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The findings call for mechanistic translational studies to understand these deleterious effects of dexmedetomidine, and warrant prospective clinical trials to assess the impact of perioperative dexmedetomidine use on outcomes in cancer patients.

Gastric cancer is the third most lethal cancer worldwide, and evaluation of the genomic status of gastric cancer cells has not translated into effective prognostic or therapeutic strategies.We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), in particular, cancerassociated fibroblasts (CAF). However, very little is known about the role of CAFs in gastric cancer. To address this, we mapped the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from patients with gastric cancer. A stromal gene signature was associated with poor disease outcome, and the transcription factor heat shock factor 1 (HSF1) regulated the signature. HSF1 upregulated inhibin subunit beta A and thrombospondin 2, which were secreted in CAF-derived extracellular vesicles to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment. Significance: This study shows how HSF1 regulates a stromal transcriptional program associated with aggressive gastric cancer and identifies multiple proteins within this program as candidates for therapeutic intervention. better understand the molecular basis of this disease, and to identify 48 biomarkers that may predict outcome and guide therapy.49 Gastric cancer is a heterogeneous disease. Traditionally, anatomical 50 location (true gastric vs. gastro-esophageal) and histologic character-51 istics (diffuse vs. intestinal; tubular vs. papillary) have been used to 52 classify gastric cancer subtypes (2). Recent advances in molecular 53 understanding have enabled classification of gastric cancer into dif-54 ferent subtypes based on chromosomal instability, microsatellite 55 instability, genomic stability, presence of Epstein-Barr virus, and 56 epithelial-mesenchymal transition (EMT), which were associated with 57 different survival outcomes (3-6). Mutations in CDH1 and KRAS, and 58 overexpression of HER2, EGFR, FGFR2, VEGF, were shown to 59 contribute to disease progression and correlate with poor out-60 come (7, 8). Despite serving as valuable guides in deciphering the 61 complexity of gastric cancer, there has been little success in applying 62 these molecular classifiers to treatment stratification and development 63 of targeted therapies (3). Prognosis in the clinic is still mostly evaluated 64 on the basis of TNM staging (tumor size, lymph node involvement, and 65 metastasis), and the standard of care for localized gastric cancer is 66 surgical intervention combined with chemotherapy (7). 67 Increasing evidence over the past decade highlighted the indispens-68 able contribution of the tumor microenvironment (TME) to disease 69 progression and treatment resistance (9). The TME is comprised of 70 various cell types, including endothelial cells, fibroblasts, macro-71 phages, and lymphocytes, as well as extracellular matrix co...

Liver metastases are a major cause of colorectal cancer death, and the perioperative period is believed to critically affect the metastatic process. Here we tested whether blocking excess release of catecholamines and prostaglandins during surgical procedures of different extent can reduce experimental liver metastasis of the syngeneic CT26 colon cancer in female and male BALB/c mice. Animals were either treated with the beta-blocker, propranolol, the COX-2 inhibitor, etodolac, both drugs, or vehicle. The role of NK cells in controlling CT26 hepatic metastasis and in mediating the effect of the drugs was assessed by in vivo depletion or stimulation of NK cells, using anti-asialo GM1 or CpG-C, respectively. Surgical extent was manipulated by adding laparotomy to small incision, extending surgical duration, and enabling hypothermia. The results indicated that combined administration of propranolol and etodolac, but neither drug alone, significantly improved host resistance to metastasis. These beneficial effects occurred in both minor and extensive surgeries, in both sexes, and in two tumor inoculation approaches. NK cell-mediated anti-CT26 activity is involved in mediating the beneficial effects of the drugs. Specifically, CpG-C treatment, known to profoundly activate mice marginating-hepatic NK cytotoxicity, reduced CT26 hepatic metastases; and NK-depletion increased metastases and prevented the beneficial effects of the drugs. Overall, given prevalent perioperative psychological and physiological stress responses in patients, and ample prostaglandin release by colorectal tumors and injured tissue, propranolol and etodolac could be tested clinically in laparoscopic and open colorectal surgeries, attempting to reduce patients’ metastatic disease.

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