Test-tube tumors

Beatrice Knudsen seeks to further develop in-laboratory methods to help physicians predict which prostate cancers will spread
glass slide of tissue array
Dr. Beatrice Knudsen displays a tissue array, a glass slide that holds bits of prostate-tumor tissue that are analyzed for markers that may predict a tumor's aggressiveness. Photo by Todd McNaught.

While an aggressive tumor can invade tissue and colonize distant sites in the body with seemingly little effort, sci- entists have found that simulating the process in a test tube is anything but easy.

Yet Dr. Beatrice Knudsen, new investigator in the Public Health Sciences Division, thinks tackling that project for prostate cancer is worth her while.

The payoff for what is likely to be a long and difficult road, she said, could be improved medical care for a disease that is the second leading cause of cancer death in men.

"Right now, men who are suspected to have recurrent disease after surgery are basically treated in the same way, even though for many of them, the cancer will not progress to become a life-threatening illness," said Knudsen, who joined the cancer-biology program last summer.

"If there were molecular markers that could distinguish early on which prostate tumors were likely to metastasize (spread) and which micrometastases develop into clinically significant metastases, treatment could be targeted to those patients with high-risk disease."

Identification of such markers, typically proteins produced at different levels in normal or tumor tissue, might be more easily accomplished if scientists could watch development of cancer in the laboratory, as opposed to working with the small snippets of tissue they can obtain from surgical biopsies.

To usefully predict whether a tumor will spread, a marker would need to be associated uniquely with an aggressive or nonaggressive form.

Knudsen, a board-certified pathologist who also has a doctoral degree in cellular biology, has developed a system for growing immature, normal, prostate epithelial cells that develop into mature, prostate epithelium, the part of the organ where prostate cancer develops. Epithelial cells are sheets of cells that typically cover the surfaces of organs.

"Prostate tumor cells don't grow in the laboratory," she said. "So it's been hard to set up a system for studying how cancer develops. The goal is to turn these normal cells into tumor."

Cell tricking

But first, Knudsen must trick the progenitor cells into developing into the specialized cells types that make up the prostate epithelium. The process depends on growth factors produced by another part of the prostate known as the stroma.

Knudsen and others believe that similar factors in the prostate stroma are at play during both the normal differentiation process and tumor development. It's suspected that what influences which path is taken is whether the signals that trigger differentiation into mature, prostate epithelial cells are carefully controlled or are deregulated, causing excess cells to form and, possibly, to acquire dangerous behaviors like invading nearby tissue or traveling to distant sites.

One of the most intriguing factors in this process, she said, is a protein called Met. Met is a receptor, a type of molecular catcher's mitt that receives growth signals from outside the cell and triggers a chemical relay race. Upon receiving a signal from the prostate stroma, Met passes the baton to other proteins that cause immature cells to differentiate into specialized mature epithelial cells. In the test tube, Met also stimulates cell motility (movement) and survival.

"Interestingly, Met is also found in high levels in all prostate cancers that have spread to distant parts of the body," she said. "This may mean that Met causes tumor cells to become invasive and to spread."

And in prostate cancer, she said, tumors that metastasize typically spread to the bone.

Knudsen plans to use the cell-growth system she has developed to learn more about invasion and cell movement, as well as to identify new factors that may influence normal cells to acquire cancerous traits.

Ultimately, the test-tube system must be complemented by analysis of potential markers in human tumor samples. To work out an effective method to check tissue biopsies for the presence of unique markers, Knudsen collaborates with Dr. Peggy Porter of Human Biology and PHS. They are examining proteins thought to correlate with a cancer's aggressiveness.

Some cancer patients who undergo surgery to remove the prostate, a procedure known as a radical prostatectomy, later test positive for high levels of PSA, a marker that is often elevated in prostate cancer. Despite the worrisome test results, many of these cancers will never progress to cause clinical symptoms. In fact, Knudsen said, in many cases, trace cancer cells are found in the bone following surgery, yet the cancer does not continue to develop.

"This means clinicians have a dilemma in treating patients suspected of recurrent cancer," she said. "They have no way to distinguish whose case is likely to warrant additional therapy."

Most men with high PSA levels following surgery are treated with drugs that interfere with the hormones that stimulate the growth of prostate tumors. In addition to causing side effects that include impotence, such therapy might actually stimulate bone metastases that have formed to grow.

Tumor screening

Knudsen and Porter are screening tumor tissue from patients who have undergone radical prostatectomies at local hospitals to see if tumor aggressiveness correlates with the presence of proteins such as Met. Future studies also will draw from patients studied by Dr. Janet Stanford, head of the prostate-cancer research program.

Knudsen believes that this work, combined with efforts to mimic cancer development in the test tube, will yield new clues into the basic biology of cancer as well as benefit patients.

"Hopefully," Knudsen said, "insight we get from studying mechanisms of migration and invasion will help us to develop new markers and ultimately help with treatment decisions.

"But it will take time."

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