Profiling the evolution of human metastatic bladder cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• Pulmonary metastases are common in aggressive bladder cancer.
• Investigating bladder cancer metastasis is hindered by a lack of human metastatic tissue and suitable animal models.

Purpose of the Study:

• To develop a novel in vivo model for studying bladder cancer lung metastasis.
• To identify genes associated with increased pulmonary metastatic potential in bladder cancer.
• To validate identified genes in human bladder cancer tissues.

Main Methods:

• Development of progressively metastatic human bladder cancer cell lines (T24T, FL1, FL2, FL3) through serial in vivo selection in nude mice.
• Oligonucleotide microarray analysis of gene expression profiles in parental and derivative cell lines.
• Comparison of gene expression profiles from the model system with those from primary human bladder tumors.

Main Results:

• 121 genes were progressively upregulated and 43 downregulated during the transition to a highly metastatic phenotype.
• Gene expression changes correlated with lung colonization propensity and reduced host survival.
• Epiregulin, urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP)14, and tissue inhibitor of metalloproteinase (TIMP-2) were consistently upregulated with increasing tumor stage in human tissues, mirroring the model system.

Conclusions:

• The developed in vivo model system is validated as a useful tool for studying lung metastasis in bladder cancer.
• Upregulation of epiregulin, uPA, MMP14, and TIMP-2 correlates with bladder cancer progression and metastatic potential.
• These four markers represent potential therapeutic targets to reduce lung metastasis incidence in bladder cancer patients.