Researchers have pinpointed a single type of cell that is responsible for most cases of invasive bladder cancer.
"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," Philip Beachy, PhD, professor of biochemistry and of developmental biology, said in a Stanford University Medical Center news release. "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."
These types of cancer stem cells and precancerous lesions have been known to express a signaling protein called sonic hedgehog, the news release reported. This finding suggests a certain weakness in the cancer progression that could possibly be targeted with therapies.
"This could be a game changer in terms of therapeutic and diagnostic approaches," Michael Hsieh, MD, PhD, assistant professor of urology and a co-author of the study, said in the news release. "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."
Bladder cancer is the fourth most common cancer in men and the ninth in women. One type of the cancer invades the muscles surrounding the bladder and can metastasize to other organs and the other is confined to the bladder lining. The milder type makes up about 70 percent of all bladder cancer cases but the more invasive type is largely untreatable.
A cell type in the bladder that can completely replace the organ's lining if it had been damaged; this cell uses the sonic hedgehog protein to communicate with other cells and prompt them to proliferate.
The researchers gave rodents drinking water laced with carcinogens found in cigarettes and BBN, a chemical activated in the bladder. Within four months many of the mice had developed precancerous lesions in the bladder and within six the majority of these cases had developed into bladder cancer.
The team watched what happened in BBN-exposed mice when their sonic hedgehog cells were marked with a fluorescent color. They also used "genetic techniques" to kill these cells.
The team noticed that after only a few months of BBN exposure the entire bladder showed signs of the fluorescent marker, suggesting the entire regeneration had come from the sonic-hedgehog-expressing basal stem cells. These cells caused bladder cancer when transplanted into other mice, while non-hedgehog cells did not.
"After four months of BBN treatment," Beachy said, "we'd most often see just one color dominating the entire epithelium. This clearly indicates that a single cell has taken over the lining of the entire bladder, elbowing out its neighbors in a way that's not been seen in other organs."
"We know that the hedgehog pathway is widely used throughout the animal kingdom to tightly regulate cellular and tissue differentiation," Hsieh said. "So its loss could make sense in this context because cancer is essentially a loss of normal regulation."
