A poorly understood protein has been shown to promote the spread of colon cancer, revealing a potential culprit behind the disease that kills tens of thousands of Americans every year.

Dr. Lilianna Solnica-Krezel, a researcher at Washington University and co-author of the new study, said that the protein PLAC8 appears to drive cancer growth by priming cells lining the colon for metastasis — that is, the process by which cancerous cells spread to neighboring organs. "We knew levels of this protein are elevated in colon cancer," she explained in a press release. "Now we've shown what PLAC8 could be doing — causing the cells to transition to a state that allows them to spread.”

The study, which is published in the Journal of Clinical Investigation, relied on an innovative research method developed by the project’s senior author, Dr. Robert Coffey. Whereas conventional cell research is conducted with flat dish cultures, this new cultivation technique allows scientist to grow and study cells in three dimensions. The team theorized that this would reveal important details about how colon cancer cells gradually spread from the original tumor site.

To investigate, the researchers began by growing colon cancer cells in 3D and observing their development. They immediately noticed something peculiar: Each cell formed either a smooth, hollow sphere or a spiky cluster. When they compared genetic data from the two cell versions, they found that the spiky clusters expressed extremely high levels of PLAC8. Additional experiments with mouse models showed that these cells also formed much more aggressive tumors.

The researchers also examined how PLAC8 behaved in zebrafish. They noticed that when there was too much of the protein, embryos would develop abnormally, with slower cell movements and developmental defects. "We realized that these defects were very similar to abnormalities we see when the protein E-cadherin is mutated," Solnica-Krezel explained. "E-cadherin is a cell adhesion molecule present on the cell surface, which allows cells to stick to one another.

“The amount of E-cadherin on the surface is very important for cell movement, with too much or too little being detrimental to mobility," she added.

The team concluded that PLAC8, by regulating levels of E-cadherin, promotes the development of more “mobile” cells. This allows the cancer to break away from the original tumor site and invade neighboring tissue and organs.

Stopping Metastasis?

Like cancers of the pancreas and lungs, colon cancer is notoriously difficult to treat, as the tumor growth tends to go unnoticed until it spreads. Today, the disease kills upward of 50,000 Americans each year, making it second only to lung cancer in terms of fatalities. The Centers for Disease Control and Prevention recommends that everyone over 50 get screened for the disease, as early detection of precancerous polyps is usually accompanied by good prognosis.

Though the new discovery broadens the current understanding of the disease, it may take some time before it inspires any therapies. "One could think about finding chemicals that might inhibit PLAC8's activity," Solnica-Krezel said. "But at present, this finding may have prognostic value. Those tumors expressing PLAC8 at high levels will be the most invasive."

 

Source: Li C, Ma H, Cao Z, Solnica-Krezel, et al. Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer. Journal of Clinical Investigation. 2014.