Colorectal liver metastases: local therapy and molecular aspects

Abstract

Colorectal cancer (CRC) is one of the most prevalent malignancies in the western world. Mortality is strongly associated with the formation of liver metastases, which eventually occurs in about 50% of patients. Once liver metastases have developed, the natural course of the disease is associated with poor survival rates. In this thesis we have focused on local ablation for unresectable liver metastases and on some of the molecular processes involved in colorectal cancer and metastases formation. Locally ablative therapies such as laser-induced thermotherapy (LITT) and radiofrequency ablation (RFA) are gaining acceptance in the treatment of unresectable liver metastases. In this thesis, we found that with the latest technique of LITT and RFA we are able to produce large coagulation lesions. Consequently, LITT and RFA are good alternatives for patients who are not suitable for surgical resection, aiming at curation with less complications. A major limitation of these local ablative therapies is the production of lesions with sufficient tumor-free margin. We have established a murine tumor model for solitary liver metastasis in which recurrent tumor growth occurs after LITT. Our results support the concept that combined LITT and adjuvant chemotherapeutic treatment can increase the extent of tumor destruction. Thus, additional chemotherapy after LITT may induce maximal efficacy and improve survival in patients with colorectal liver metastases. Activating mutations in the KRAS oncogene are frequently observed during the early stages of colorectal cancer. We have analyzed the effect of suppression of the mutant KRAS allele by RNA interference in a highly aggressive mouse CRC cell line (C26). After KRAS knockdown, the incidence of subcutaneous tumor formation was spectacularly reduced, the lag time was increased and KRAS-knockdown tumors grew noninvasively and did not cause morbidity. Surprisingly, KRAS-knockdown tumors elicited an anti-tumor immune response that resulted in spontaneous regression in some KRAS-knockdown tumors. In conclusion, the reduced incidence of tumor formation by KRAS knockdown tumor cells is at least in part a result of tumor cell clearance by the host immune system and not to an intrinsic inability of these cells to grow out as a tumor. Mutant KRAS in CRC cells enhances their metastatic potential and invasiveness, and facilitates immune evasion. This makes mutant KRAS an interesting therapeutic target for treatment against metastases of CRC. The Wnt, Notch, and TGFbeta signaling pathways control tissue homeostasis and tumor development in the intestine. These same pathways are also involved in the trans-differentiation of epithelial tumor cells into cells with mesenchymal characteristics, a process that shares some features with the epithelial-mesenchymal transition (EMT). Liver metastases of CRC demonstrated low levels of activated Notch en TGFbeta signaling components, suggesting these signaling pathways are less involved in metastases growth. These findings have important consequences for the use of inhibitors that target these pathways in the treatment against metastatic colorectal cancer.