New Preclinical Study Shows Esophageal Cancers Driven by 'Marginal Gain' Rather Than Speed
Wellcome Trust Sanger Institute scientists have shown that unexpectedly, esophageal cancer cells do not divide faster than their normal neighbors. Unlike normal cells, however, the tumor cells produce slightly more dividing daughter cells than nondividing cells, forming a tumor. The study, published by Frede et al in Nature Cell Biology, could lead to the development of new treatments for cancers that do not respond to current therapies targeting fast-growing cells.
Normal cells produce equal numbers of dividing and nondividing cells, a balance that sustains the tissue. For every 100 normal cells, 50 of them will divide and 50 of them will not.
Study Findings
The researchers found that for 100 precancer cells, the balance was slightly skewed in favor of dividing cells, with 52 of those cells dividing and 48 remaining undivided. This is the first time this phenomenon has been shown. The subtle shift loads the odds in favor of cell division, and, over time, this can lead to tumor growth.
Philip Jones, PhD, 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 precancerous cells produced a small excess of dividing over nondividing cells—it was this marginal gain of cells that led to malignant tumors.”
Tissues can naturally change the ratio of dividing vs nondividing 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 tumor tissue development, multiple different cells, each with different alterations in their DNA, came together to form a polyclonal precancerous tumor. However, the researchers showed that as these various pretumor 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 tumor that dominated and outcompeted the other cells in the tumor.
Julia Frede, PhD, 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.”
Justine Alford, PhD, 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.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
