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

Most people probably think of cancer tests in setting of early detection. The idea is that anyone who might wonder if they have a particular type of cancer could submit a sample of some easily obtained bodily fluid (saliva, blood, urine, sweat, etc.), send it off to the laboratory, and get a clear result. Unfortunately, developing and effectively using such a test is incredibly difficult. Perhaps the most widely used such test at the moment is the Prostate Specific Antigen blood test for prostate cancer. Some argue that use of this test has resulted in a decline in the death rate due to prostate cancer and is therefore a huge success. Nevertheless, it is clear that in a substantial number of cases, the test falsely identifies men without cancer, or incorrectly gives a clean bill of health to men who actually have the disease. You can read about the controversies here. My personal opinion is that the test, like essentially all other medical tests, requires careful use by a knowledgeable doctor and engaged patient who understand the test’s strengths and weaknesses.

In the setting of folks who have cancer and have been treated for it, non-invasive tests are very useful for monitoring cancer recurrence. PSA rises in men who have had their prostates surgically removed or irradiated are very reliable indicators of disease recurrence, for example.

Our friend Spiros effectively articulated one of the biggest issues in bladder cancer (his comment and question are here) — In patients with a risk of recurrent bladder cancer, is there a non-invasive test that we can use to supplement or replace cystoscopy? Let’s first describe cystoscopy, in case it’s useful for some readers. This is an examination of the bladder by a urologist performed by inserting a flexible tube into the urethra. The tip of the tube has a camera and a light source, and images are projected onto a video screen in the operating room or doctor’s office. Now imagine the alternative. Drop off a urine sample at the doctor’s office and be on your way. The sample is analyzed in a laboratory for protein, DNA, RNA, and/or microsocopic appearance of cells in the urine, and a report is generated.

It should work, but so far it doesn’t seem to work very well for the most common kind of bladder cancer, called low grade noninvasive urothelial carcinoma. These lesions are not harmful in and of themselves, but they carry with them an increased risk of high grade invasive cancers, which do cause harm.

It is therefore important to monitor patients with low grade carcinoma for recurrence, but especially important to monitor them for progression. Turns out that neither microscopic examination of urine cells (called cytology) nor molecular tests are very good at detecting low grade cancer, but both are pretty good at detecting high grade cancer.

First, what is the muscularis propria? In order to understand what it is and its significance we first must briefly discuss what is normally seen microscopically in a bladder biopsy. When the pathologist looks under the microscope he/she is looking at the different layers that make up the bladder. The most common type of bladder cancer is urothelial cancer. This type of cancer arises from the urothelial cells that line the bladder. These are the cells that line the inside surface of the bladder and are in contact with the urine (which is why sometimes these cancer cells are present in the urine and can be evaluated by urine cytology). Just beneath the urothelial cell layer is the lamina propria. Beneath the lamina propria is a thick muscle layer called the muscularis propria. Urothelial cancer can be non-invasive (also called in situ) which means that the cancer is confined to the urothelial layer. An invasive cancer breaks through the urothelial layer and extends into the lamina propria and may extend into the muscularis propria (in some cases the invasive cancer may even extend beyond the bladder and into structures such as the prostate or uterus that are next to the bladder). The presence or absence of the muscularis propria becomes important when there is an invasive urothelial cancer. The reason that the muscularis is important is because the presence of tumor in the muscularis propria results in a higher cancer stage. The treatment for urothelial cancer may differ depending on the stage (staging will be discussed in later post). Therefore, in cases where the biopsy has invasive cancer, but the muscularis propria was not present in the biopsy (for example the report may say something like “Invasive high grade urothelial carcinoma. Muscularis propria is not identified” ), it may be necessary for the urologist to get another biopsy that contains muscularis propria to get an accurate cancer stage.

Some pathologists will report the absence of muscularis propria even when the cancer is non-invasive (for example the report may say something like “Non-invasive high grade urothelial carcinoma. Muscularis propria is not identified” or “Flat urothelial carcinoma in situ. Muscularis propria is not identified. ), in these cases since the cancer is non-invasive the absence of muscularis propria in the biopsy is of no concern. In some cases of invasive cancer it is difficult to determine if the invasive cancer involves muscularis propria (for example the report may say something like “Invasive high grade urothelial carcinoma. Invasion of muscularis propria cannot be determined with certainty” ). In such cases, the urologist may decide to obtain a repeat biopsy in order to more adequately determine the tumor stage. In summary, the presence or absence of muscularis propria on a bladder biopsy is only important when the tumor is invasive. Absence of muscularis propria in a biopsy with invasive cancer may necessitate further biopsies to adequately stage the tumor.

Daniel Fajardo MD PhD

Bladder cancer is best looked at as two diseases rather than one: A “superficial” disease and a “deep” disease.  The superficial one can lead to recurrences and in a minority of cases will lead to progression into deep disease. Frequent follow-ups and urine cytology examination will help identify early recurrences and hopefully prevent progression in patients with superficial disease.

Research opportunities in the superficial type of bladder cancer reside in finding markers that will help us better identify which lesions are more likely to progress. By identifying such markers of early recurrence and high risk of progression, one can then limit intense follow up efforts to high risk patients while extending intervals between doctor visits and cystoscopies in low risk patients.

Next time will talk about challanges and opportunities in the more aggressive “deep” disease category of bladder cancer.

What would the cure for cancer look like? My hope is that it would look a lot like the cure for strep throat — a pill that a patient would take for a few days to wipe out the offending invaders while leaving the rest of the body unharmed. To get to this Utopian place, cancer treatment will need to adopt several strategies from the battle against infectious disease, including:

1. Exploit biological differences between the invader (cancer cell) and the host (the patient).
2. Develop laboratory tests to determine which drugs are useful for a given individual’s disease (personalized therapy).
3. Simultaneously attack multiple molecular targets so that if one attack fails, the others can still win the war.

I lead a research team whose work is aimed at understanding how bladder cancers form and spread. Through this work, we hope to develop new treatments that specifically target the cancer without harming healthy organs.

Our institution has a large number of experts in bladder cancer risk factors, research, treatment, and diagnosis. From time to time, my colleagues and I will be bringing you expert analysis on these topics.

Now, we need your help in starting this conversation.

What topics would you like to see discussed here?

What information is hard to find or difficult to understand?l

What would be most helpful for people with bladder cancer and their families?

We’re looking forward to hearing from you.