Researchers discover potential mechanism for tumor growth

Researchers at Columbia University Medical Center have identified an inherent feature of stem and progenitor cells that may promote initiation and progression of cancerous tumors.

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.