New Cancer Stem Cell Identified Fueling Metastatic Tumors

The molecular profile of cancer stem cells that initiate metastatic colon tumors has been found to be significantly different from those responsible for primary tumors.

Cancer researchers have long believed that a protein called CD133 identifies a population of cancer stem cells (so-called CD133+ cells), the only subset of cells that are responsible for tumor initiation. However, in the experiment in which immunocompromised mice were injected with human metastatic colon cancer, the researchers from Weill Cornell Medical College (New York, NY, USA) discovered that cancer cells that do not express CD133 can also spur metastatic disease.

"In fact, metastatic tumors originating with these CD133- cells are more aggressive than those spurred by CD133+ cells,” stated study senior author Dr. Shahin Rafii, a professor in genetic medicine and director of the Ansary Center for Stem Cell Therapeutics at Weill Cornell. "Our discovery shows that metastatic and primary cancer may not initiate in the same way. This could have significant implications for research going forward--we believe the discovery opens up new avenues of investigation in cancer stem cell biology.”

The findings were published in an article in the May 22, 2008, online issue of the Journal of Clinical Investigation. Cancer stem cells are a small, discrete class of cells that investigators believe are responsible for malignancies and are solely control tumor maintenance. For years, scientists have monitored expression of the CD133 protein as a way of identifying a population of tumor-initiating cells.

To understand the biology of CD133+ cells in a healthy state and during tumor formation, the researchers generated a transgenic mouse in which the CD133 gene is replaced with a reporter gene called lacZ. "We relied on the expression of lacZ to detect the spatial and temporal location of CD133+ cells in vivo,” explained co-researcher Andrea T. Hooper, a graduate student in Dr. Rafii's lab.

Examining the expression of CD133 in this genetic model, the researchers, for the first time, were able to visualize a real pattern of CD133 expression in a living organism. "It came as a big surprise that CD133 expression is not restricted to stem cells, but rather defines mature epithelial cells. This finding directed us to explore the actual contribution of CD133+ cells in tumorigenesis,” noted the study's lead author Dr. Sergey Shmelkov, an instructor in genetic medicine at Weill Cornell. We examined human primary colon tumors, and we also induced colon cancer in CD133 transgenic mice, and discovered that all cancerous epithelial cells in the tumor express CD133, explaining why tumor-initiating cells in primary colon cancer are CD133+.”

To find out if this was the same situation as in metastatic disease, the researchers transferred fresh human metastatic colon cancer cells into immunocompromised mice. They then tracked the tumor formation ability of CD133+ and CD133- cells during metastases in these mice.

The investigators encountered yet another surprise. "We found that not all human colon cancer cells that form metastases were CD133+, as occurs in primary tumors,” said co-lead author and postdoctoral fellow Dr. Jason Butler. "CD133- cells--probably derived from CD133+ cells from the primary tumor--were also capable of tumor initiation and appeared to play a major role in the formation of metastases. In fact, tumors generated by CD133- cancer stem cells tended to be more aggressive than those originating from CD133+ cells.”

The most important conclusion to come from this study, according to the Weill Cornell–led team, is that origins of metastatic disease appear to be much more complex than that seen with primary cancer. "There is a subpopulation of cancer stem cells that appears to lose CD133 expression during tumor progression, but then is able to move to the site of metastasis and form new tumors there,” remarked co-senior author Dr. David Lyden, associate professor in pediatric cardiology, and an associate professor of cell and developmental biology at Weill Cornell.

The results of this research could change the direction of research into cancer stem cell biology and stimulate the search for new authentic cancer stem cell markers, according to the researchers. "The origins of primary and metastatic tumors are decidedly not the same, and we must broaden our thinking beyond CD133+ cells when it comes to the investigation of metastatic disease,” Dr. Rafii said. "We expect this paper will have a tremendous impact in cancer stem cell biology, aiding research into the causes of cancer in laboratories worldwide.”


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