Abstract
Current knowledge of the molecular mechanism driving tumor budding is limited. Here, we focused on elucidating the detailed mechanism underlying tumor budding in urothelial cancer of the bladder. Invasive urothelial cancer was pathologically classified into three groups as follows: nodular, trabecular, and infiltrative (tumor budding). Pathohistological analysis of the orthotopic tumor model revealed that human urothelial cancer cell lines MGH-U3, UM-UC-14, and UM-UC-3 displayed typical nodular, trabecular, and infiltrative patterns, respectively. Based on the results of comprehensive gene expression analysis using microarray (25 K Human Oligo chip), we identified two collagens, COL4A1 and COL13A1, which may contribute to the formation of the infiltrative pattern. Visualization of protein interaction networks revealed that proteins associated with connective tissue disorders, epithelial-mesenchymal transition, growth hormone, and estrogen were pivotal factors in tumor cells. To evaluate the invasion pattern of tumor cells in vitro, 3-D collective cell invasion assay using Matrigel was performed. Invadopodial formation was evaluated using Gelatin Invadopodia Assay. Knockdown of collagens with siRNA led to dramatic changes in invasion patterns and a decrease in invasion capability through decreased invadopodia. The in vivo orthotopic experimental model of bladder tumors showed that intravesical treatment with siRNA targeting COL4A1 and COL13A1 inhibited the formation of the infiltrative pattern. COL4A1 and COL13A1 production by cancer cells plays a pivotal role in tumor invasion through the induction of tumor budding. Blocking of these collagens may be an attractive therapeutic approach for treatment of human urothelial cancer of the bladder.
Highlights
Urothelial cancer of the bladder (UCB) is the second most frequent neoplasm of the urogenital tract [1]
Four urothelial cancer cell lines were inoculated into the bladder cavities of C.B- 17/ severe combined immunodeficiency (SCID) mice
Migration and invasion of cancer cells are heterogeneous processes consisting of cell–cell and cell– matrix adhesion, cytoskeletal polarity, and pericellular proteolysis under pathological conditions [24, 25]
Summary
Urothelial cancer of the bladder (UCB) is the second most frequent neoplasm of the urogenital tract [1]. Non-invasive, well-differentiated tumors (Ta) are relatively indolent, but T1 high-grade-UCB and muscle invasive bladder cancer (≥ T2; MIBC) are known to be life-threatening [2]. Tumor tissue is composed of cancer cells and various types of stromal cells including endothelial cells, macrophages, and fibroblasts. Their interaction and crosstalk might lead to the formation of a cancer-specific microenvironment for tumor invasion and metastasis. The pathological evaluation of growth patterns at the tumor invasion front in human UCB was first reported by Jimenez et al in 2000 [10]. Subsequent studies including our reports demonstrated that this pathological parameter was a significant prognostic factor for both T1 tumors and MIBC [2, 11,12,13,14,15]
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