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Invasive bladder cancer (IBC), a malignant disease that currently affects more than 375,000 people worldwide, has been found to be caused by a single type of cell in the lining of the bladder, according to researchers with the Stanford University School of Medicine.

The researchers say this is the first study to pinpoint the normal cell type that can give rise to IBC. It is also the first study to show that most bladder cancers and their precancerous lesions arise from just one cell, which could also explain why many bladder cancers recur after therapy.

Weve learned that, at an intermediate stage during cancer progression, a single cancer stem cell and its progeny can quickly and completely replace the entire bladder lining, Philip Beachy, PhD, professor of biochemistry and of developmental biology, said in a statement. All of these cells have already taken several steps along the path to becoming an aggressive tumor. Thus, even when invasive carcinomas are successfully removed through surgery, this corrupted lining remains in place and has a high probability of progression.

Beachy and colleagues found that while cancer stem cells and the precancerous lesions they form express an important signaling protein known as sonic hedgehog, the cells of subsequent invasive cancers invariably do not a critical switch that appears vital for invasion and metastasis. This switch may explain certain confusing aspects of previous studies on the cellular origins of bladder cancer in humans. It also pinpoints a possible weak link in cancer progression that could be targeted by therapies.

This could be a game changer in terms of therapeutic and diagnostic approaches, said Michael Hsieh, MD, PhD, assistant professor of urology and a co-author of the study. Until now, its not been clear whether bladder cancers arise as the result of cancerous mutations in many cells in the bladder lining as the result of ongoing exposure to toxins excreted in the urine, or if its due instead to a defect in one cell or cell type. If we can better understand how bladder cancers begin and progress, we may be able to target the cancer stem cell, or to find molecular markers to enable earlier diagnosis and disease monitoring.

Bladder cancer is the fourth most common cancer in men and the ninth in women. There are two main types of bladder cancer: one that invades the muscle around the bladder and then metastasizes to other organs, and another that remains confined to the bladder lining. Unlike noninvasive cancers, most invasive bladder cancers are untreatable. Those that can be treated are expensive and difficult to cure, and with a high likelihood of recurrences, ongoing monitoring is required.

To determine what genes or cell types are at play in the formation of bladder cancer, the study team used a mouse model that closely mimicked what happens in humans. Usually, researchers rely on prior knowledge or guesses as to what genes are involved and often genetically alter cell types in animals to induce overexpression of a gene known to be involved in tumorigenesis or to block the expression of a gene that inhibits cancer development.

LINK TO SMOKING

Previous work by Beachy and his colleagues suggested that basal cells play a role in bladder cancer. However, the new study offered an unbiased approach.

See the original post:
Single Cell Type Found To Cause Most Invasive Bladder Cancers: Study

PUBLIC RELEASE DATE:

20-Apr-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. A single type of cell in the lining of the bladder is responsible for most cases of invasive bladder cancer, according to researchers at the Stanford University School of Medicine.

Their study, conducted in mice, is the first to pinpoint the normal cell type that can give rise to invasive bladder cancers. It's also the first to show that most bladder cancers and their associated precancerous lesions arise from just one cell, and explains why many human bladder cancers recur after therapy.

"We've learned that, at an intermediate stage during cancer progression, a single cancer stem cell and its progeny can quickly and completely replace the entire bladder lining," said Philip Beachy, PhD, professor of biochemistry and of developmental biology. "All of these cells have already taken several steps along the path to becoming an aggressive tumor. Thus, even when invasive carcinomas are successfully removed through surgery, this corrupted lining remains in place and has a high probability of progression."

Although the cancer stem cells, and the precancerous lesions they form in the bladder lining, universally express an important signaling protein called sonic hedgehog, the cells of subsequent invasive cancers invariably do not a critical switch that appears vital for invasion and metastasis. This switch may explain certain confusing aspects of previous studies on the cellular origins of bladder cancer in humans. It also pinpoints a possible weak link in cancer progression that could be targeted by therapies.

"This could be a game changer in terms of therapeutic and diagnostic approaches," said Michael Hsieh, MD, PhD, assistant professor of urology and a co-author of the study. "Until now, it's not been clear whether bladder cancers arise as the result of cancerous mutations in many cells in the bladder lining as the result of ongoing exposure to toxins excreted in the urine, or if it's due instead to a defect in one cell or cell type. If we can better understand how bladder cancers begin and progress, we may be able to target the cancer stem cell, or to find molecular markers to enable earlier diagnosis and disease monitoring."

Beachy is the senior author of the study, which will be published online April 20 in Nature Cell Biology. He is the Ernest and Amelia Gallo Professor in the School of Medicine and a member of the Stanford Cancer Institute and the Stanford Institute for Stem Cell Biology and Regenerative Medicine. He is also a Howard Hughes Medical Institute investigator. Kunyoo Shin, PhD, an instructor at the institute, is the lead author.

Bladder cancer is the fourth most common cancer in men and the ninth most common in women. Smoking is a significant risk factor. There are two main types of the disease: one that invades the muscle around the bladder and metastasizes to other organs, and another that remains confined to the bladder lining. Unlike the more-treatable, noninvasive cancer which comprises about 70 percent of bladder cancers the invasive form is largely incurable. It is expensive and difficult to treat, and the high likelihood of recurrence requires ongoing monitoring after treatment.

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Stanford scientists identify source of most cases of invasive bladder cancer