Targeting the receptor tyrosine kinase MerTK shows therapeutic value in gastric adenocarcinoma.

BACKGROUND: Despite multiple therapeutic modalities, the overall survival of patients with gastric adenocarcinoma remains poor, especially for advanced tumor stages. Although the tyrosine kinase MerTK has shown therapeutic relevance in several tumor entities, its potential effects in gastric adenocarcinoma have not yet been sufficiently characterized. METHODS: MerTK expression and its influence on patient survival were evaluated by immunohistochemistry in a cohort of 140 patients with gastric adenocarcinoma. CRISPR/Cas9 knockout and siRNA knockdown of MerTK in the gastric cancer cell lines SNU1, SNU5, and MKN45 was used to analyze protein expression, growth, migration, and invasion properties in vitro and in a murine xenograft model. MerTK was pharmacologically targeted with the small molecule inhibitor UNC2025 in vitro and in vivo. RESULTS: In patients, high MerTK expression was associated with decreased overall survival (OS) and lymph node metastasis especially in patients without neoadjuvant therapy (p < 0.05). Knockout and knockdown of MerTK reduced cell proliferation and migration both in vitro and in vivo. UNC2025, a small-molecule inhibitor of MerTK, exhibited a significant therapeutic response in vitro and in vivo. Additionally, MerTK expression attenuated the response to neoadjuvant treatment, and its inhibition sensitized tumor cells to 5-Fluorouracil (5-FU)-based chemotherapy in vitro. CONCLUSIONS: Our findings demonstrate the potential value of MerTK as a prognostic biomarker for gastric adenocarcinoma. Targeting MerTK may become a new treatment option, especially for patients with advanced tumors, and may overcome resistance to established chemotherapies.

Anaesthesia as an influence in tumour progression.

PURPOSE: Tumour growth and the formation of metastases are essential elements in the progression of cancer. The centre of treatment is the surgical resection of primary solid tumours. But even if the tumour can be removed without microscopic residual cells, local recurrences and distant metastases occur and determine the patient's fate. During the operation, tumour cells are shed from the primary tumour and released into the circulation. These circulating tumour cells might play an important role in the formation of new tumour sites. Therefore, a functional innate and adaptive immune system is essential, especially in this perioperative period. Anaesthesia influences consciousness and pain perception and interacts directly with the immune system and tumour cells. METHODS: Review of the current literature concerning intra- and postoperative anaesthetic decisions and tumour progression. RESULTS: There are beneficial aspects for patient survival associated with total intravenous anaesthesia, the use of regional anaesthetics and the avoidance of allogeneic red blood cell transfusions. Alternatives such as irradiated intraoperative blood salvage and preoperative iron supplementation may be advantageous in cases where transfusions are limited or not wanted. The immunosuppressive properties of opioids are theoretical, but strong evidence to avoid them does not exist. The application of nonsteroidal anti-inflammatory drugs and postoperative nausea and vomiting prophylaxis do not impair the patient's survival and may even have a positive effect on tumour regression. CONCLUSION: Anaesthesia does play an important part in the perioperative period in order to improve the cancer-related outcome. Further research is necessary to make more concrete recommendations.