Abstract
Recent data suggest that patients with a basal/stem-like bladder cancer (BC) subtype tend to have metastatic disease, but this is unconfirmed. Here we report the identification of murine MB49 cell line sub-clones with stem-like characteristics in culture. Subcutaneous implantation of S2 and S4 MB49 sub-clones into immunocompetent mice resulted in lung metastases in 50% and 80% of mice respectively, whereas none of the mice implanted with the parental cells developed metastasis. Gene profiling of cells cultured from S2 and S4 primary and metastatic tumors revealed that a panel of genes with basal/stem-like/EMT properties is amplified during metastatic progression. Among them, ITGB1, TWIST1 and KRT6B are consistently up-regulated in metastatic tumors of both MB49 sub-clones. To evaluate clinical relevance, we examined these genes in a human public dataset and found that ITGB1 and KRT6B expression in BC patient tumor samples are positively correlated with tumor grade. Likewise, the expression levels of these three genes are correlated with worse clinical outcomes. This MB49 BC metastatic pre-clinical model provides a unique opportunity to validate and recapitulate results discovered in patient studies and to pursue future mechanistic therapeutic interventions for BC metastasis.
Highlights
Bladder cancer (BC) is one of the most prevalent cancers in American men and is consistently among the six most common cancers in the United States, with approximately 429,800 new cases and 165,100 deaths annually worldwide[1]
We have characterized the behavior of the MB49 sub-clones in vitro and in vivo, and molecular profiling of cells derived from primary tumors vs. metastatic tumors suggests a panel of differentially expressed cancer stem cells (CSC)- and epithelial-to-mesenchymal transition (EMT)-related genes in primary tumors that can be predictive of their metastatic potential
We chose the S2 and S4 spheroidal sub-clones for further in vitro and in vivo characterization due to their moderate tumor growth rates. Consistent with their stem-like morphology, we showed that S2 cells are enriched in CSC marker CK14, and S4 cells are enriched in CSC markers ALDH1A1 and CD90 and as well as basal markers KRT5 and KRT6B, as compared to MB49 parental cells (Fig. 1b)
Summary
Bladder cancer (BC) is one of the most prevalent cancers in American men and is consistently among the six most common cancers in the United States, with approximately 429,800 new cases and 165,100 deaths annually worldwide[1]. Recent data obtained from whole genome/exome profiling of individual patient tumors revealed the molecular features and clinical implications of BC subtypes[7,8,9]. These data have not identified specific genetic alterations that drive disease progression, and these findings have not yet translated to evidence-based molecular cancer diagnostics and targeted therapies. Basal/CSC human BC orthotopic xenografts in mice are more metastatic than luminal/epithelial cells[20] These reports support the functional role of CSCs in metastasis of BC. We have characterized the behavior of the MB49 sub-clones in vitro and in vivo, and molecular profiling of cells derived from primary tumors vs. metastatic tumors suggests a panel of differentially expressed CSC- and EMT-related genes in primary tumors that can be predictive of their metastatic potential
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
