO confocal microscope. Collagen I fiber distribution was characterized using an in-house 3D analysis software developed to quantify fiber distance distributions and fiber volumes. Significant differences in the ECM structure and function were evident between high COX-2 expressing MDA-MB-231 tumors compared to Clone 13 tumors with low COX-2 expression. Tumors arising from Clone 13 cells demonstrated an increase in vascular volume, a decrease of draining voxels, an increase of pooling voxels, and a decrease of collagen fiber density. Collectively, these data provide direct evidence for COX-2-mediated changes in the ECM. Here, for the first time, we have shown that dowregulating COX-2 in TNBC cells profoundly impacts collagen I fiber density and volume and alters macromolecular transport. Understanding the role of COX-2 in TNBC and its impact on the ECM and macromolecular transport may provide new insights into preventing relapse and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2970. doi:1538-7445.AM2012-2970
