On tumor’s surface, a telltale molecule

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.”