Blockade of perioperative β-adrenergic and prostaglandin signaling modulates tumor secretome and immunity to suppress metastasis
2Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel
3Department of Molecular Cell Biology, Weizmann Institute of Science, Israel
4Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), USA
5Faculty of Medical and Health Sciences, Edmond J Safra Center for Bioinformatics, Innovation Labs (Tilabs), Sagol School of Neuroscience, Tel Aviv University, Israel
6Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Israel
Introduction:
Although surgery for primary tumor (PT) removal is a necessary approach, it can promote life-threatening metastasis. Preclinical and clinical studies suggest that perioperative sympathetic stress and inflammatory responses, through secretion of catecholamines and prostaglandins, support metastasis. Notably, most pre-clinical cancer models do not include a PT-resection surgery, nor address surgical stress responses, failing to reveal perioperative metastasis-promoting mechanisms. This study investigates how surgery-induced β-adrenergic and prostaglandin signaling affect tumor secretome, metastasis, and anti-tumor immunity in melanoma and breast cancer models, and evaluates the potential of perioperative blockade of these pathways to mitigate metastasis.
Methods:
Using syngeneic B16F10 melanoma and 4T1 mammary carcinoma cell lines in C57BL/6J and Balb/C mice, respectively, we induced spontaneously metastasizing PTs. Stress and inflammatory responses were manipulated by conducting minimally-invasive versus extensive surgery, and/or administration of propranolol & etodolac to reduce β-adrenergic and prostaglandin signaling, respectively. Tumor secretome was studied using proteomics, cytokine array, and whole-genome RNA sequencing, employing bioinformatic analyses to assess tumor infiltrating leucocytes.
Results:
To assess the relation between PT secretome and survival outcomes, PT secretome of survivors vs. relapsed animals were compared using proteomics. Results indicated a signature of upregulated proteins in secretome of survivors, which were functionally related to anti-tumor immunity, suggesting the clinical significance of secretome profiling. To examine clinically-relevant settings, PT-bearing animals were subjected or not to an extensive abdominal surgery (laparotomy), and were treated with propranolol & etodolac, or with vehicle. Surgery upregulated PT secretion of the pro-metastatic SerpinE1 and EGF, while the drug treatment antagonized these effects, upregulated M1-macrophage polarization, and increased expression of apoptosis-related genes, suggesting upregulation of myeloid anti-tumor immunity. Importantly, the drug treatment reduced lung and kidney/adrenal metastases, reduced metastatic secretion of EGF, and reduced spleen size and weight, which are related to lower metastatic load.
Conclusions:
This study indicates the significance of surgery-induced β-adrenergic and prostanoid responses, which can alter tumor secretome towards a pro-metastatic profile, while their blockade may enhance anti-tumor immunity and reduce metastasis. These results highlight the deleterious impact of stress responses within the perioperative period on immunity and metastasis, and call for perioperative interventions to mitigate these effects.