Extending tumour margins

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  • Published: May 10, 2010
  • Author: Steve Down
  • Channels: Proteomics & Genomics

Everyone knows someone who has been the victim of cancer, or so it seems. It is hardly surprising when you consider the official statistics. Every year, more than 11 million people worldwide are diagnosed with cancer and 7 million people die from it.

Nevertheless, overall cancer rates and deaths are falling across the globe. The major contributions to these trends come from declines in incidences and deaths from the three major male cancers, lung, prostate, and colorectal, and the two main female cancers, breast and colorectal.

Enough is already known about the causes to prevent at least one third of all cancers. When prevention fails, the treatment options are ever improving too, with better and more targeted therapies available, as well as surgery. In theory, the surgical option appears to be the best. Cut out the whole tumour and the problem is gone but it is not as straightforward as that.

During the operation, surgeons have to decide where the tumour ends and where normal tissue begins. They are assisted by pathologists, who can test resected tissue by staining to determine if any cancerous cells remain and to identify the margins of the tumour. This can be performed during surgery, but is generally a post-operative procedure.

The subsequent recurrence of some tumours at their original sites suggests that tumour margin assessment is not always successful. Cancers can recur just a few months after surgery, especially for certain types such as breast, lung, head and neck, and soft tissue cancer. This uncanny ability to reappear prompted Richard Caprioli and co-researchers from Vanderbilt University, Nashville, TN, to examine the molecular makeup of tissue in and around tumours to try and find clues as to why it happens so frequently.

The researchers concentrated on clear cell renal cell carcinoma (ccRCC), the most malignant of all renal cancers with a poor prognosis. They studied 34 samples of ccRCC tissue which had the "normal" adjacent tissue still attached, as well as 41 patient-matched, but separate, tumour and normal tissues

The technique they employed was imaging MALDI MS, which has been shown to be capable of detecting molecular species such as peptides and proteins across sections of tissue by scanning back and forth. For comparison, the tissues were assigned to one of four regions: tumour, tumour-margin, normal-margin and normal. The normal region was set to 6 mm or more from the margin between tumour and normal tissue that was identified by histological staining.

The mass spectra were averaged by region and subjected to statistical processing to try and identify differences across the regions and a surprising result emerged. The profile for margin-normal tissue, which was adjacent to, but separate from the tumour, looked more like cancer tissue than normal tissue.

Some proteins in the tumour that were present in different amounts compared with normal tissue, were still present at those levels in the normal region for distances of several centimetres. Under normal surgical conditions, the surgeon would leave part of this modified normal tissue behind during resection, because it showed up as normal during staining.

Unfortunately, the distance of these concealed changes from the tumour margin were not the same for each case, so simply extending the surgical cut would not necessarily catch all of this tissue. In addition, this distance did not correlate with the tumour stage or grade, so appears to be independent of the aggressiveness of the tumour.

Caprioli and his team speculated as to the nature of this anomalous region. It might be the result of infiltrating tumour cells, or precancerous cells which have undergone molecular changes but do not yet show up clinically, or they might be caused by cell secretory interactions between cancerous cells and neighbouring tissue.

Some of the proteins that were involved in this cross-margin behaviour were identified by mass spectrometry. A group that were under-expressed in the tumour and in the normal-margin tissue were associated with the mitochondrial electron transport system. Mitochondrial deficiency in cancer cells is a well-known phenomenon but it has not been reported in adjacent tissue.

The results could lead to the regular use of MALDI MS in path labs for the direct analysis of tissue sections, and even during surgery, to assist in the identification of the true tumour margins.

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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