Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines ...derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.
Summary Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on ...sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action.
Tumor cell metastasis is a complex process that has been mechanistically linked to the epithelial-mesenchymal transition (EMT). The double-negative feedback loop between the microRNA-200 family and ...the Zeb1 transcriptional repressor is a master EMT regulator, but there is incomplete understanding of how miR-200 suppresses invasion. Our recent efforts have focused on the tumor cell-matrix interactions essential to tumor cell activation. Herein we utilized both our Kras/p53 mutant mouse model and human lung cancer cell lines to demonstrate that upon miR-200 loss integrin β1-collagen I interactions drive 3D in vitro migration/invasion and in vivo metastases. Zeb1-dependent EMT enhances tumor cell responsiveness to the ECM composition and activates FAK/Src pathway signaling by de-repression of the direct miR-200 target, CRKL. We demonstrate that CRKL serves as an adaptor molecule to facilitate focal adhesion formation, mediates outside-in signaling through Itgβ1 to drive cell invasion, and inside-out signaling that maintains tumor cell-matrix contacts required for cell invasion. Importantly, CRKL levels in pan-cancer TCGA analyses were predictive of survival and CRKL knockdown suppressed experimental metastases in vivo without affecting primary tumor growth. Our findings highlight the critical ECM-tumor cell interactions regulated by miR-200/Zeb1-dependent EMT that activate intracellular signaling pathways responsible for tumor cell invasion and metastasis.
Objectives
The primary objective was to determine the rate of occult cervical nodal metastasis in patients undergoing elective neck dissection (END) during salvage laryngectomy. The secondary ...objective was to compare survival and postoperative complication rates between patients undergoing END versus observation.
Methods
A medical librarian performed a comprehensive search for END outcomes in laryngeal cancer patients undergoing salvage laryngectomy after primary chemoradiation therapy. Seventeen retrospective studies and 1 prospective study met inclusion criteria, with a total of 1,141 patients (799 END, 350 observed).
Results
The rate of nodal positivity was 11% among patients who underwent END during their salvage laryngectomy. Three studies and 155 patients were included in a 5‐year overall survival (OS) analysis with no significant difference in OS (95% confidence interval CI: 0.82‐2.22). After inclusion of six studies and 494 patients (249 END, 245 observed), the risk of fistula formation was not statistically different (95% CI: 0.61‐2.56). Due to significant heterogeneity between studies and inadequate data, most patients could not be included in the meta‐analysis of outcomes.
Conclusion
Salvage laryngectomy patients undergoing END have an occult nodal positivity rate of 11%. Meta‐analysis showed no statistically significant differences in 5‐year OS between patients undergoing END versus observation. Laryngoscope, 130:899–906, 2020
The microRNA-200 (miR-200) family restricts epithelial-mesenchymal transition (EMT) and metastasis in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma. To determine the ...mechanisms responsible for EMT and metastasis regulated by this microRNA, we conducted a global liquid chromatography/tandem mass spectrometry analysis to compare metastatic and nonmetastatic murine lung adenocarcinoma cells which had undergone EMT because of loss of miR-200. An analysis of syngeneic tumors generated by these cells identified multiple novel proteins linked to metastasis. In particular, the analysis of conditioned media, cell surface proteins, and whole-cell lysates from metastatic and nonmetastatic cells revealed large-scale modifications in the tumor microenvironment. Specific increases were documented in extracellular matrix (ECM) proteins, peptidases, and changes in distribution of cell adhesion proteins in the metastatic cell lines. Integrating proteomic data from three subproteomes, we defined constituents of a multilayer protein network that both regulated and mediated the effects of TGFβ. Lastly, we identified ECM proteins and peptidases that were directly regulated by miR-200. Taken together, our results reveal how expression of miR-200 alters the tumor microenvironment to inhibit the processes of EMT and metastasis.
Better understanding of the biophysical and biochemical cues of the tumor extracellular matrix environment that influence metastasis may have important implications for new cancer therapeutics. ...Initial exploration into this question has used naturally derived protein matrices that suffer from variability, poor control over matrix biochemistry, and inability to modify the matrix biochemistry and mechanics. Here, we report the use of a synthetic polymer-based scaffold composed primarily of poly(ethylene glycol), or PEG, modified with bioactive peptides to study murine models of lung adenocarcinoma. In this study, we focus on matrix-derived influences on epithelial morphogenesis of a metastatic cell line (344SQ) that harbors mutations in Kras and p53 (trp53) and is prone to a microRNA-200 (miR-200)-dependent epithelial-mesenchymal transition (EMT) and metastasis. The modified PEG hydrogels feature biospecific cell adhesion and cell-mediated proteolytic degradation with independently adjustable matrix stiffness. 344SQ encapsulated in bioactive peptide-modified, matrix metalloproteinase-degradable PEG hydrogels formed lumenized epithelial spheres comparable to that seen with three-dimensional culture in Matrigel. Altering both matrix stiffness and the concentration of cell-adhesive ligand significantly influenced epithelial morphogenesis as manifest by differences in the extent of lumenization, in patterns of intrasphere apoptosis and proliferation, and in expression of epithelial polarity markers. Regardless of matrix composition, exposure to TGF-β induced a loss of epithelial morphologic features, shift in expression of EMT marker genes, and decrease in mir-200 levels consistent with EMT. Our findings help illuminate matrix-derived cues that influence epithelial morphogenesis and highlight the potential utility that this synthetic matrix-mimetic tool has for cancer biology.
Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient's likelihood of long-term survival. The ZEB1 transcriptional repressor promotes ...metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.
ObjectivesWhile almost 60% of the world has received at least one dose of COVID-19 vaccine, the global distribution of vaccination has not been equitable. Only 4% of the population of low-income ...countries (LICs) has received a full primary vaccine series, compared with over 70% of the population of high-income nations.DesignWe used economic and epidemiological models, parameterised with public data on global vaccination and COVID-19 deaths, to estimate the potential benefits of scaling up vaccination programmes in LICs and lower-middle-income countries (LMICs) in 2022 in the context of global spread of the Omicron variant of SARS-CoV2.SettingLow-income and lower-middle-income nations.Main outcome measuresOutcomes were expressed as number of avertable deaths through vaccination, costs of scale-up and cost per death averted. We conducted sensitivity analyses over a wide range of parameter estimates to account for uncertainty around key inputs.FindingsGlobally, universal vaccination in LIC/LMIC with three doses of an mRNA vaccine would result in an estimated 1.5 million COVID-19 deaths averted with a total estimated cost of US$61 billion and an estimated cost-per-COVID-19 death averted of US$40 800 (sensitivity analysis range: US$7400–US$81 500). Lower estimated infection fatality ratios, higher cost-per-dose and lower vaccine effectiveness or uptake lead to higher cost-per-death averted estimates in the analysis.ConclusionsScaling up COVID-19 global vaccination would avert millions of COVID-19 deaths and represents a reasonable investment in the context of the value of a statistical life. Given the magnitude of expected mortality facing LIC/LMIC without vaccination, this effort should be an urgent priority.
The World Health Organization (WHO) has prepared a draft Global action plan on antimicrobial resistance that will be discussed at this year's World Health Assembly. However, more is required if the ...world is to grapple effectively with this huge and complex problem. Global collective action is required in three areas: 1. access, 2. conservation, and 3. innovation. The problem of antimicrobial resistance requires that all three areas be tackled simultaneously. Without conservation and innovation, universal access will simply drive resistance and deplete existing stocks of effective antimicrobials. Given these global coordination issues, there is a clear role for a binding international legal framework to encompass the issues of access, conservation and innovation.
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