Surgery-stimulated tumor growth : preclinical and clinical studies on colorectal liver metastases

In the Netherlands, every year 12.000 new patients are diagnosed with colorectal cancer. In approximately 50% of cases liver metastases will develop. In this thesis, we first address the role of oncogenic K-Ras on the development of liver metastases. K-Ras is a frequently mutated gene in colon cancer. We demonstrate that a mutation in K-Ras contributes to liver metastases formation based on a switch in death receptor signaling, which is an important defense mechanism of the liver. Colon carcinoma cells harboring a K-Ras mutation do not die in response to death receptor signaling (i.e. CD95- and TRAIL-receptor signaling) which normally occurs. Instead, colon cancer cells with the K-Ras mutation show an invasive phenotype upon death receptor signaling and increased survival in the liver based on reduced signaling of the Rho-ROCK-LIMK-cofilin pathway mediated by Raf-1. In patients, once metastases have formed, liver surgery is the only curative treatment option. Unfortunately, the disease will recur in approximately 70% of the cases. In this thesis, we mainly focused on the role of liver surgery itself on tumor recurrence in the liver. The effects of two distinct surgical interventions in the liver (radiofrequency ablation and vascular clamping) on residual tumor tissue have been investigated using a highly standardized mouse model. We demonstrated that the outgrowth of tumor cells that were located in the rim of induced necrosis was approximately 4 times faster than tumor cells that were located elsewhere in the liver. It was demonstrated that surgery-induced hypoxia (low oxygen) plays an important role in the accelerated tumor outgrowth following the surgical interventions in the liver based on stabilization of Hypoxia Inducible Factors (HIFs). Moreover, aforementioned autocrine CD95 signaling of the tumor cells in the rim of the necrosis by hypoxia was responsible for the observed invasion and accelerated outgrowth of tumor cells. Finally, we demonstrated in patients with colorectal liver metastases that severe ischemia (resulting in hypoxia) during partial liver resections was associated with a reduced time to tumor recurrence in the liver. In conclusion, our results increase the understanding how liver surgery affects residual tumor tissue. The role of hypoxia and subsequent HIF stabilization and/or CD95 activation is important in this phenomenon.