Pancreatic Tumor Growth Prevented in Mice by Suppressing Key Protein

Blocking the expression of the protein slowed or prevented tumor growth in mice and made cultured cancer cells susceptible to the conditions of low oxygen that occur in solid tumors.

"This research clearly shows that inhibiting the protein inhibits the tumor's ability to grow,” said cancer biologist Amato Giaccia, Ph.D., from the Stanford University School of Medicine (Stanford, CA, USA). "Ultimately, we'd like to be able to specifically knock out the expression of this protein in pancreatic tumors in humans.”

Pancreatic cancer is a very aggressive and deadly disease that accounts for more than 30,000 deaths in the United States yearly, and current therapies are mostly ineffective.

"Right now, we have very little to offer these patients,” said Dr. Giaccia, who is a professor of radiation oncology and the senior author of the study, which was published February 1, 2009, in the journal Cancer Research. Dr. Giaccia is also a member of the Stanford Cancer Center.

The researchers examined a protein called connective tissue growth factor (CTGF). Also known as CCN2, the protein is involved in the abnormal growth of connective tissue in response to injury or disease. It was also believed to be involved in pancreatic tumor progression, although the exact role it played was unknown.

Dr. Giaccia and his collaborators discovered that human pancreatic cancer cells expressing high levels of CCN2 grew vigorously when injected under the skin of mice. In fact, in the developing tumor these cells soon out-competed others that expressed lower levels of the protein. Conversely, pancreatic cancer cells in which CCN2 expression was suppressed were either less likely or unable to form tumors when injected into mice.

The researchers noticed similar effects when the cancer cells were injected directly into the animals' pancreases. Cancer cells expressing high levels of CCN2 formed tumors that grew more rapidly and metastasized more aggressively than did those expressing lower levels, and the mice died sooner than others injected with cancer cells expressing less CCN2.

It is difficult for many types of quickly growing solid tumors to recruit and generate enough blood vessels to keep all the cancer cells sufficiently oxygenated. Normal cells undergo a process of programmed cell death when oxygen levels fall too far. Overcoming this response to low oxygen levels--a condition called hypoxia--is a critical step in tumor progression.

The researchers wondered if CCN2 played a role in keeping tumor cells alive in hypoxic conditions. If so, this might clarify why CCN2-expressing cancer cells are preferred during tumor growth. They found that blocking CCN2 expression in cultured pancreatic cancer cells made them considerably more sensitive to hypoxia-induced death than their peers. Moreover, CCN2 was more highly expressed in pancreatic tumor samples from human patients than in neighboring tissue and CCN2 expression seemed to correlate with the expression of another protein expressed by hypoxic cells. Finally, hypoxic conditions themselves cause the pancreatic cancer cells to produce CCN2.

Many other cellular conditions can also trigger CCN2 expression, including the presence of CCN2 itself. The activation of other pathways known to be involved in cancer also increases its expression. As a result, many of the events that occur in a developing tumor work together to support the production of ever-larger amounts of CCN2, which then support additional tumor growth and metastasis.

Looking ahead, the researchers would like to know whether people with pancreatic cancer could benefit from therapies targeting CCN2. A phase 1 clinical trial testing the safety of an antibody that binds CCN2 and blocks its activity in a small number of patients began in December 2008 at Stanford and Dartmouth-Hitchcock Medical Center (Lebanon, NH, USA). Phase 1 clinical trials are not designed to determine whether a treatment works--only whether it is safe enough for further testing. Albert Koong, M.D., Ph.D., an assistant professor of radiation oncology and a member of the Cancer Center, is the lead investigator for the Stanford arm of the trial.

"We saw a pronounced effect of CCN2 inhibition in these experiments in mice,” said Dr. Giaccia. "Our hope is that one day a combination of standard therapy and antibody treatment will have an effect on tumor progression in human patients.”

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