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From OncoLog, April-May 2010, Vol. 55, No. 4-5

Graphic: In Brief

Fight-or-Flight Hormones Linked to Metastasis

Ovarian cancer cells that break away from the primary tumor are protected by heightened levels of two stress hormones, a research team at MD Anderson Cancer Center recently discovered. The finding links chronic stress to the ability of ovarian cancer cells to metastasize.

In preclinical research, the team found that heightened levels of the fight-or-flight stress hormones epinephrine and norepinephrine permit more malignant cells to safely leave the primary tumor, a necessary step in metastasis and cancer progression. Researchers also found that ovarian cancer patients die earlier when the FAK protein, which is activated by the hormones, is present at high levels in their tumors. Further, depressed patients were found to have higher levels of FAK.

“When normal cells become detached from neighboring cells or from the supportive scaffolding known as the extracellular matrix, they die from anoikis, a form of programmed cell death,” said first author Anil Sood, M.D., a professor in the Departments of Gynecologic Oncology and Cancer Biology. “Cancer cells find a way to bypass anoikis, so they survive as individual cells circulating in the blood or in ascites.” Resistance to cell death helps malignant cells migrate from the primary tumor and reattach to colonize new sites.

“Restoring cancer cells’ vulnerability to anoikis would open a new avenue for suppressing tumor growth and metastasis,” Dr. Sood said. Two promising approaches—directly silencing FAK or using beta blockers to preempt its activation—worked in cell culture and mouse models, making them candidates for human use.

The team showed that increases in epinephrine, also known as adrenaline, and norepinephrine reduced the number of ovarian cancer cells killed by anoikis by activating FAK. The researchers previously showed that FAK is abundantly present in ovarian cancer cells.

Lab experiments showed that resistance to cell death by anoikis begins when one of the hormones connects with the ß2-adrenergic receptor (ADRB2), which activates FAK via other intermediate proteins. Treating cells with beta blockers to inhibit the ADRB2 connection or using small interfering RNA (siRNA) to shut down FAK increased cell death.

In a mouse model of human ovarian cancer, mice subject to restraint stress had smaller tumors with fewer nodules and greater cell death when treated with siRNA to suppress FAK. Treatment with the beta blocker propranolol had a similar effect.

The researchers examined 80 cases of invasive epithelial ovarian cancer to assess the role of stress-induced FAK activity. They found increased FAK expression in 67% of patients and heightened levels of phosphorylated FAK in 50%.

Patients with high levels of either measure had greatly reduced overall survival over 3 years. About 65% of those with low FAK expression survived at least 3 years compared with 30% of those with high expression. For activated FAK, the values were 65% compared with about 15%.

Using depression as an indicator of stress, the researchers found major depression was associated with higher levels of activated FAK and increased levels of norepinephrine in the tumors.

The research was published in Journal of Clinical Investigation.

Drug Combination Shows Promise for Colon Cancer Chemoprevention

A two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer, a team of MD Anderson scientists reported recently in Nature.

The regimen, tested so far in mouse models and on human colon cancer tissue in the lab, appears to address a problem with chemopreventive drugs—they must be taken continuously over the long term to be effective, exposing patients to possible side effects, said senior author Xiangwei Wu, Ph.D., an associate professor in the Department of Head and Neck Surgery.

“This combination can be given short term and periodically to provide a long-term effect, which would be a new approach to chemoprevention,” Dr. Wu said.

The team found that a combination of vitamin A acetate (RAc) and TRAIL, short for tumor necrosis factor-related apoptosis-inducing ligand, kills precancerous polyps and inhibits tumor growth in mice that have deficiencies in a tumor-suppressor gene. That gene, adenomatous polyposis coli (APC), and its downstream signaling molecules are mutated or deficient in 80% of all human colon cancers, Dr. Wu said.

Early experiments with APC-deficient mice showed that the two drugs given in combination or separately did not harm normal colon epithelial cells. And given separately, the drugs showed no effect against adenomas, or premalignant polyps.

However, RAc and TRAIL given together killed adenoma cells via apoptosis, a form of programmed cell death. RAc, researchers found, sensitizes polyp cells to TRAIL. Reduction in polyps was first seen in experiments using mice; follow-up studies with biopsy samples from patients with familial adenomatous polyposis showed that treatment of normal tissue caused little cell death, while 57% of polyp cells were killed via apoptosis.

Before human clinical trials can be considered, Dr. Wu said, the team will conduct additional research to identify potential side effects and also will try to develop an injectable version of the combination.

For more information on this topic or for questions about MD Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, April-May 2010 issue:

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