Research Group BOREL RINKES/ KRANENBURG

Faculty of Medicine, University Medical Centre Utrecht, Dept. of Medical Oncology
Contact: Prof. dr. Inne H.M. Borel-Rinkes
E-mail: i.h.m.borelrinkes@umcutrecht.nl
Website: http://www.umcutrecht.nl/subsite/oncology/Research-groups/Borel-Rinkes/

General research focus: Liver metastases of colon cancer

Our hospital is a reference centre for patients with metastases of colorectal cancer. It is our principal interest to improve the treatment efficacy of this category of patients. A minority (~10-20%) of patients that present with liver metastases of colorectal cancer are eligible for traditional liver surgery (resection). The curative rate of these procedures is about 30-40%, but recurrence is common. About 20-30% of non-resectable tumors can be treated by alternative techniques that locally destroy the tumor tissue by heating. In our hospital we are routinely performing interstitial laser coagulation (ILC) and radio frequency ablation (RFA) in clinical and pre-clinical settings. The curative rate of these procedures is about 10-20% in selected cases, but local recurrence rates are very high.
Although surgery is usually performed with curative intent, it may adversely affect disease progression through stimulation of the outgrowth of residual (micro-) metastases. Vascular clamping is a routine surgical procedure that prevents excessive blood loss during liver resections. However, we have recently found that vascular clamping has a major, previously unrecognised, adverse effect: It stimulates the outgrowth of residual micro-metastases in the liver. In addition, we have found that laser-coagulation promotes the outgrowth of microscopic tumor deposits localized in the vicinity of the ablated region. We are presently investigating the mechanism(s) underlying these phenomena.
Our current research is aimed at understanding how vascular clamping and laser coagulation stimulate the outgrowth of micrometastases. A better understanding of these phenomena should eventually lead to adjustments in the treatment protocols that minimize recurrence.

K-ras in tumor metastasis
Death from colorectal cancer is almost invariably the result of metastatic disease. A detailed understanding of the molecular mechanisms that underlie the dissemination of cancer cells from the primary tumor and their outgrowth in distant organs is essential for the rational development of therapeutics that suppress metastasis formation.
Research in our group is focused on understanding how the KRAS oncogene, which is mutated in ~35% of all human colorectal tumors, promotes metastasis formation. Mutations in KRAS are usually acquired during the very early pre-malignant stages of tumor development. Our recent work shows that oncogenic KRAS is essential for the formation of liver metastases, which is manifested much later during disease progression. Mutant KRAS may control distinct phases and distinct aspects of metastasis formation.
In particular, we are studying how it affects the clearance of tumor cells by cells of the innate and adaptive immune system. We have recently shown that suppression of oncogenic KrasD12 in murine colorectal tumor cells allows CTL-mediated tumor cell clearance which frequently results in spontaneous and complete tumor regression.
In addition, we are studying how the presence of KRAS in CRC cells affects their sensitivity to chemotherapeutics and to novel/alternative therapeutics. Our work has shown that the presence of oncogenic KRAS has a strong stimulatory effect on tumor cell sensitivity to classical chemotherapeutics like oxaliplatin and 5-fluorouracil, and also to Reovirus T3D, an oncolytic virus that has recently entered clinical trials.
Conversely, mutant KRAS protects tumor cells from death receptor ligand-induced apoptosis, a phenomenon that is also likely to contribute to metastasis formation. We are presently studying the molecular mechanisms underlying these phenomena. A better insight into these mechanisms should help in devising combination strategies that either exploit enhanced sensitivity or subvert reduced sensitivity to selected therapeutic compounds.

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