Breast cancer (BC) is one of the most common causes of cancer in the world and the second leading cause of cancer deaths among women. Mortality is associated mainly with the development of ...metastases. Identification of the mechanisms involved in metastasis formation is, therefore, a major public health issue. Among the proposed risk factors, chemical environment and pollution are increasingly suggested to have an effect on the signaling pathways involved in metastatic tumor cells emergence and progression. The purpose of this article is to summarize current knowledge about the role of environmental chemicals in breast cancer progression, metastasis formation and resistance to chemotherapy. Through a scoping review, we highlight the effects of a wide variety of environmental toxicants, including persistent organic pollutants and endocrine disruptors, on invasion mechanisms and metastatic processes in BC. We identified the epithelial-to-mesenchymal transition and cancer-stemness (the stem cell-like phenotype in tumors), two mechanisms suspected of playing key roles in the development of metastases and linked to chemoresistance, as potential targets of contaminants. We discuss then the recently described pro-migratory and pro-invasive Ah receptor signaling pathway and conclude that his role in BC progression is still controversial. In conclusion, although several pertinent pathways for the effects of xenobiotics have been identified, the mechanisms of actions for multiple other molecules remain to be established. The integral role of xenobiotics in the exposome in BC needs to be further explored through additional relevant epidemiological studies that can be extended to molecular mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Adverse outcome pathways (AOP) link a molecular initiating event to an adverse event.•The aryl hydrocarbon receptor (AhR) may be involved in breast cancer metastasis.•We created an AOP connecting ...activation of the AhR to breast cancer related death.•Artificial intelligence tools were used to collect and assess the evidence of our AOP.•This AOP is essential for regulatory health issues in toxicology.
Adverse outcome pathways (AOPs) are formalized and structured linear concepts that connect one molecular initiating event (MIE) to an adverse outcome (AO) via different key events (KE) through key event relationships (KER). They are mainly used in eco-toxicology toxicology, and regulatory health issues. AOPs must respond to specific guidelines from the Organization for Economic Co-operation and Development (OECD) to weight the evidence between each KE.
Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer related death (AO), through different KEs, constituting a new AOP.
An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, angiogenesis, and invasion. These KEs promote an increased tumor growth, angiogenesis and migration which leads to breast cancer metastasis and breast cancer related death.
The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines. The confidence in our AOP was considered strong. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer-related death with an innovative use of an artificial intelligence literature search.
Breast cancer (BC) is a major public health concern with over 2 million new cases diagnosed and over 600,000 deaths in 2018 in women worldwide. When distant metastases are present at diagnosis, the ...5-year survival rate is only 26%. Recent studies have suggested that persistent organic pollutants (POPs) that accumulate in adipose tissue (AT) can influence tumor phenotype and stimulate cellular processes important for metastasis such as invasion. We, therefore, tested the hypothesis that POP exposure is associated with BC metastasis.
We conducted an exploratory case-control study in which the concentrations of 49 POPs were measured in both AT and serum samples from BC patients, with or without lymph node metastasis, who underwent partial or total mastectomies, lymph node biopsies and sampling of the adipocytic tumor microenvironment. Adjusted, unconditional logistic models were used to study the associations between the POP concentrations and the risk of metastasis and other hallmarks of cancer aggressiveness.
2.3.7.8-TCDD concentrations in AT are positively associated with the risk of metastasis in 43 patients who have BMIs equal or higher than 25 kg/m2 (odds ratio: 4.48 (1.32–20.71)). Furthermore, the concentrations of 2.3.7.8-TCDD and two coplanar PCBs (77&169) in AT also were positively associated with the risk of lymph node metastasis and the tumor size.
Our study suggests that 2.3.7.8-TCDD and some PCBs contribute to the development of tumor metastasis and other hallmarks of cancer aggressiveness. While these results should be considered with caution, this is the first study to identify such potential risk factors. Larger longitudinal studies are necessary to confirm our results.
Clinical Trial Protocol Record: 2013-A00663-42.
•No observational studies have been conducted to evaluate the link between EDC and breast cancer metastasis.•The concentrations of 49 POPs were measured in AT from breast cancer patients with or without lymph node metastasis.•The concentrations of TCDD in AT are positively associated with the risk of metastasis in overweight patients.•The concentrations of TCDD, PCB77 and PCB 169 in AT were positively associated with the tumor size.
•Breast cancer (BC) is a frequent disease with a poor prognosis in case of metastasis.•We assessed the impact of a mixture of pollutants (POP) on BC aggressiveness.•POP were measured in the serum and ...adipose tissue of patients operated for a BC.•Mixtures of POP were associated with aggressiveness in patients with a BMI > 22 kg/m2.•These were mainly driven by dioxins and chemical homologues.
Breast cancer (BC) is frequent with a poor prognosis in case of metastasis. The role of the environment has been poorly evaluated in its progression. We searched to assess whether a mixture of pollutants could be responsible of BC aggressiveness.
Patients undergoing surgery for their BC were prospectively included in the METAPOP cohort. Forty-two POPs were extracted, among them 17 dioxins (PCDD/F), 16 polychlorobiphenyls (PCB), 8 polybromodiphenylethers (PBDE) and 2,2′,4,4′,5,5′-hexabromobiphenyl (PBB153) were measured in the adipose tissue surrounding the tumor. BC aggressiveness was defined using tumor size and metastasis (distant or lymph nodes). Two complementary models were used to evaluate the impact of the mixture of pollutants: the BKMR (Bayesian Kernel machine regression) and WQS (weighted quantile sum regression) models. The WQS estimates the weight (positive or negative) of a certain chemical based on its quantile and the BKMR model applies a kernel-based approach to estimate posterior inclusion probabilities. The sub-group of patients with a body mass index (BMI) > 22 kg/ m2 was also analyzed.
Ninety-one patients were included. Of these, 38 patients presented a metastasis, and the mean tumor size was 25.4 mm. The mean BMI was 24.5 kg/m2 (+/- 4.1). No statistical association was found in the general population. However, in patients with a BMI > 22 kg/ m2, our mixture was positively associated with tumor size (OR: 9.73 95 %CI: 1.30–18.15) and metastasis (OR = 3.98 95 %CI = 1.09–17.53) using the WQS model. Moreover, using the BKMR model on chemical families, dioxin like chemicals and PCDD were associated with a higher risk of metastasis.
These novel findings identified a mixture associated with breast cancer aggressiveness in patients with a BMI > 22 kg/ m2.
Growing epidemiological evidence suggests that organochlorine chemicals (OCCs), including 2,3,7,8-tetrachlorodibenzo-
-dioxin (TCDD), may play a role in the pathogenesis of endometriosis.
We aimed to ...systematically review the experimental evidence (
and
) on the associations between exposure to OCCs and endometriosis-related end points.
A systematic review protocol was developed following the National Toxicology Program /Office of Health Assessment and Translation (NTP/OHAT) framework and managed within a web-based interface.
studies designed to evaluate the impact of OCCs on the onset or progression of endometriosis and proliferation of induced endometriotic lesions were eligible. Eligible
studies included single-cell and co-culture models to evaluate the proliferation, migration, and/or invasion of endometrial cells. We applied the search strings to PubMed, Web of Science, and Scopus®. A final search was performed on 24 June 2020. Assessment of risk of bias and the level of evidence and integration of preevaluated epidemiological evidence was conducted using NTP/OHAT framework Results: Out of 812 total studies, 39 met the predetermined eligibility criteria (15
, 23
, and 1 both). Most studies (
) tested TCDD and other dioxin-like chemicals.
evidence supported TCDD's promotion of endometriosis onset and lesion growth.
evidence supported TCDD's promotion of cell migration and invasion, but there was insufficient evidence for cell proliferation.
evidence further supported the roles of the aryl hydrocarbon receptor and matrix metalloproteinases in mediating steroidogenic disruption and inflammatory responses. Estrogen interactions were found across studies and end points.
Based on the integration of a high level of animal evidence with a moderate level of epidemiological evidence, we concluded that TCDD was a known hazard for endometriosis in humans and the conclusion is supported by mechanistic
evidence. Nonetheless, there is need for further research to fill in our gaps in understanding of the relationship between OCCs and their mixtures and endometriosis, beyond the prototypical TCDD. https://doi.org/10.1289/EHP8421.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Endometriosis is a hormone-dependent gynaecological disease characterised by the presence and growth of endometrial tissues outside of the uterus. There is growing experimental evidence that suggests ...environmental endocrine disrupting chemicals, specifically organochlorine chemicals (OCCs), may play a role in the pathogenesis of endometriosis, but to date, there are no studies attempting to gather and synthesise the published literature systematically.
The main objective of this SR is to evaluate the associations between the exposure to OCCs and endometriosis in experimental models (in vivo and in vitro).
The SR framework has been developed following the guidelines established in National Toxicology Program/ Office of Health Assessment and Translation (NTP/OHAT) Handbook for Conducting a Literature-Based Health Assessment, which provides a standardised methodology to implement the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to environmental health assessments. The review process will be managed and documented through HAWC, an open-source content management system, to guarantee transparency.
Only experimental studies, in vivo, ex vivo or in vitro, exploring associations between controlled exposures to OCCs and endometriosis and related outcomes will be included. Eligible studies will include peer reviewed articles of any publication date which are sources of primary data. Only studies published in English will be considered.
We will apply the search strings to the scientific literature databases NCBI PubMed, Web of Science and SCOPUS. Manual searches will be performed through the list of references of included articles.
Data will be extracted according to a pre-defined set of forms and synthesised in a narrative report. Given sufficient commensurate data, a meta-analysis may also be performed.
A quality assessment will be performed for in vivo and in vitro studies using the NTP/OHAT Risk of Bias Rating Tool for Human and Animal Studies.
Following a comprehensive assessment of the quality of evidence for both in vivo and in vitro studies, a confidence rating will be assigned to the body of literature and subsequently translated into a rating on the level of evidence (high, moderate, low, or inadequate) regarding the research question.
Systematic review registration: PROSPERO CRD42018102618.
•A rigorous protocol is presented for systematic reviews of experimental evidence•Associations between organochlorines and endometriosis will be explored•OHAT approach is used to develop the work-flow of evidence rating•HAWC interface is used to manage and visualize data
Environmental factors including diet, sedentary lifestyle and exposure to pollutants largely influence human health throughout life. Cellular and molecular events triggered by an exposure to ...environmental pollutants are extremely variable and depend on the age, the chronicity and the doses of exposure. Only a fraction of all relevant mechanisms involved in the onset and progression of pathologies in response to toxicants has probably been identified. Mitochondria are central hubs of metabolic and cell signaling responsible for a large variety of biochemical processes, including oxidative stress, metabolite production, energy transduction, hormone synthesis, and apoptosis. Growing evidence highlights mitochondrial dysfunction as a major hallmark of environmental insults. Here, we present mitochondria as crucial organelles for healthy metabolic homeostasis and whose dysfunction induces critical adverse effects. Then, we review the multiple mechanisms of action of pollutants causing mitochondrial toxicity in link with chronic diseases. We propose the Aryl hydrocarbon Receptor (AhR) as a model of "exposome receptor", whose activation by environmental pollutants leads to various toxic events through mitochondrial dysfunction. Finally, we provide some remarks related to mitotoxicity and risk assessment.
Purpose
Ever since the recent findings showing the lack of benefit of minimally invasive surgery (MIS) versus open surgery in early-stage cervical cancer, gynecologists have tried to explain these ...results. The primary objective of our study was to assess the impact of pre-operative conization on disease-free survival (DFS) in early-stage cervical cancer. The secondary objective was to analyze the peri-operative morbidity associated with a pre-operative conization.
Methods
All patients undergoing a surgical management for early-stage squamous carcinoma or adenocarcinoma cervical cancer (IA1, IA2, IB1 and IB2 FIGO 2018) at a French university hospital from 2004 to 2018 were retrospectively included. We examined the association between conization and DFS using a Cox regression model. We also analyzed the morbidity associated with pre-operative conization.
Results
48.4% (44/91) of the patients had a pre-operative conization (defined by a conization up to 90 days prior to surgery). 86.8% underwent MIS. There was a non-significant increase in the DFS with one patient presenting a recurrence in the conization group (2.3%) and six (12.8%) in the no conization group (log rank = 0.09). In univariate analysis, conization, definitive FIGO stage and pre-operative tumor size were associated with DFS (
p
< 0.2). Only pre-operative tumor size was significantly associated with DFS in multivariate analysis. There was a non-significant increase of adverse events in the conization group (43.2% in the conization group versus 23.4%,
p
= 0.06).
Conclusion
Conization, through a reduction of tumor size, could improve DFS. Carefully selected patients could still benefit from minimally invasive surgery.
Few data have been reported on robot-assisted surgery in elderly. The objectives were to compare feasibility, complication data, and survival of patients under and upper the age of 70 who are managed ...for endometrial cancer by robot-assisted laparoscopy.
This is a retrospective comparative single-center study including patients treated between January 2007 and December 2016. Patients were divided into 2 groups: less than 70 years and greater than or equal to 70 years. The primary endpoint was the rate of complications. The secondary endpoints were conversion rate and follow-up.
148 patients were included: 86 under 70 (group A) and 62 aged 70 and over (group B). More adhesiolysis was performed in group B (p < .01); the pelvic and para-aortic lymph node dissection rates were not different between both groups (p = .2 and p = .9). The operating times were significantly longer in group B (220.1 vs. 234.4 min, p = .02). The conversion rate was similar between the 2 groups (p = .7). The tumors were endometrioid adenocarcinomas for 77.9 and 66.7% respectively (p = .2), with grade 3 tumors more represented in older patients (24.4% vs. 48.4%, p < .01). There were more tumors at high risk of recurrence after 70 years (33.7 vs. 45.2%, p = .04). No significant difference was found for postoperative complications. There was no difference in overall survival (p = .7) or progression-free survival (p = .2). Undertreated women rate was similar in both groups (p = .1).
Robotic surgery appears feasible and reproducible and could bring a benefit and allow optimal surgery without increasing the morbidity in the management of endometrial cancers whatever the age is.
•We compared the robotic management of endometrial cancer in patients ≥ 70 years and <70 years.•Elderly patients have more advanced and aggressive cancers.•They benefit from as much lymph node dissections despite more advanced stages.•Robot-assisted laparoscopy is feasible in elderly with similar complications rates.•There is no difference in survival.
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