Abstract
Abstract As major constituents of the extracellular matrix (ECM), collagens affect numerous biological processes including cell differentiation, proliferation, migration, and tumorigenesis. Collagen type XI alpha 1 (COL11A1) encodes one of the alpha chains of type XI minor fibrillar collagen, which is normally expressed in cartilage. We and others have detected aberrant expression of COL11A1 in several types of cancer. Increased levels of COL11A1 are associated with more invasive and metastatic tumors, abundant cancer-associated desmoplastic stroma, and poor clinical outcome. However, the functional significance of COL11A1 expression in cancer remains poorly understood. Previously, we identified COL11A1 as one of ten signature genes associated with poor survival in serous ovarian cancer. Furthermore, we identified COL11A1 as the most significantly upregulated metastasis gene in matched pairs of primary and metastatic tumors. In situ hybridization and immunohistochemistry analyses showed that COL11A1 expression patterns correlate with disease progression in clinical samples; with low, intermediate, and high levels of COL11A1 observed in primary tumors, concurrent metastases, and recurrent/persistent metastases, respectively. COL11A1 was mainly expressed in the intra/peri-tumoral stromal cells. Endothelial cells and other stromal cells >1 mm from the tumor epithelial cells were negative for COL11A1. Although COL11A1 expression was predominantly confined to stromal cells, rare clusters of tumor epithelial cells were also positive. Taken together, these data suggest that COL11A1 is a biomarker of metastatic progression in serous ovarian cancer and a biomarker of cancer-associated desmoplastic stroma. Functionally, we hypothesize that COL11A1 expression may contribute to poor patient survival through several mechanisms. Knockdown of COL11A1 in the human ovarian cancer cell line A2780 resulted in a significant decrease in cell migration in vitro, and diminished invasion and metastasis in mouse xenografts. In the clinical setting, the development of chemoresistance is one of the most significant obstacles to effective therapy. To this end, we showed that expression of COL11A1 in cisplatin resistant A2780 cells is 100-fold higher in comparison to the cisplatin sensitive parental cell line. In addition, we observed a significant decrease in the ALDH+ cancer stem cell (CSC) population after COL11A1 knockdown in A2780 cells, implying that COL11A1 may contribute to cisplatin resistance through modulation of the CSC population. Our current research focuses on the role and mechanism by which COL11A1 expressed by cancer-associated stroma influence cisplatin resistance and the CSC population. At this meeting, we will present our most current data on COL11A1 as a critical player in chemoresistance and metastasis in ovarian cancer. Citation Format: Dong-Joo Cheon, Jessica Beach, Ann Walts, Beth Karlan, Sandra Orsulic. COL11A1 is a regulator of tumor microenvironment and a biomarker of metastatic progression. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A39. doi:10.1158/1538-7445.CHTME14-A39
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