U-M scientists find common virus in human prostate tissue

08/05/04

Study suggests possible role for BK virus in prostate cancer

ANN ARBOR, Mich. — Chances are excellent that your urinary tract is home to a pathogenic organism called the human BK virus. Most of the time, the virus lurks quietly in the kidneys without causing problems. But in people with a depressed immune system — especially those who have just received a kidney transplant — the virus can cause serious kidney and bladder disease.

Now, new research by scientists at the University of Michigan Medical School suggests the intriguing possibility that this common virus also may play a role in prostate cancer — the second-leading cause of deaths from cancer in American men.

A team of scientists directed by Michael J. Imperiale, Ph.D., U-M professor of microbiology and immunology, have found DNA and proteins from the BK virus in prostate tissue with abnormal cell changes. Called atrophic lesions, these changes can be the first step in a series of progressive cell changes leading to prostate cancer.

"Other studies have detected DNA from the BK virus in prostate cancer cells, but this study is the first to pinpoint the location of viral protein expression to one precursor stage in the development of prostate cancer, and to a specific location within prostate cells," Imperiale says. Results from the U-M study, published July 19 in the advance online edition of the journal Oncogene, are available at www.nature.com/onc/journal/vaop/ncurrent/.

"The development of cancer is a multi-step process," Imperiale adds. "Expression of BK viral protein may be just one step among several genetic and environmental factors. We are not saying that BK virus causes prostate cancer, but our results do suggest that the virus plays a role in the transition from normal to uncontrolled growth of prostate cells."

BK is a human virus in the polyomavirus family. It was first discovered in kidney transplant patients who take immunosuppressive drugs to prevent their body from rejecting a new kidney. Scientists have found BK virus in several types of human cancer and it has been shown to cause kidney tumors in laboratory mice. While the virus has received scientific study for its role in kidney disease, only a handful of scientists are studying a possible connection to cancer.

"Polyomaviruses have very small genomes, and they don't have the genes required to copy their own DNA," says Dweepanita Das, Ph.D., a U-M post-doctoral fellow and first author on the paper. "The virus must induce its host cell to divide, so it can use the cell's genes to make proteins the virus needs to reproduce. BK virus uses a protein called T antigen, or TAg, to induce cell division. The problem is that when you interrupt the normal cell cycle to force a cell to divide, sometimes the cell continues to divide abnormally."

U-M scientists analyzed 21 samples of prostate tissue from men with adenocarcinoma whose prostates were surgically removed to prevent the spread of cancer. Tissue samples were obtained from the Tissue Procurement Core at the U-M's Comprehensive Cancer Center. Samples contained benign, pre-cancerous and cancerous tissue.

Using new TAg-specific protein assays they developed, the research team searched the tissue to identify cells containing TAg. Scientists also removed DNA from the prostate tissue samples for sequencing and identification in the U-M's DNA Sequencing Core facility.

The results showed that 71 percent of the prostate samples analyzed for the study contained gene segments from the BK virus. TAg protein from the BK virus was present in 43 percent of the tissue samples, but only in atrophic lesions — a precursor stage of prostate cancer development. TAg was not expressed in normal cells or cancerous cells.

"Atrophic lesions comprise a spectrum of architectural and cytological differences in the appearance of epithelial cells lining the glands in the prostate," says Rajal B. Shah, M.D. M.B.B.S., a clinical assistant professor of pathology and urology in the U-M Medical School and co-author of the study. "Several recent studies have demonstrated that they potentially represent the first stage in a series of progressive cell changes, which can lead to prostate cancer."

In addition to TAg protein, atrophic lesions also contained high levels of protein expressed by the p53 tumor suppressor gene. When U-M scientists discovered that TAg and p53 proteins were located together in the cytoplasm of atrophic lesion cells, but not in the nucleus, an important piece of the puzzle fell into place.

"We know that for p53 to function as a tumor suppressor gene, its protein product must be in the cell's nucleus," explains Imperiale. "TAg apparently sequesters p53 protein in the cell's cytoplasm, preventing it from entering the nucleus and giving the signal for the cell to stop dividing and die."

Imperiale's working hypothesis is that the BK virus infects epithelial cells in the prostate and transforms them into atrophic lesions through TAg expression. This produces an area of uncontrolled cell growth, which — if circumstances are right — can eventually develop into prostate cancer.

If he's right, prostate cancer may have something in common with cervical cancer, which is caused by a different virus — the human papillomavirus.

"Papillomavirus makes proteins with the same function as T antigen," Imperiale says. "They induce cell growth and inactivate the p53 gene, preventing it from killing abnormal cells. So, it's a logical possibility that a similar mechanism occurs in at least some cases of prostate cancer, but much additional research will be needed before we can know for sure."

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