Role of novel tumor suppressors in colon cancer : Mechanisms and therapeutic opportunities

Sammanfattning: Colon cancer is the third most common cancer in the world and the fourth most common cause of cancer related deaths. Inflammation is one of the risk factors for development of colon cancer. Interestingly immune cells as mast cells and inflammatory mediators as LTC4 play an important role in colon cancer. Genetic predisposition, which might lead to either activation of oncogenes or inhibition of tumor suppressor genes, are risk factors of colon cancer development.The aim of my thesis was to evaluate the clinical significance of the tumor suppressors 15-PGDH and WNT5A in colon cancer patients. I investigated the underlying mechanisms/signaling triggered by these tumor suppressors in colon cancer cells and whether the re-expression of these tumor suppressors could be an attractive therapeutic strategy for treatment of colon cancer patients.I found that presence of mast cells in colon cancer tissue was associated with better prognosis of colon cancer patients, and the presence of mast cells in polyps/tumors in a colitis-associated colon cancer mouse model was also beneficial. I found that the tumor suppressor gene 15-PGDH is down-regulated in colon cancer patients as well as in colon cancer cell lines. This down- regulation is often seen in parallel with down-regulated WNT5A, the non-canonical Wnt/β-catenin signaling ligand. I found that down-regulation of both these proteins is associated with poor prognosis for colon cancer patients. My results show that treatment of colon cancer cells with Foxy-5, a WNT5A mimicking peptide, leads to up-regulation of 15-PGDH through JNK/AP-1 pathway. In addition, I also found that the pro-inflammatory mediator LTC4 via CysLTR2 can induce the expression of 15-PGDH through the JNK pathway, which indicate that LTC4 via CysLTR2 has an anti-tumor effect.In conclusion, these findings provide important information for better understanding of the tumor microenvironment and the tumor suppressor genes in colon cancer and might help to identify new therapeutic targets for colon cancer patients.