CD133 cells can initiate metastatic disease; could redirect cancer research

The molecular profile of cancer stem cells that initiate metastatic colon tumours is significantly different from those responsible for primary tumours, according to new research from a team at Weill Cornell Medical College, US.

Cancer researchers have long believed that a protein called CD133 identifies a population of cancer stem cells (CD133+ cells), the only subset of cells that are responsible for tumour initiation. But in the experiment, in which immunocompromised mice were injected with human metastatic colon cancer, the team discovered that cancer cells that do not express CD133 can also spur metastatic disease.

"In fact, metastatic tumours originating with these CD133- cells are more aggressive than those spurred by CD133+ cells," says study senior author Dr. Shahin Rafii, Professor in Genetic Medicine 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 released as a special article in the May 22 online edition of the Journal of Clinical Investigation.

Cancer stem cells are a small, discrete class of cells that scientists believe give rise to malignancy and are solely responsible for tumour maintenance. For years, experts have tracked expression of the CD133 protein as a means of identifying a population of tumour-initiating cells.

To understand the biology of CD133+ cells in a healthy state and during tumour 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," explains co-researcher Andrea T. Hooper, a graduate student in Dr. Rafii's lab.

Studying the expression of CD133 in this genetic model, the researchers, for the first time, were able to visualise 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 tumourigenesis," notes the paper's lead author Dr. Sergey Shmelkov, an instructor in genetic medicine at Weill Cornell. "We examined human primary colon tumours, and we also induced colon cancer in CD133 transgenic mice, and discovered that all cancerous epithelial cells in the tumour express CD133, explaining why tumour-initiating cells in primary colon cancer are CD133+."

To establish whether the scenario was the same in metastatic disease the researchers transferred fresh human metastatic colon cancer cells into immunocompromised mice and tracked the tumour formation ability of CD133+ and CD133- cells during metastases.

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

Thus the 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 tumour progression, but then is able to move to the