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Ludwig researchers develop a new way to evaluate aggressiveness of bladder cancer

A Ludwig Cancer Research study published in the current issue of Scientific Reports describes a new method and risk model to assess how aggressive a bladder cancer is likely to be. “If confirmed in larger studies, our findings could help physicians get a better handle on how a patient’s bladder cancer is likely to progress and allow them to personalize treatment on the basis of that knowledge,” said Ralph Weichselbaum, director of the Ludwig Center at the University of Chicago, who led the study. More than 70,000 new cases of bladder cancer are diagnosed each year and it is the fourth most common cause of cancer-related death among men.

For the current study, Weichselbaum and colleagues obtained tumor samples from 71 patients and used a standard laboratory procedure called flow cytometry to isolate and count specific subtypes of bladder tumor cells in each sample. They showed that an excess of one relatively rare subtype—the basal tumor cell (BTC)—in early stage cancers suggests a poor prognosis for the disease. In more advanced, invasive tumors, however, the presence of BTCs has little prognostic utility. Rather, it is the ability of BTCs from such tumors to take hold and grow when injected into immune-deficient mice that indicates poorer outcomes.

Analyzing the global expression of genes in BTCs, the researchers also identified a potentially new biomarker for bladder cancer: CDC25C, a protein that drives cell division. An analysis of three data sets covering the treatment and outcomes of 400 bladder cancer patients revealed that the expression of this protein is associated with a higher risk of death even after radical cystectomy, or the wholesale removal of the cancerous bladder. Notably, this association disappeared in patients who had received chemotherapy. A test for CDC25C could, in other words, help determine whether any bladder cancer patient is likely to benefit from chemotherapy.

The current study is based on work done by Ludwig Stanford Director Irv Weissman and his team that identified three subtypes of tumor cells based on the degree of their differentiation into specialized cells. Weissman and his colleagues noted in their 2012 study that the least differentiated of these subtypes, the BTCs, expressed three proteins on their surface (CD90, CD44 and CD49f) and had the potential to seed new tumors. They reported that as the cells become increasingly specialized, they lose these surface markers one by one.

Based on that report, Weichselbaum and his colleagues hypothesized that bladder tumors with the largest numbers of BTCs would also be the most aggressive. They used the three cell-surface markers to sort and count the three cellular subtypes in tumors and, in parallel, began injecting the BTCs isolated from each tumor into immune-deficient mice to see if they’d take hold and grow.

BTCs are relatively rare and have been poorly characterized in part because they tend to differentiate quickly into more specialized cells when cultivated in the lab. They’re of particular interest to researchers because they have stem-like properties, or the ability to seed new tumors and expand the boundaries of existing ones. A drug that selectively destroys such cells could effectively tear a cancer out by its roots, preventing its spread and recurrence. With a method to isolate and grow BTCs, researchers can begin to look for unique ways to target these stem-like cancer cells.

Weichselbaum is just as excited about the clinical potential of integrating his team’s risk model with other indicators to improve bladder cancer care.

“Prognostic knowledge can change a lot about how you choose to treat a cancer,” says Weichselbaum. “For example, you may want to treat an early stage bladder cancer with relatively less aggressive therapy, avoiding debilitating interventions like radical cystectomy. But if you know a bladder tumor has a lot of basal cells, you may need to take the bladder out and offer chemotherapy. Conversely, you may be able to safely avoid such aggressive measures if you find a tumor has relatively few basal cells.”

Weichselbaum notes, however, that before this can happen, the accuracy of his team’s new prognostic model and biomarker will need to be confirmed in larger studies.

The study was supported by Ludwig Cancer Research, Rosalind and Burton Spellman Family Cancer Fund, The Foglia Foundation and Mr. and Ms. Vincent Foglia.


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