Hypoxia in Surgery Stimulated Tumour Outgrowth

Abstract

In chapter 2 an overview is given of the factors involved in surgery-stimulated tumour growth in the context of liver surgery for (metastatic) cancer. Most of the data is based on an overwhelming amount of pre-clinical work while clinical evidence has been lagging behind. We describe several novel developments such as new imaging modalities and more extensive use of patient derived material, which may have the potential to elucidate whether this concept represents a true clinical phenomenon. In chapter 3 we show that surgery-induced hypoxia is sufficient to accelerate metastatic outgrowth in murine livers. Moreover, hypoxia is associated with a rapid loss of differentiation markers and increased expression of cancer stem cell (CSC) markers and clone-forming capacity. Despite their renowned general resistance to chemotherapy, clone-forming CSCs are readily killed in a hypoxic microenvironment by the hypoxia-activated prodrug tirapazamine (TPZ). In chapter 4 we test this prodrug as an adjuvant treatment following radiofrequency ablation (RFA) in mice harbouring colorectal liver metastases. Combination treatment resulted in a ̴ 60% decrease of (surgery-stimulated) tumour outgrowth. By reviewing the literature in chapter 5 we found that RFA was superior to chemotherapy alone in patients with non-resectable colorectal liver metastases without extrahepatic disease. Combination treatment of RFA and chemotherapy demonstrated to be feasible and safe, lending support to the concept of RFA, whenever possible followed by chemotherapy, in order to reduce local recurrence rates and prolong survival. In chapter 6 we identify a significantly shorter time to recurrence and overall survival in patients with intrahepatic recurrence following liver resection, compared to patients developing extrahepatic recurrence. Pulmonary recurrence following resection is associated with longer survival. In chapter 7 we demonstrate that an external stimulus, such as liver surgery (resection or RFA), is sufficient to induce tumour formation in p53/ retinoblastoma protein (Rb) deficient mouse livers, most likely originating from bile duct cells. This may be of interest as patients with hepatitis B and C viral infection (who often have an inactivated p53 and Rb status) are at risk to develop bile duct cancer following surgical intervention.