Colorectal cancer

Colorectal cancer

Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract. Different mutations can underlie colorectal cancer, however frequently mutations in the Wnt signaling pathway are found that result in artificially increased Wnt signaling. The mutations can either be inherited or acquired, and most probably occur in the intestinal crypt stem cell. The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. Globally, colorectal cancer is the third most common type of cancer making up about 10% of all cases. It is more common in developed countries where more than 65% of all cases occur. Colorectal cancer was diagnosed in 1.23 million people worldwide (EU 333,000) in 2008 and 608,000 (EU 148,000) died of the disease. Treatments used for colorectal cancer may include some combination of surgery, radiation therapy, chemotherapy and targeted therapy.

Colorectal cancer: Architecture of the colon epithelium.

Architecture of the colon epithelium. The colon epithelium is shaped into a surface and in crypts, and is designed to effectively digest, absorb food contents and to create a barrier against invading micro-organisms. For this purpose a very effective and rapid turnover of the epithelium is present in the intestines depending on stem cells. In the colon, stem cells (marked by LGR5) at the crypt base generate rapidly proliferating Trans Amplifying (TA) cells in the lower half of the crypt (middle panel). TA cells subsequently differentiate into the mature lineages of the surface epithelium (goblet cells, enterocytes, enteroendocrine cells and tuft cells), as shown in the lineage tree on the right panel. Turnover of the entire epithelium occurs every 5–7 days. Reprinted with permission from Macmillan Publisher Ltd: [Nature Reviews|Molecular Cell Biology] (Nat Rev Mol Cell Biol. 2014;15:19-33)© (2014).

While some new treatments have been advanced in colorectal cancer, many have failed clinical testing; as a result, metastatic colorectal cancer is still largely incurable. In colorectal cancer, cancer stem cells are responsible for tumor progression and they are resistant to standard chemotherapies. The Wnt signal transduction cascade controls normal colon physiology but also cancer stem cell maintenance. Deregulation of Wnt and other mitogenic pathways results in formation of aggressive tumors with metastatic potential. Novel combinatorial drugs targeting cancer stem cells are required to address signaling redundancy and subvert resistance- and escape mechanisms. However, to test them effectively, better drug screening tools must be developed. The high failure rate in cancer drug research has been linked to the poor predictive capacity of drug screening models for cancer and the inability to select the right patients for treatment.