Colorectal cancer is, unfortunately, a common condition, making up 10% of global cancer cases. Therefore, a full understanding of the initiation and development of these tumor types should improve diagnosis and treatment decisions. A recent study from the University of Oxford has identified a potentially important mechanism of colorectal tumor formation that not only challenges current thinking, but also highlights the role of the stem cell micro-environment in cell fate determination.
It is widely accepted that colorectal tumors arise from stem cells that lie at the bottom of the numerous U-shaped crypt-villus structures, which line the intestine and colon – the crypt base stem cell niche. Highly-regulated signaling keeps cells at the bottom of the crypt in a stem cell-like state (high Wnt signaling), while differentiating stem cell progeny move away from this niche and travel up the crypt to an area with a differing signaling environment (high BMP signaling). Dysregulation of this precise signaling environment can cause tumorigenesis, as is seen in patients suffering from hereditary mixed polyposis syndrome (HMPS). This condition is caused by the heightened expression of a gene which dampens BMP signaling (GREM1) and can eventually lead to colorectal tumor formation.
The research groups of Ian Tomlinson and Simon J Leedham explored the development of HMPS using human tissue and a mouse model, and in doing so, they discovered a novel mechanism in colorectal tumorigenesis.
This study found that:
- GREM1 over-expression disrupts normal intestinal crypt signaling, leading to stem cell niche-like signaling in areas where more differentiated cells usually reside.
- This dysregulated micro-environmental signaling allows the persistence/reacquisition of stem cell properties in stem cell progeny that had exited the stem cell niche.
- These cells can then form ectopic crypts, proliferate, and thereby accumulate mutations which ultimately lead to tumorigenesis. This indicates that the crypt base stem cell is not the sole cell of origin of colorectal cancer.
- GREM1 over-expression also occurs in other sporadic premalignant lesions (traditional serrated adenomas).
Overall, this engaging study suggests that the intestinal microenvironment is vitally important in maintaining control of cell-fate determination, and breaks with what is currently understood about the development of colorectal tumors. This information should aid in understanding tumor relapse, chemotherapy resistance and influence decision making in therapeutic choices, as the reversion of daughter cells to a stem-like state could replace stem cells lost during anti-tumor treatment.
Read about this new paradigm in colorectal tumorigenesis in Nature Medicine, December 2014.