On tumor’s surface, a telltale molecule

Yale scientists discern an abnormal sugar that gives cancer cells mobility but also gives them away.

The little white grains that sweeten our cereal at breakfast are usually all we have in mind when we speak of “sugar.” Inside the human body, though, sugar exists in many forms, most of them readily convertible to energy. Each of these contributes to everyday functioning and the maintenance of general good health. But when John M. Pawelek, Ph.D., senior research scientist in dermatology, observed strangely branched oligosaccharide molecules crowded together on the surface of one particular type of cell, he knew those sugars had nothing to do with good health: the cells had all come from human metastatic tumors.

“There have been 20 years of work, in vitro and in animal models, showing that cancer cells tend to exhibit sugars on their outer surface that aren’t present on their normal-cell counterparts, but no one had sat down and said, ‘Let’s look for these sugars in human cancer cells,’” said Pawelek. When he and Tamara Handerson, M.D., of Tufts University did just that, using a Yale-designed tumor microarray, they were surprised at the near-universal results. “We’ve now looked at slides from perhaps 500 different human metastases and found just a handful that don’t have these sugars,” said Pawelek. Handerson and Pawelek published their findings in the September 1 issue of the journal Cancer Research.

Normally, such oligosaccharides appear only on the surface of the immune system’s white blood cells, or leukocytes, where their function is to allow the leukocytes to move on their own—as they must do in order to patrol the body and attack foreign cells effectively. In cancer cells, the same power of movement is conferred by the abnormal oligosaccharides on their surface and may play a key role in metastasis, the spread of malignant disease from one organ or part of the body to another.

But the oligosaccharide coating on the cell surface that makes the tumor cells mobile may also make them easier to find and more vulnerable to cancer-suppressing therapy, says Pawelek. Since the branched oligosaccharides appear almost exclusively on cancerous cells and are readily detected by a method of staining known as lectin histochemistry, the sugar coating provides a strong tool for diagnosis as well as for locating precisely the populations of cells that require treatment. Pawelek and Handerson, in collaboration with Robert L. Camp, M.D., Ph.D., associate research scientist in pathology, and David L. Rimm, M.D., Ph.D., associate professor of pathology, also carried out studies focusing specifically on breast cancer, in which they found that the quantity of abnormal sugar present in cells from a patient’s biopsy is a reliable inverse index of the patient’s odds for survival: the more oligosaccharides, the greater the likelihood that the cancer will be fatal. The index seems to work independently of the well-known risk factors: stage and type of cancer, age of patient and even the extent of metastasis. As Pawelek sees it, “This is a completely new predictor.”

At the same time, the pervasiveness of the sugar coating among cancerous cells means that any treatment that destroys tumors by attacking the oligosaccharide molecules could probably be applied to a broad range of carcinomas, from cancer of the breast, lung or colon to prostate cancer or Hodgkin’s lymphoma. “What we have now is a universal target,” said Pawelek, adding, “If you have something that is characteristic of all metastases, it’s really worth your while to go after it.”

While continuing to apply the tumor microarray technique to as many types of cancer as possible, the scientists are also seeking to learn more about the workings of the branched oligosaccharide structures on the surface of tumor cells. Most important, said Pawelek, “We’re going to put all our efforts into exploiting these sugars for therapy, because in the end, we’d rather get rid of them than have them here to study.”

—Sandra Ackerman

A new class of RNA molecule may help cells decide how and when to grow

Two members of a class of tiny RNA molecules discovered only a decade ago have been shown to play a role in the timing of cell differentiation, according to a Yale researcher.

Biologist Frank J. Slack, Ph.D., who four years ago discovered the microRNA let-7, the second microRNA known to scientists, says that understanding the function of these regulatory RNAs in the millimeter-long nematode C. elegans may provide insight into human biology as well.

“Because C. elegans shares half its genes with humans, we hope to extend to humans what we’ve learned about how microRNAs function in C. elegans,” said Slack, an assistant professor of molecular, cellular and developmental biology, whose findings were published in Developmental Cell last May.

Slack showed that these noncoding RNAs provide temporal cues that control the larval worm’s maturation. The microRNAs determine when key DNA-binding proteins are active. MicroRNAs turn off the genes that block neuronal development and cell differentiation, thus ensuring that differentiation occurs at the right time.

Although the first microRNA, lin-4, was not detected until 1993, microRNAs are now known to occur in the cells of many organisms, from weeds to humans. MicroRNAs are identified by their shape, initially a hairpin, and by their small size. (The ones Slack studied are 21 nucleotides long, while messenger RNAs generally exceed 1,000 nucleotides.) “They’re pretty widespread, and yet we didn’t know about them for so long. That’s why everybody is so excited,” said Slack. “The field has exploded.”

Slack was a postdoctoral fellow at Harvard in 2000 when he identified let-7, seven years after the discovery of lin-4 by Victor R. Ambros, Ph.D., at Dartmouth. Slack’s discovery suggested that the microRNA that Ambros had identified was not an anomaly. Since then, researchers have identified about 400 microRNAs, the products of genes encoded in the genomes of a wide range of organisms. So far, however, scientists understand how only a handful of those microRNAs function.

Researchers hope that humans may be able to harness the ability of microRNAs to turn off harmful processes, such as the development of cancer cells or the replication of disease-causing viruses. Slack speculated that such applications are a decade away.

—Cathy Shufro

Et cetera

Touched by an illusion

Why would multiple real stimuli register as a single stimulus in the brain? A paper published September 18 in the online edition of Science explains this quirk of perception, known as the tactile funneling illusion.

Yale neurobiologist Anna W. Roe, Ph.D., and her colleagues studied the illusion in a portion of the primary somatosensory cortex (SI) of squirrel monkeys. They found that whenever they administered a mild electrical stimulus simultaneously to two nonadjacent fingers of the animal’s hand, the SI showed two separate activation spots that corresponded to the two sites of stimulation. By contrast, when they delivered simultaneous stimuli to two adjacent fingers, the SI showed a single activation spot located midway between the two sites. The study indicates that, contrary to previous thought, a finger’s “receptive field” for sensory stimuli can sometimes extend beyond the finger itself—a notion that could someday find clinical application, for example in rehabilitation after injury or stroke.

—Sandra Ackerman

Ro’s role in lupus

An estimated 1.5 million Americans suffer from lupus erythematosus, an autoimmune disorder that causes aching joints, fever, fatigue, numerous skin lesions and hypersensitivity to light. Many lupus patients carry in their blood an antibody against the autoantigen Ro 60-kDa. This RNA-binding protein passes unnoticed in the normal immune system but is the target of an abnormal immune response in these patients. Nevertheless, the role of Ro in lupus erythematosus has been unclear.

When Sandra L. Wolin, M.D./Ph.D. ’85, associate professor of cell biology and molecular biophysics and biochemistry and a Howard Hughes Medical Institute associate investigator, and colleagues developed a knockout mouse without the gene for making the Ro protein, the mouse developed an autoimmune syndrome similar to lupus. The authors suggest that Ro may serve a quality control function by recognizing misfolded, defective RNA molecules. When Ro is absent, abnormal RNA-protein complexes may accumulate and be viewed as foreign by the immune system.

—Sandra Ackerman


			Originally published in Yale Medicine, Winter 2004. Copyright © 2004 Yale University School of Medicine. All rights reserved.