Background and Aim: Heart disease might be an independent risk factor for cancer (reverse cardio-oncology). The cellular and molecular mechanisms that link heart disease to cancer remain elusive, and specific therapies are limited. We hypothesized that cardiac extracellular vesicles (cEVs) secreted by diseased hearts carry and disseminate factors that promote tumor growth. Methods & Results: We subjected female mice to myocardial infarction (MI) or sham-MI and 28 days of follow-up. Left ventricular remodeling was confirmed by echocardiography. To determine the role of cEVs in tumor growth, we focused on cardiac mesenchymal stromal cells (cMSCs), which play a central role in cardiac repair, remodeling, and fibrosis. Thus, we isolated cMSCs from mice hearts 10 or 28 days after MI or sham MI. cMSCs after MI secreted more small EVs than cMSCs from sham-MI. Proteomic analysis revealed a distinctive profile of cEVs after MI ( Fig A ). Purified cMSC-EVs targeted both breast and lung cancer cells in vitro. A scratch assay showed that MI-cEVs facilitated cancer cell proliferation and migration two times faster than sham-MI cEVs ( Fig B , p=0.0002). Finally, lung or breast cancer cells were inoculated into the hind limb or mammary pad 10 days before or after MI. Tumor growth was monitored by serial ultrasound examinations. While MI stimulated tumor growth, EV inhibition by GW4869 markedly attenuated this effect ( Fig C ). Conclusions: We show, for the first time, that cMSCs from the infarcted and remodeling heart secret EVs that target tumor cells and facilitate tumor growth. We propose cEVs as potential mediators and therapeutic targets in patients with concomitant heart disease and cancer.

Aims Heart disease might be an independent risk factor for cancer (reverse cardio-oncology). The co-occurrence of these diseases worsens patients' prognoses and limits therapeutic options. However, the cellular and molecular mechanisms that link heart disease to cancer remain elusive. Therefore, we hypothesized that cardiac extracellular vesicles (cEVs) secreted by diseased hearts carry and disseminate factors that promote tumor growth. Methods and results We subjected female mice to myocardial infarction (MI) or sham-MI and 28 days of follow-up. Left ventricular remodeling and dysfunction were assessed by echocardiography. To determine the role of cEVs in tumor growth, we focused on cardiac mesenchymal stromal cells (cMSCs), which play a central role in cardiac repair, remodeling, and fibrosis. We isolated cMSCs from mice hearts 10 or 28 days after MI or sham MI and purified cMSC-EVs from the conditioned medium using size exclusion chromatography. cEVs were characterized by nanoparticle tracking analysis (NTA), the classical EV markers: CD81 and Tumor susceptibility gene 101, and electron microscopy. cMSCs after MI secreted more small EVs than cMSCs from sham-MI (Fig. 1A, p<0.0001). Proteomic and biological process analysis revealed a distinctive profile of cEVs after MI with more EV-encapsulated proteins related to inflammation, angiogenesis, and cell cycle (Fig. 1B). Purified cMSC-EVs were labeled with PKH26 dye and found to target both breast and lung cancer cells in vitro. Colorimetric proliferation assay showed that MI-cEVs facilitated cancer cells proliferation compared with sham-MI cEVs (n=7 in each group, p<0.0001). Furthermore, by scratch assay, MI-cEVs facilitated cancer cell migration two times faster than sham-MI cEVs (Fig. 1C, p=0.0002). Finally, we established 2 models of heart disease with cancer. Lung or breast cancer cells (750x103 or 250x103) were inoculated into the hind limb or mammary pad 10 days before or after MI. Serial ultrasound examinations monitored tumor growth. While MI significantly stimulated lung cancer growth, EV inhibition by GW4869 markedly attenuated the tumorigenic effect of MI and left ventricular (LV) dysfunction (Fig. 1D, p for GW4869 <0.0001). Moreover, we found an inverse correlation between LV ejection fraction (LVEF) and the volume of breast cancer tumors. cEV inhibition by GW4869 attenuated this inverse correlation (for vehicle group: n=14, r=−0.54 and p=0.04. for GW4869 group: n=13, r=−0.43, and p=0.14). Conclusions Our results suggest, for the first time, that cMSCs from the infarcted and failing heart secret EVs that target tumor cells and accelerate tumor growth. We propose cEVs as potential mediators and therapeutic targets in patients with concomitant heart disease and cancer. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Seymour Fefer Grant

Introduction: Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1) is present on a subset of the immune cells in the tumor microenvironment (TME) and plays an essential and diverse role in cancer progression. However, its potential function in the irradiated TME remains unknown.Materials and Methods: Mouse lung cancer model was performed by subcutaneously inoculating Lewis Lung Carcinoma (LLC) cells expressing luciferase (Luc-2) and mCherry cells in CX3CR1GFP/GFP , CX3CR1DTR/+ , and wild–type (WT) mice. Bioluminescence imaging, clonogenic assay, and flow cytometry were used to assess tumor progression, proliferation, and cell composition after radiation.Results: Radiation provoked a significant influx of CX3CR1-expressing immune cells, notably monocytes, into the TME. Co-culturing irradiated LLC cells with CX3CR1-deficient monocytes and macrophages resulted in reduced clonogenic survival and increased apoptosis of the cancer cells. Interestingly, depletion of CX3CR1 in macrophages led to a redistribution of the irradiated LLC cells in the S-phase, parallel to increased expression of cyclin E1, required for cell cycle G1/S transition. In addition, deletion of CX3CR1 expression in macrophages altered the cytokine secretion with a decrease of interleukin-6, a crucial mediator of cancer cell survival and proliferation. Next, LLC cells were injected subcutaneously into CX3CR1DTR/+ mice, sensitive to diphtheria toxin (DT), and WT mice. After injection, tumors were irradiated with 8Gy, and mice were treated with DT, leading to conditional ablation of CX3CR1-expressing cells. After three weeks, CX3CR1 depleted mice displayed reduced tumor progression. Furthermore, combining the S-phase specific chemotherapy gemcitabine with CX3CR1 cell ablation resulted in additional attenuation of tumor progression.Conclusion: CX3CR1-expressing mononuclear cells invade the TME after radiation therapy in a mouse lung cancer model. CX3CR1 cell depletion attenuates tumor progression following radiation and sensitizes the tumor to S–phase-specific chemotherapy. Thus, we propose a novel strategy to improve radiation sensitivity by targeting the CX3CR1-expressing immune cells.

Obese and morbidly obese patients are a growing group of individuals that generates medical, social and economicproblems worldwide. They undergo various interventions that require anesthesia and/or analgesia. Despite theirhealthy look, these individuals are graded at high ASA physical status, mainly because of their impaired respiratoryand cardiovascular conditions, and the metabolic changes their body undergoes. Opioids are the default drugsfor perioperative analgesia. Nevertheless, their use has reached a frightening epidemic-like condition worldwide.Multimodal analgesia regimens have been recommended as a perioperative standard of care, particularly useful in theobese. These regimens employ combinations of opioids and non-opioid compounds that reciprocate each analgesicpotencies, thus providing superior pain relief at rest, movement, or on effort, while reducing opioid consumption andtheir concerned adverse effects. The most important perioperative IV adjuvant currently employed is ketamine thatsees resurgence among physicians from diverse medical specialties. After summarizing obese patients’ perioperativedrawbacks, this review will illustrate ketamine’s neuropharmacology, and will describe its therapeutic usefulness asan analgesic adjuvant. Since data regarding the use of the drug in obese patients is scarce, brief exemplifications ofits benefits in non-obese cohorts will be portrayed as well.