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.
Using MDA-MB-231
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-231
-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-231
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-231
-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.
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-231
xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.
In response to adverse social-environmental conditions, leukocytes gene expression profile is altered in a pattern recognized as the conserved transcriptional response to adversity (CTRA). This ...entails the up-regulated expression of pro-inflammatory genes and down-regulated expression of genes involved in type-I interferon (IFN) related anti-viral immunity. In contrast, vagal nerve activity is recognized as a significant anti-inflammatory modulator. In this work, we investigated the association between CTRA and vagal activity indicated by the standard deviation of all NN interval (SDNN), a measure of heart-rate variability, in breast cancer patients awaiting surgery (n = 16). This association was tested both at the molecular leukocyte transcription factor activity level, as well as at the cytokines serum levels. We found an association between higher SDNN and increased interferon (IFN) related anti-viral pathways, both on the leukocyte transcription factor level and serum protein level. Unexpectedly, we also found a positive correlation between higher SDNN and pro-inflammatory transcription factor activity and cytokine serum level, potentially suggesting that increased vagal activity was induced by increased inflammation, in the context of pre-surgical stress and the presence of malignant tissue. Transcription origin analysis (TOA) suggests a role for monocyte and B-cells in the anti-inflammatory and anti-metastatic effects induced by vagal nerve signaling. Larger prospective studies are needed to verify and elaborate on the results from this small cross-sectional study.
•Increased HRV is associated with increased anti-viral immunity.•Unexpectedly, HRV is also associated with increased pro-inflammatory signaling.•Findings are evident separately at transcription factor activity level as well as at cytokine serum levels.•Macrophages and B cells emerge as the origin of these differences.•Findings may shed light on novel pathways in which vagal nerve activity modulate cancer progression.
Background
Preclinical studies have implicated excess release of catecholamines and prostaglandins in the mediation of prometastatic processes during surgical treatment of cancer. In this study, we ...tested the combined perioperative blockade of these pathways in patients with colorectal cancer (CRC).
Methods
In a randomized, double‐blind, placebo‐controlled biomarker trial involving 34 patients, the β‐blocker propranolol and the COX2‐inhibitor etodolac were administered for 20 perioperative days, starting 5 days before surgery. Excised tumors were subjected to whole genome messenger RNA profiling and transcriptional control pathway analyses.
Results
Drugs were well‐tolerated, with minor complications in both the treatment group and the placebo group. Treatment resulted in a significant improvement (P < .05) of tumor molecular markers of malignant and metastatic potential, including 1) reduced epithelial‐to‐mesenchymal transition, 2) reduced tumor infiltrating CD14+ monocytes and CD19+ B cells, and 3) increased tumor infiltrating CD56+ natural killer cells. Transcriptional activity analyses indicated a favorable drug impact on 12 of 19 a priori hypothesized CRC‐related transcription factors, including the GATA, STAT, and EGR families as well as the CREB family that mediates the gene regulatory impact of β‐adrenergic– and prostaglandin‐signaling. Alterations observed in these transcriptional activities were previously associated with improved long‐term clinical outcomes. Three‐year recurrence rates were assessed for long‐term safety analyses. An intent‐to‐treat analysis revealed that recurrence rates were 12.5% (2/16) in the treatment group and 33.3% (6/18) in the placebo group (P = .239), and in protocol‐compliant patients, recurrence rates were 0% (0/11) in the treatment group and 29.4% (5/17) in the placebo group (P = .054).
Conclusions
The favorable biomarker impacts and clinical outcomes provide a rationale for future randomized placebo‐controlled trials in larger samples to assess the effects of perioperative propranolol/etodolac treatment on oncological clinical outcomes.
Simultaneous 20‐day perioperative inhibition of β‐adrenergic and COX2 signaling in patients with colorectal cancer has a favorable impact on tumor biomarkers associated with metastatic progression. Our results suggest scientific, medical, and safety justifications to conduct large‐scale clinical trials, assessing long‐term cancer outcomes.
Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined ...perioperative blockade of these pathways in breast cancer patients.
In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a β-adrenergic antagonist (propranolol) and a COX-2 inhibitor (etodolac), beginning 5 days before surgery. Excised tumors and sequential blood samples were assessed for prometastatic biomarkers.
Drugs were well tolerated with adverse event rates comparable with placebo. Transcriptome profiling of the primary tumor tested
hypotheses and indicated that drug treatment significantly (i) decreased epithelial-to-mesenchymal transition, (ii) reduced activity of prometastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and (iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells. Drug treatment also significantly abrogated presurgical increases in serum IL6 and C-reactive protein levels, abrogated perioperative declines in stimulated IL12 and IFNγ production, abrogated postoperative mobilization of CD16
"classical" monocytes, and enhanced expression of CD11a on circulating natural killer cells.
Perioperative inhibition of COX-2 and β-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer.
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Evidence suggests that excess perioperative activation of the sympathetic nervous system and the consequent release of catecholamines (ie, epinephrine and norepinephrine) in the context of cancer ...surgery and inflammation may significantly facilitate prometastatic processes. This review first presents biomedical processes that make the perioperative timeframe pivotal in determining long‐term cancer outcomes nonproportionally to its short duration (days to weeks). Then, it analyzes the various mechanisms via which the excess release of catecholamines can facilitate the progression of cancer metastases in this context by directly affecting the malignant tissues and by regulating, via indirect pathways, immunological and other mechanisms that affect metastatic progression in the tumor microenvironment and systemically. In addition, this review addresses the need to supplement β‐adrenoreceptor blockade with cyclooxygenase 2 inhibition, especially during surgery and shortly thereafter, because similar mechanisms are simultaneously activated by surgery‐induced inflammatory responses. Importantly, this review presents translational and clinical evidence showing that perioperative β‐adrenoreceptor blockade and cyclooxygenase 2 inhibition can reduce the prometastatic process and cancer recurrence, and the clinical feasibility and safety of this approach are demonstrated as well. Lastly, alternative psychophysiological approaches to the use of β‐adrenergic blockers are presented because a substantial portion of patients have medical contraindications to this pharmacological treatment. The adaptation of existing psychophysiological interventions to the perioperative period and principles for constructing new approaches are discussed and exemplified. Overall, pharmacobehavioral interventions, separately or in combination, could transform the perioperative timeframe from being a prominent facilitator of metastatic progression to an opportunity for arresting or eliminating residual disease, potentially improving long‐term survival rates in cancer patients.
Evidence based on animal models, retrospective clinical studies, and recently also randomized controlled trials indicates that simultaneous use of β‐blockers and cyclooxygenase 2 inhibitors can effectively reduce promalignant effects of perioperative stress‐inflammatory responses and may reduce patients’ recurrence rates and mortality. Hypothetically, perioperative psychological interventions may have similar benefits.
•Even before surgery, we observed pro-inflammatory/pro-metastatic responses in breast cancer patients.•Propranolol (β-blocker) and etodolac (COX2 inhibitor) abolished these responses.•Propranolol and ...etodolac improved numerous perioperative pro-metastatic biomarkers in blood and in excised tumors.•Larger clinical trials are needed to study the effect of the treatment on cancer recurrence.
Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (n = 38), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5 days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.
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