Bladder Cancer

HOPKINS SCIENTISTS FIND CELLS RESPONSIBLE FOR BLADDER CANCER’S SPREAD

Powerful cells located in same tissue location as bladder stem cells

Aug. 6, 2009 – Johns Hopkins scientists have tracked down a powerful set of cells in bladder tumors that seem to be primarily responsible for the cancer’s growth and spread using a technique that takes advantage of similarities between tumor and organ growth. The findings, reported in the July Stem Cells, could help scientists develop new ways of finding and attacking similar cells in other types of cancer.

Researchers have long suspected that a subset of cells in cancerous tumors act much like developmentally primitive cells known as stem cells, which spur organ development early in life and remain present in nearly all the body’s organs to repair or replace injured and aging tissues. These cancer cells and stem cells share a variety of characteristics including an unlimited lifespan and a propensity to migrate through tissues.

These same properties are the ones that make cancer particularly dangerous, says David Berman, M.D., Ph.D., associate professor of pathology, oncology, and urology at the Johns Hopkins University School of Medicine. If researchers had a way to identify and specifically target cancer cells with these properties, they could wipe out the population that sustains tumors and makes them grow.

Other researchers have identified proteins on the surfaces of these cancer cells that could work as markers, but because other cells sometimes shared these proteins, this approach can lead to errors, Berman says.

In the new study, led by Berman’s postdoctoral research fellow Xiaobing He, Ph.D., the researchers reasoned that if these stem-like cancer cells behave like healthy stem cells, they might be physically located in the same compartments in tissue where stem cells normally reside. Using a surface protein marker previously identified for healthy bladder stem cells, the Hopkins team searched for cells with the same marker in sections from 55 human bladder tumors. They found that cancer cells displaying the marker were localized in an area at the intersection of two layers of cells known as epithelium and stroma, the place where bladder stem cells are typically located.

Using cancer cell lines grown from other bladder cancer patients, the researchers separated cells displaying the stem cell marker from those without it and injected these two populations into different sets of mice. Mice injected with the cancer cells displaying the marker always grew tumors, but those injected with the other cancer cells rarely did, suggesting that the stem-like cancer cells have an ability to create new tissue much like healthy stem cells do.

When the researchers surveyed both cancer cell populations to see which of their genes were most active, they found that genes with roles that are well-known hallmarks of cancer, such as cell proliferation and metastasis, were significantly more active in the stem-like cells than in the other cancer cells. Genes known to help cancers survive chemotherapy and radiation were also more active in the stem-like cells.

Other researchers who participated in this study include Luigi Marchionni, Wayne Yu, Akshay Sood, Jie Yang, Giovanni Parmigiani, and William Matsui, all of Johns Hopkins; and Donna E. Hansel of the Cleveland Clinic.

For more information, go to:

http://urology.jhu.edu/index.html

http://urology.jhu.edu/about/faculty.php?id=69

http://pathology.jhu.edu/berman/

Media Contact:
Christen Brownlee, 410-955-7832; cbrownlee@jhmi.edu

Bladder cancer is one of the most frequently diagnosed malignancies, with estimated 68,810 new cases in the US in 2008. It is the fourth most common cancer in men, accounting for 6.9% of all cancers, and 10th most common cancer in women, accounting for 2.6% of all cancers. Thus, men have significantly higher risk of bladder cancer than women. Excessive exposure to cigarette smoke and industrial chemicals in men had been suggested to result in the development of bladder cancer. However, our recent report shows molecular evidence that male hormone (androgen) plays an important role in bladder cancer, which may explain the gender-specific difference in incidence.

As described in the previous posts, bladder cancer can be divided into two distinct types: superficial, often low-grade (less aggressive) tumors, and invasive, mostly high-grade (more aggressive) tumors. Although most of the superficial tumors are not life-threatening disease, the patients frequently (50-70%) suffer from tumor recurrence with occasional (10%) progression to muscle invasion after surgery. In contrast, patients with invasive tumor frequently need more aggressive treatment. Therefore, early detection of bladder cancer for both initial diagnosis and recurrence is important to improve patients’ prognosis.

Cystoscopy is the “gold standard” for the detection of bladder cancer, but is an invasive and relatively expensive procedure. Urine cytology (examination of collected urine under a microscope to look for cancerous cells) is a non-invasive test widely utilized with cystoscopy for both screening and surveillance for recurrence. It is generally good for detecting high-grade bladder tumors. One limitation, however, is the inability to definitively identify low-grade cancer cells. In addition, the accuracy of diagnosis in urine cytology is dependent on the level of expertise of the cytopathologist. It is noteworthy that due to lifelong need for monitoring recurrence, the typical cost per bladder cancer patient from diagnosis to death was estimated to be the highest among all cancers ($96,000-$187,000 in the US). Thus, new non-invasive tests for detecting bladder cancer will minimize patient discomfort, reduce costs, and eventually lead to reducing bladder cancer mortality.

There are four urine-based tests for bladder cancer approved by the US Food and Drug Administration (FDA). In my posts, I will describe these tests, as well as other markers that have been shown to be clinically useful, some of which could be substitutes of cystoscopy and/or cytology.

Hiroshi Miyamoto, MD, PhD