All bladder cancers are not alike. In an attempt to differentiate such tumors, researchers from Baylor College of Medicine and Stanford University have identified three subtypes, based on their developmental stage, which may have implications for the course of the disease.

In the study published online in the journal of the Proceedings of the National Academy of Sciences, the team data-mined a large gene expression database to classify bladder cancer specimens by their differentiation states. Differentiation is the process by which cells progress from primitive to mature.

Currently, bladder cancer has no clinically relevant identified subtypes like that in breast cancer, said Dr. Keith Syson Chan, assistant professor in the Scott Department of Urology and of molecular and cellular biology at BCM and a senior author on the study, together with Dr. Irving Weissman at Stanford University.

This work was initiated when Chan was a trainee with Weissman. Other lead authors include Dr. Jens-Peter Volkmer and Dr. Debashis Sahoo, both of Stanford University, and Dr. Robert Chin of The University of Chicago Medical Center.

Markers distinguish cells

Decisions are made on classification of the tumor and the cells within it. "Bladder cancer tumors are heterogeneous or filled with many different types of tumor-initiating cells," said Chan. "Each of those cells is characterized by markers or proteins that distinguish them from other cells in that tumor’s population."

Chan and colleagues hypothesized different sets of tumors found in patients are likely to have different markers characteristic of the cells from the developmental stage which the tumors originated.

Using public available pre-existing gene expression databases, Stanford collaborator and computer scientist Sahoo designed a computational approach that looked specifically at the differentiation stage of the cells to see if they could predict markers that corresponded with each stage.

Basal, intermediate, differentiated

Based on their data, the team found bladder cancer can be classified into three subtypes that they called basal, intermediate and differentiated, depending on the tumor’s state of differentiation. The markers that correspond with each state are part of the keratin (KRT) protein family – basal corresponds with KRT14; intermediate, KRT5 and differentiated KRT20.

In another key finding validated by Dr. Philip Levy Ho, resident physician at BCM, and Dr. Matt van de Rijn, of Stanford University, the team found that KRT14 expression precedes KRT5 and KRT20 expression, and KRT14 expression is consistently associated with more aggressive cancers that are difficult to treat effectively.

"Currently there is no way to predict if a patient has the less or more aggressive subtype of bladder cancer early on," said Volkmer. "This technique might be used to identify the patients with the more aggressive subtype before the cancer becomes invasive or metastatic."

"The hope is that one day we can screen these markers in patient tumors through biopsy, and then help clinicians better determine the course of treatment," said Chan. "But, large-scale prospective clinical studies are needed to validate this work."

In addition to Chan, BCM researchers involved include: Dr. Philip Levy Ho; Antonina V. Kurtova; Dr. Senthil K. Pazhanisamy; Dr. Seth Lerner and Dr. Guilherme Godoy.

Other primary collaborators included Dr. Jens-Peter Volkmer; Dr. Debashis Sahoo; Dr. Matt van de Rijn; Linda D. Shortliffe and Dr. Irving L. Weissman from Stanford University; and Dr. Robert Chin of The University of Chicago Medical Center.

Funding for this research was supported by the Pride Family Fund, National Cancer Institute, V Foundation V Scholar Award and Bladder Cancer Partnership Fund.