DISCOVERY OF ABNORMAL SUGARS PRESENT IN MANY CANCERS COULD LEAD TO NEW DRUG TARGETS
22 September 2003 - Yale University

The study, published in the September issue of Cancer Research, showed the presence of these sugars, called "branched oligosaccharides," associated with structures called autophagosomes. This finding is a common and pervasive trait of melanomas and a wide variety of other cancers, including those of the lung, colon, breast, prostate, kidney and lymphomas.

Previous laboratory and animal studies showed that the sugars and the enzyme that produces them are associated with metastasis, but there was little information on the actual abundance and distribution of the sugars in human tumors. The sugars are normally associated with certain white blood cells and are used by these cells and cancer cells alike to move throughout the body.

"That they were most abundant on metastases is particularly encouraging, because locating and killing metastatic cancer cells is the most difficult aspect of cancer therapy," said John Pawelek, senior research scientist at Yale School of Medicine who co-authored the study with Tamara Handerson, M.D., of Tufts University School of Medicine. "Our lab has initiated some projects in this regard, and we are excited that at least under experimental conditions, the sugars can indeed be exploited as signals for targeting and destroying human cancer cells."

Pawelek said that although the sugars were seen in other areas of the cancer cell, they were always found associated with autophagosomes, which come in all sizes and function as part of the cellular digestive system. "We don't understand the significance of these structures to cancer," said Pawelek. "That they are a common trait of most cancers wasn't noticed before, probably because they were not visible to pathologists unless special tissue stains were used. Autophagosomes were readily visible with a staining technique called lectin histochemistry because they were coated with the sugars.

Nearly 90 percent of more than 300 metastic breast cancers examined expressed the sugars and autophagosomes in abundance. Along with colleagues in the pathology department at Yale, Robert Camp, M.D., and David Rimm, M.D., Pawelek and Handerson have determined that expression of this trait in primary breast cancer tumors is a high risk factor and predictive of poor patient prognosis.

Pawelek said the study also unexpectedly provided an explanation for the well-known hyperpigmented or dark areas of primary melanomas, used by dermatologists in the clinical diagnosis of melanoma of the skin. Handerson and Pawelek found that these areas were darker because they contained cells rich in autophagosomes and the abnormal branched oligosaccharides. "In melanoma, the autophagosomes were often filled with melanin, so we could see them without any other stains," said Pawelek. "Curiously, these cells tended to make more melanin than normal pigment cells, hence the dark areas of the tumors."

Now that the initial results have emerged, Pawelek said the work raises many questions for future research: What causes a cancer cell to start producing these structures? What is the underlying relationship between expression of this trait and metastasis? and can the structures, particularly the sugars, be exploited for new directions in cancer therapy?

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