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Gastric cancer, also known as stomach cancer, is the second most lethal form of cancer worldwide, standing only behind lung cancer. There is a marked variation in occurrence from country to country and this has been attributed to two main factors: diet and infection with the bacterium Helicobacter pylori. Foods that are high in salt, pickled and smoked, in regions where food refrigeration is absent, are associated with a higher risk of gastric cancer. Despite reduced incidence in Western Europe and the US over the last 60 years, it remains one of the more difficult cancers to treat because the symptoms often do not appear until the disease is in its advanced stages. In the US, less than 20% of stomach cancers are diagnosed before they have spread beyond the stomach. However, early diagnosis can yield 5-year survival rates of 90% or more. For this reason, gastric cancer is one of those diseases being targeted by proteomics researchers. If biomarkers can be identified that signal early onset, then the chances of successful treatment and survival are radically increased. In fact, already a number of research groups have independently proposed the protein SM22, also known as transgelin, as a candidate biomarker for several cancers, including gastric cancer. Differential proteomics studies have shown that the production of SM22 is increased in cancerous tissue. On the other hand, some researchers have noted that the pattern of expression of SM22 differs between tumour varieties and even for the same cancer. Three independent studies showed that SM22 was either up-regulated, down-regulated or unchanged in human colon cancers. Clearly, there are some other factors at play and these discrepancies have helped to fuel the debate on the suitability of SM22 as a cancer biomarker. Now, researchers in China and the US have undertaken a joint study to try and clarify the behaviour of this protein in cancer, especially for gastric cancer. The procdures were described by senior authors Rong Wang from the Mount Sinai School of Medicine and Siqi Liu and Youyong Lu from the Beijing Genomics and Proteomics Institutes. They began by examining biopsy cancer tissue and the adjacent normal tissue from 8 gastric cancer patients. The proteins were extracted from the tissues and separated by two-dimensional gel electrophoresis with silver staining. Comparison between cancerous and non-cancerous samples showed which proteins had been differentially expressed and these were selected for enzymatic digestion and mass spectrometric analysis. Protein spots in the gel corresponding to SM22 at a molecular mass of 22 kDa were up-regulated in 7 of the 8 cases. This was confirmed by Western blotting of the proteins from the same tissues and by reverse transcription polymerase chain reaction (RT-PCT) studies. So far, so good, but expanded studies revealed a different story. Using monoclonal anti-SM22 antibodies and imunohistochemical staining, different tissue types from 126 gastric cancers and 31 samples of adjacent tissue were examined for their SM22 content in microarrays. In all of the cancerous tissues, no SM22 was found in the epithelial cells from gastric mucosa. This is a surprising result because these cells are believed to be the principal location for gastric malignancy. Instead, the protein was localised in three types of tissue: smooth muscle fibres, blood vessel walls and myofibroblasts. These results were supported by similar studies on colon and oesophageal cancer which gave similar SM22 distribution patterns, suggesting that expression of SM22 is associated with smooth muscle cells, blood vessels and myofibroblasts, but not tumour cells. Further evidence was supplied by comparing the expression of SM22 in smooth muscle cell lines with that in two gastric cancer cell lines. Levels of SM22 were notably higher in the smooth muscle cells than the cancer cells. This finding may also help to explain the inconsistent reports of levels of SM22 in colon cancers. Regardless of the care taken by the relevant personnel, the results are questionable, say Wang and the team, because immunohistochemical staining was not employed to locate SM22 in the tissues. Taken together, the data indicate that SM22 should not be used as a reliable marker of gastric cancer. There is no doubt, say the researchers, that the protein is associated in some way with the disease, but its role as a biomarker has to be questioned. The smooth muscle cells, rather than the epithelial cells, are the main source of SM22. Related links:
The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.
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