Researchers have identified a previously unknown role for a somewhat mysterious molecule. It appears to activate machinery in colorectal cells so that they avoid becoming cancerous.
The molecule is called NLRC3 and is a member of the large NOD-like receptor (NLR) family of “sensor proteins” that are found inside cells, where they help to control immune and other functions. However, until now, scientists did not realize that NLRC3 might also protect cells from cancer.
The new research – led by Dr. Thirumala-Devi Kanneganti, of the immunology department at St. Jude Children’s Research Hospital in Memphis, TN – is published in the journal Nature.
Cancer arises when cells in the body start to grow out of control. This can begin in almost any part of the body and may spread to other areas. Colorectal cancer starts in the epithelial cells that line the colon and rectum.
Excluding skin cancers, colorectal cancer is the third most common cancer diagnosed in both men and women in the United States.
Colorectal cancer is the second leading cause of cancer-related deaths among those in the U.S. It is expected to cause about 49,190 deaths in 2016.
In their report, the researchers note that previous studies have revealed tumor tissue from patients with colorectal cancer show a dramatically reduced expression of the gene that codes for NLRC3. This has been responsible for “highlighting an undefined potential function” for the sensor protein in the development of cancer.
In their investigation, Dr. Kanneganti and colleagues
For their study, the team used mice bred to develop colon cancer. They found their tumors had significantly lower levels of NLRC3, as previous studies had found in human patients.
- In the U.S., the
lifetime riskof developing colorectal cancer is about 1 in 21 for men and 1 in 23 for women
- The death rate in both men and women has been falling for several decades, which is likely due to improved screening and treatment
- There are currently more than 1 million survivors of colorectal cancer in the U.S.
They also showed that mice lacking NLRC3 are much more prone to colitis and colorectal cancer. Furthermore, mice engineered to develop colon polyps also showed greater tumor development when they lacked NLRC3.
In further studies with mice, the team found that NLRC3 plays an active role mainly in the colon’s epithelial cells, helping to prevent inflammation and tumor development.
The researchers also carried out experiments in human colon cells. There, they found that over-expression of the NLRC3 gene greatly reduced cell proliferation.
Further investigation revealed that NLRC3 inhibits PI3K-mTOR pathways. The team also found these pathways are switched on early during tumor formation.
Dr. Kanneganti says that altogether, the findings show that NLRC3 plays an important role in stopping abnormal cell growth. When it is not present, tumors develop.
This raises the question of whether increasing NLRC3 expression might be a way to block the cell processes that lead to tumor formation (tumorigenesis).
“In developing drug therapies, it might be difficult to target the PI3K-mTOR pathway itself, because it is such a central node in cell signaling,” notes Dr. Kanneganti. “Thus, we could target NLRC3 itself and block tumorigenesis early on.”
Speculating further, Dr. Kanneganti suggests that NLRC3 is probably involved in many other cell processes aside from tumor prevention. “We really do not know its role in infectious and inflammatory diseases,” she adds.
Additional studies may uncover even more valuable clues about the role of other members of the NLR family.
“NLRs have multiple functions in regulating immunity and inflammation and blocking tumorigenesis. None of us really thought NLRs could be involved in the PI3K-mTOR pathway. So, this study is really intriguing, because it opens up our ability to think more in depth about the function of NLRs and the diverse roles they play.”
Dr. Thirumala-Devi Kanneganti