Surgery for colorectal cancer: a trigger for liver metastases development? New insights into the underlying mechanisms

Surgery is the mainstay of treatment for colorectal cancer. Despite surgical resection with curative intent and advances in (neo)adjuvant therapies, liver metastases remain common and carry high mortality. In my thesis, I have discussed new insights in the underlying mechanism of surgery-induced metastases development and addressed the role of SDD to prevent this phenomenon in experimental models. In this thesis I show that LPS translocation during primary CRC surgery activates the innate immune system through TLR4. Activated KCs and PMNs lead to oxidative stress due to an imbalance in ROS production which changes the morphology of the liver endothelial lining. This subsequently leads to the exposure of the sub-endothelial ECM proteins to which circulating tumor cells can bind and grow out into metastasis (Figure 2). My thesis demonstrates encouraging results with preoperative SDD administration in prevention of CRC surgery-induced liver metastasis. However, it is essential to individualize therapy on the basis of both the gut microbiota and tumor Immunoscore. So far, most of the studies in my thesis have been performed in animal studies. The next step would be to translate these results into clinical studies to relate individual pathogen species or different microbiota compositions with the development of infectious complications and oncologic outcome in the long-term. The results described in this thesis emphasize the critical role of the gut microbiota and tumor immune characteristics. A favorable gut microbiota is mandatory for SDD to succeed in reducing postoperative infectious complications. Future studies should focus on treatment options to modulate the gut homeostasis, such as dietary therapy. In the human population a high-fat obesogenic Western-type diet is known to negatively alter the gut microbial composition.79,80 A recent experimental mice model study also demonstrated an important link between diet, antibiotic exposure and anastomotic surgery, by studying the effect on the microbiota and anastomotic healing. This study highlighted that a high-fibre/low-fat diet preserved the healthpromoting gut microbiota, which may competitively suppress pathogens anaerobe Gram negative bacteria from impairing anastomotic healing.81 Another treatment option to modulate the gut microbiota is the use of fecal microbiota transplantation (FMT), which is a therapeutic method of reintroducing healthy microbes into the gastrointestinal tract via the administration of healthy donor feces. The goal is to restore the normal healthy microbiota. FMT has been effectively used in refractory Clostridium difficile infections, inflammatory bowel disease and in restoring fecal microbiota in the setting of bone marrow transplant.82 Prolonged courses of antibiotics result in significant intestinal dysbiosis.83 The exact mechanism by which specific bacteria species within the FMT are able to engraft within the host are not clear yet. Given the pivotal role of the adaptive immune system in cancer treatment, careful preoperative assessment of the tumor immune cell infiltrate is recommended. Preoperative determination of the immunoscore and gut microbiota may help predict and stratify patients who will benefit from SDD or will need additional gut modulation treatments. Enhanced Recovery After Surgery (ERAS) protocols are implemented to achieve early recovery postoperatively by reducing major complications. Preoperative measures such as smoking cessation, and exercise have become standard measures for patients undergoing major surgery. We recommend to add dietary modifications in the form of a low-fat/high-fibre composition or FMT to the pre-habilitation program for patients with an unfavorable gut microbiota. Taken together, the results in my thesis have demonstrated growing evidence that supports the concept of CRC surgery induced liver metastasis. The pre- and perioperative period provides a window of opportunity for developing relevant patient tailored therapies to reduce the risk of metastasis development.