Perioperative escape from dormancy of spontaneous micro-metastases: A role for malignant secretion of IL-6, IL-8, and VEGF, through adrenergic and prostaglandin signaling.

We recently showed that a minimally-invasive removal of MDA-MB-231HM primary tumors (PTs) and elimination of their secreted factors (including IL-6, IL-8, VEGF, EGF, PDGF-aa, MIF, SerpinE1, and M-CSF), caused regression of spontaneous micro-metastases into a non-growing dormant state. To explore the underlying mechanisms and potential clinical ramifications of this phenomenon, we herein used the MDA-MB-231HM human breast cancer cell-line, in-vitro, and in vivo following orthotopic implantation in immune-deficient BALB/C nu/nu mice. Employing bioluminescence imaging, we found that adding laparotomy to minimally-invasive removal of the PT caused an outbreak of micro-metastases. However, perioperative ß-adrenergic and COX-2 inhibition, using propranolol + etodolac, maintained metastatic dormancy following laparotomy. In-vitro, ß-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231HM secretion of the pro-metastatic factors IL-6, IL-8, and VEGF, whereas cortisol reduced their secretion, effects that were maintained even 12 h after the washout of these agonists. In-vivo, laparotomy elevated IL-6 and IL-8 levels in both plasma and ex-vivo PT spontaneous secretion, whereas perioperative propranolol + etodolac administration blocked these effects. Similar trends were evident for EGF and MIF. Promoter-based bioinformatics analyses of excised PT transcriptomes implicated elevated NF-kB activity and reduced IRF1 activity in the gene regulatory effects of laparotomy, and these effects were inhibited by pre-surgical propranolol + etodolac. Taken together, our findings suggest a novel mechanism of post-operative metastatic outbreak, where surgery-induced adrenergic and prostanoid signaling increase the secretion of pro-metastatic factors, including IL-6, IL-8, and VEGF, from PT and possibly residual malignant tissue, and thereby prevent residual disease from entering dormancy.

Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome.

BACKGROUND: Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms. RESULTS: Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival. CONCLUSIONS: These results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.

Immunotherapy during the Immediate Perioperative Period: A Promising Approach against Metastatic Disease.

Tumor excision is a necessary life-saving procedure in most solid cancers. However, surgery and the days before and following it, known as the immediate perioperative period (IPP), entail numerous prometastatic processes, including the suppression of antimetastatic immunity and direct stimulation of minimal residual disease (MRD). Thus, the IPP is pivotal in determining long-term cancer outcomes, presenting a short window of opportunity to circumvent perioperative risk factors by employing several therapeutic approaches, including immunotherapy. Nevertheless, immunotherapy is rarely examined or implemented during this short timeframe, due to both established and hypothetical contraindications to surgery. Herein, we analyze how various aspects of the IPP promote immunosuppression and progression of MRD, and how potential IPP application of immunotherapy may interact with these deleterious processes. We discuss the feasibility and safety of different immunotherapies during the IPP with a focus on the latest approaches of immune checkpoint inhibition. Last, we address the few past and ongoing clinical trials that exploit the IPP timeframe for anticancer immunotherapy. Accordingly, we suggest that several specific immunotherapies can be safely and successfully applied during the IPP, alone or with supporting interventions, which may improve patients' resistance to MRD and overall survival.

Sleep-like changes in neural processing emerge during sleep deprivation in early auditory cortex.

Insufficient sleep is commonplace in modern lifestyle and can lead to grave outcomes, yet the changes in neuronal activity accumulating over hours of extended wakefulness remain poorly understood. Specifically, which aspects of cortical processing are affected by sleep deprivation (SD), and whether they also affect early sensory regions, remain unclear. Here, we recorded spiking activity in the rat auditory cortex along with polysomnography while presenting sounds during SD followed by recovery sleep. We found that frequency tuning, onset responses, and spontaneous firing rates were largely unaffected by SD. By contrast, SD decreased entrainment to rapid (≥20 Hz) click trains, increased population synchrony, and increased the prevalence of sleep-like stimulus-induced silent periods, even when ongoing activity was similar. Recovery NREM sleep was associated with similar effects as SD with even greater magnitude, while auditory processing during REM sleep was similar to vigilant wakefulness. Our results show that processes akin to those in NREM sleep invade the activity of cortical circuits during SD, even in the early sensory cortex.

Stress and cancer: mechanisms, significance and future directions.

The notion that stress and cancer are interlinked has dominated lay discourse for decades. More recent animal studies indicate that stress can substantially facilitate cancer progression through modulating most hallmarks of cancer, and molecular and systemic mechanisms mediating these effects have been elucidated. However, available clinical evidence for such deleterious effects is inconsistent, as epidemiological and stress-reducing clinical interventions have yielded mixed effects on cancer mortality. In this Review, we describe and discuss specific mediating mechanisms identified by preclinical research, and parallel clinical findings. We explain the discrepancy between preclinical and clinical outcomes, through pointing to experimental strengths leveraged by animal studies and through discussing methodological and conceptual obstacles that prevent clinical studies from reflecting the impacts of stress. We suggest approaches to circumvent such obstacles, based on targeting critical phases of cancer progression that are more likely to be stress-sensitive; pharmacologically limiting adrenergic-inflammatory responses triggered by medical procedures; and focusing on more vulnerable populations, employing personalized pharmacological and psychosocial approaches. Recent clinical trials support our hypothesis that psychological and/or pharmacological inhibition of excess adrenergic and/or inflammatory stress signalling, especially alongside cancer treatments, could save lives.