In a study published in the December issue of Cancer Cell, the team showed that stem and progenitor cells are susceptible to a specific error during cell division that can result in severe chromosomal defects. This susceptibility may explain how a tumor-initiating cell, also known as a cancer stem cell, arises from a normal cell. It may also explain how a cancer stem cell acquires additional mutations that increase tumor malignancy.
According to Timothy Bestor, Ph.D., and Marc Damelin, Ph.D., of Columbia University College of Physicians and Surgeons, understanding the nature of cancer stem cells could result in new therapies that specifically target those cells, which are thought to be the driving force of tumor progression.
The process of cell division is closely monitored by the cell, because a mistake can result in a cancer-causing chromosome abnormalities. Typically during cell division, cells monitor quality control with a series of checkpoints. One such checkpoint confirms that the cell's chromosomes have been disentangled before they are to be pulled apart in mitosis, to ensure that the chromosomes will be separated appropriately.
The Columbia researchers found, however, that stem and progenitor cells are deficient in this checkpoint and will divide even if the chromosomes are entangled. All three cell types tested by the researchers - mouse embryonic stem cells, mouse neural progenitor cells, and human bone marrow progenitor cells - attempted cell division with entangled chromosomes. The researchers think it likely that cancer stem cells, which closely resemble normal stem cells, have the same deficiency.
"The failure to untangle before dividing undoubtedly will lead to chromosomal defects," said Dr. Bestor, professor of genetics and development and the study's principal investigator. "Surviving cells may end up with too many chromosomes, they may lose chromosomes, or some chromosomes may get rearranged." These same types of chromosomal defects are the hallmark of cancer cells, and there are chromosomal abnormalities in all types of cancer.
"We may have found how a stem cell without any pre-existing mutation can become a cancer stem cell," said Dr. Damelin, a CUMC postdoctoral fellow of the Damon Runyon Cancer Research Foundation and the lead author on the study.
The research also points to potential obstacles involved with stem cell therapies. In the lab, stem cells are pushed to divide many times more than they normally would divide in an organism. The more stem cells divide, the more likely they are to acquire abnormal chromosome constitutions. Further research will be necessary to understand and address these risks.
Columbia University Medical Center provides international leadership in pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders in health care and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians & Surgeons, the School of Dental & Oral Surgery, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center researchers are leading the discovery of novel therapies and advances to address a wide range of health conditions. http://www.