An Early Warning System for Cancer

Autoantibodies could alert doctors to cancer development.

A new screening tool developed by scientists in Denmark may help detect the earliest stages of cancer by taking advantage of the body’s own defenses. The researchers constructed a microarray system that analyzes patients’ blood for a specific class of immune agents called autoantibodies. These are agents that attack the body’s own tissue, targeting what they perceive as “foreign” cells, such as specific molecules on the surface of tumors.

Immune tracer: This image shows the overexpression of cancer-associated glycan structures (green) on proteins in cancer cells. The cells’ nuclei are stained in blue.

The researchers found that, within a limited number of blood samples, the screening test could detect cancer-associated autoantibodies in patients recently diagnosed with prostate, breast, and ovarian cancer. Healthy individuals showed no signs of the immune agents in their blood. Their findings, published in the journal Cancer Research, suggest that autoantibodies may be effective biomarkers for early cancer development.

Normally, the immune system launches an antibody attack in the presence of a foreign invader or antigen, such as a bacteria or virus. However, in some cases, such as in rheumatoid arthritis and diabetes, the immune system turns on the body itself, releasing autoantibodies that attack its own tissues. In the case of cancer, these autoantibodies attack certain antigens on the surface of tumor cells. Hans Wandall, associate professor of cellular and molecular medicine at Copenhagen University in Denmark, says that in the near future, a simple blood test could detect the presence of autoantibodies as a warning sign of cancer.

Physicians can already administer blood tests that screen for certain cancers. These tests detect elevated levels of tumor markers–chemicals associated with tumors that circulate in the blood, such as prostate-specific antigen for prostate cancer, or cancer antigen 125 for ovarian cancer. However, these antigens can also sometimes be made by healthy cells, and have also been found in other, noncancerous diseases, making such tests less than foolproof.

Wandall adds that such tumor antigens are difficult to detect in the early stages of cancer, since these chemicals, once made by the tumor, are sloughed into the bloodstream and eventually absorbed by the liver. “You’re fighting an uphill battle, because a tumor might produce a protein, but if it’s at the early stages, it will be in small amounts, which will be cleared by the liver,” says Wandall. “So that’s why we turn to the immune response, which acts as sort of an immunological mirror of what’s going on in cancer.”

Wandall says the immune system can recognize and seek out tumor antigens, even at low levels, and attack them with autoantibodies that bind to the antigens before they reach the liver. These immune agents can circulate longer and at greater numbers compared to the tumor antigens themselves, making them more easily detectable.

Wandall and his colleagues set out to design a test to detect cancer-related autoantibodies that act on a specific class of tumor antigen called mucins. In recent years, researchers have focused on mucins as possible tumor markers because they are present in abnormally high levels in multiple types of cancer. However, like other tumor markers, mucins have also been observed in noncancerous conditions.

To elicit a cancer-specific autoantibody response, the researchers theorized that they would have to engineer the mucin antigen to include a cancer-specific trait. In the past few years, scientists have discovered novel changes that occur on the surfaces of cells as they turn cancerous. Normally, the surface of healthy cells is covered with proteins attached to long chains of sugars. In cancer, these sugar chains, or glycans, are abnormally cut short–and the trait is expressed only in cancerous cells.

The Denmark team hypothesized that by combining a tumor-associated antigen like mucin with a cancer-specific glycan change, they could detect a robust autoantibody response specific to cancer.

The researchers chemically synthesized a mucin called MUC1, and attached it to short glycan chains similar to those found in cancer. They then bound the structures to the surface of a microarray. The team collected serum samples from three groups, each including 20 patients with prostate, breast, or ovarian cancer. Wandall and his team passed each serum sample through the microarray, followed by a solution containing a fluorescent agent illuminating the presence of autoantibodies.

The group found that autoantibodies were present in 20 to 30 percent of cancer patients, versus none in samples from healthy individuals. Wandall says in the future, he plans to increase the specificity of the test by combining the short glycan structures with other cancer-associated proteins.

Michael Hollingsworth, a professor of biochemistry and molecular biology at the University of Nebraska Medical Center, collaborated with Wandall in designing the screening test. Hollingsworth envisions such a test as a regular screening tool incorporated into a yearly physical. “You wouldn’t want to use this as a diagnostic to say yeah, you have pancreatic cancer,” says Hollingsworth. “You just want to use it to say, okay, you want to look at this more closely.”

Suzanne Miyamoto, associate professor of hematology and oncology at the Cancer Center at the University of California, Davis, is developing a similar cancer screening tool by incorporating cancer-related changes in glycan structures. Miyamoto sees promise in Hollingsworth and Wandall’s design. “I think it has potential,” says Miyamoto. “It’s only preliminary, and they will definitely need to do more validation processes to look at different cancers like benign versus malignant, and see how well that stands up to a clinical lab test. But their platform is very adaptable to the clinical lab.”

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