BETHESDA, MD USA (UroToday.com) - Dr. Colin Dinney from the MD Anderson Cancer Center discussed work done in his lab addressing the identification of genes key to the development of metastatic disease in bladder cancer. His group hypothesized that genes differentially expressed between primary tumors and metastases must be important in the development of distant disease.
His group set about trying to identify these differentially expressed genes by profiling 33 matched sets of primary tumors and occult lymph node metastases. This work led to the identification of the TCF21 gene which, despite overexpression in primary tumors, was found to demonstrate loss of expression in lymph node metastases. TCF21 is a transcription factor which is important in development and proliferation, and specifically promotes an epithelial phenotype. Its loss is associated with development of a mesenchymal or stromal phenotype, potentially implicating it in epithelial-mesenchymal transition (EMT). Examination of survival data in their cohort, stratified by TCF21 expression level, demonstrated that patients with low levels of TCF21 expression in lymph node metastases had a significantly worse disease-specific survival. Further in vivo work confirmed the loss of TCF21 in metastatic disease and circulating tumor cells (CTCs) in an orthotopic murine model. The introduction of TCF21 into tumor xenografts in this model resulted in increased tumor growth but decreased invasion, production of CTCs and development of metastatic disease.
Dr. Dinney’s lab then examined genes whose expression was altered by TCF21, and 4 candidate genes were identified: CD24 and SPRY1, which are upregulated by an increase in TCF21 expression, and ARHGDIB and ITGB2, which are downregulated with TCF21 expression. In vivo SPRY1 was confirmed to demonstrate a significant loss of expression in lymph node metastasis compared to primary bladder tumors. The presence of TCF21 and SPRY1 was shown to cluster with the luminal subtype of bladder cancer, which has been demonstrated to be associated with improved prognosis compared to the basal subtype. Overall this work identified novel genes involved in the development of metastatic disease. TCF21 appears to function as a metastasis suppressor in bladder cancer. It would be interesting to see if loss of TCF21 also plays a role in the development of metastatic disease in other malignancies. Further elucidation of the upstream and downstream players in metastasis will provide more potential therapeutic targets for possibly treating or preventing the development of bladder cancer metastases.
Presented by:
Colin P.N. Dinney, MD
University of Texas MD Anderson Cancer Center, Houston, TX USA
Reported by:
Timothy Ito, MD* from the 2014 Winter Meeting of the Society of Urologic Oncology (SUO) "Defining Excellence in Urologic Oncology" - December 3 - 5, 2014 - Bethesda, MD USA
*Fox Chase Cancer Center, Philadelphia, PA USA
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