Esophageal cancers driven by 'marginal gain' rather than speed

The study, published in Nature Cell Biology today, could lead to the development of new treatments for cancers that do not respond to current therapies which target fast-growing cells.

Normal cells produce equal numbers of dividing and non-dividing cells, a balance which sustains the tissue. For every 100 normal cells, 50 of them will divide and 50 of them will not. The researchers found that for 100 pre-cancer cells the balance was slightly skewed in favour of dividing cells, with 52 of those cells dividing and 48 remaining undivided. This is the first time this has been shown. The subtle shift loads the odds in favour of cell division and over time this can lead to tumour growth.

esophageal cancer is the sixth most common cause of cancer death in the UK. Each year 8,750 people are diagnosed with the disease, which is hard to treat even with aggressive therapy. Understanding the processes underlying tumour growth could help in the development of new cancer treatments.

Dr Philip Jones, lead researcher from the Wellcome Trust Sanger Institute, said: "We created a new model of human squamous cancer of the esophagus in mice, and measured the rate of cell division. In these mice all the cells in the body divided once per day, proving that precancerous and cancerous cells can divide at the same speed as surrounding normal cells. But the pre-cancerous cells produced a small excess of dividing over non-dividing cells -- it was this marginal gain of cells that led to malignant tumours."

Tissues can naturally change the ratio of dividing versus non-dividing cells in response to certain events. For example, cells divide at the edge of a wound, but this imbalance in cell division stops once the wound has healed.

The scientists saw that in very early tumour tissue development, multiple different cells, each with different alterations in their DNA, came together to form a polyclonal pre-cancerous tumour. However, the researchers showed that as these various pre-tumour cells became cancerous, they evolved differently with some gaining an advantage by producing a greater proportion of dividing daughters. This led to a group of cells in the tumour that dominated and out-competed the other cells in the tumour.

Dr Julia Frede, a lead author from the Sanger Institute, said: "Our research showed that esophageal carcinoma and possibly other hard-to-treat cancers may behave in a very similar manner to normal cells, rather than dividing more rapidly. This would explain why treatments such as radiation therapy that target fast-dividing cells don't work with all cancers. More research is needed to find the mechanisms that drive the proportion of cells that divide."

Dr Justine Alford, Cancer Research UK's Senior Science Information Officer, said: "This study, carried out in mice, uncovered surprising evidence that unbalanced cell division is important in the development of a certain type of esophageal cancer. The next important step will be finding out whether the same is true in patients with the disease. If scientists can unpick the biology causing the imbalance, then it may lead to new treatments for this hard to treat type of cancer and boost the number of people surviving."

About esophageal Cancer:

• esophageal cancer is cancer of the foodpipe that carries food from your mouth to your stomach. The foodpipe is also called the esophagus or gullet.
• Cancers in the upper part and middle part tend to be squamous cell carcinomas. These develop from cells that make up the inner lining of your esophagus.
• 8,750 people in the UK are diagnosed with esophageal cancer each year in the UK, and it is currently the sixth largest cause of cancer death worldwide