Investigators: Keith Chan, Jens-Peter Volkmer, Robert Chin, Debashis Sahoo, Stephen Willingham, Mark Chao, Inigo Espinosa, Harcharan Gill, Joseph Presti, Matt van de Rijn, Ying Pan, Joe Liao, Mark Gonzalgo, Eddy Leman, Linda Shortliffe, and Irving Weissman
In previous work, these researchers defined CD44+ as a marker enriching for tumorigenic populations in bladder cancer. They have also shown that bladder cancer cells and, even more importantly, tumor-initiating populations express the “don’t eat me signal” CD47 and that blocking CD47 with a monoclonal antibody (antibody: Ab; monoclonal antibody: mAb) enables phagocytosis of cancer cells in vitro.
- This group has shown that therapeutic mAb targeting of CD47 on bladder cancer cells in patient xenograft tumors can significantly reduce tumor growth in a dose-dependent manner and that it can block metastasis to the lungs and lymph nodes in a clinically relevant xenograft model. Based on these data, CD47 may be a very promising target for bladder cancer treatment. They have also developed an orthotopic bladder cancer xenograft mouse model to determine the effect of local anti-CD47 Ab treatment alone or in combination with the established local immunotherapy, Bacillus Calmette-Guérin, commonly referred to as BCG).
- In 2010, these scientists identified CD47 as a diagnostic target for bladder cancer. In patient bladders that had been surgically removed due to advanced disease, they could specifically identify cancer tissue after application of flurochrome-labled anti-CD47 Ab followed by fluorescence microscopy within the bladders. In addition, the researchers developed an orthotopic bladder cancer xenograft mouse model to investigate CD47 Ab as a diagnostic tool in vivo.
- The group has developed a mathematical approach, termed MiDReG (Mining Developmentally Regulated Genes), to prospectively identify a CSC evolutionary hierarchy within bladder cancer using data from publicly available gene-expression datasets. For bladder cancer, this involved first selecting genes whose expression correlated with patient survival. Next, a gene hierarchy was identified based on cytokeratin (KRT14, KRT5, KRT20) expression patterns and corresponding cell-surface markers (CD90, CD44, CD49f). The team validated the hierarchical relationship between these cell populations in vivo in xenograft models. Finally, they showed that these three different subtypes of bladder cancer are strongly correlated with patient survival using both the cytokeratins and corresponding surface markers. This study supports the existence of multiple bladder CSCs with strong associations to patient survival and hierarchical relationships between them. The markers defining these CSC populations in the three bladder cancer subtypes are strong, independent markers to predict patient survival using both univariate and multivariate analysis.