Stem cell markers, including NANOG, have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. Here, we show that NANOG is ...induced by Toll-like receptor 4 (TLR4) signaling via phosphorylation of E2F1 and that downregulation of Nanog slows down hepatocellular carcinoma (HCC) progression induced by alcohol western diet and hepatitis C virus protein in mice. NANOG ChIP-seq analyses reveal that NANOG regulates the expression of genes involved in mitochondrial metabolic pathways required to maintain tumor-initiating stem-like cells (TICs). NANOG represses mitochondrial oxidative phosphorylation (OXPHOS) genes, as well as ROS generation, and activates fatty acid oxidation (FAO) to support TIC self-renewal and drug resistance. Restoration of OXPHOS activity and inhibition of FAO renders TICs susceptible to a standard care chemotherapy drug for HCC, sorafenib. This study provides insights into the mechanisms of NANOG-mediated generation of TICs, tumorigenesis, and chemoresistance through reprogramming of mitochondrial metabolism.
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•Stem cell marker NANOG is activated by the TLR4-E2F1 pathway•NANOG ChIP-seq identifies target genes involved in OXPHOS and FAO•Nanog represses OXPHOS and mitochondrial ROS in TICs•Restoration of OXPHOS and inhibition of FAO restores TIC susceptibility to drugs
Chen et al. show that the pluripotency transcription factor NANOG contributes to liver cancer progression by reprogramming mitochondrial metabolism to promote self-renewal ability, tumor-initiation property, and chemoresistance of tumor-initiating stem-like cells (TICs). Restoration of OXPHOS activity and inhibition of fatty acid oxidation restores TIC susceptibility to chemotherapy drugs.
Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M ...HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients.
Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks q2w), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response.
Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72–1.08; P = 0.20 or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85–1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9–43.1), 30.4% (24.7–36.3), and 30.5% (24.7–36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively.
There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab.
ClinicalTrials.gov: NCT02369874.
•OS was not significantly different for durvalumab or for durvalumab plus tremelimumab compared with SoC.•The study was not designed to assess OS between immunotherapies, but adding tremelimumab did not appear to enhance durvalumab activity.•Failure to meet the primary end point may have been impacted by factors resulting in an unexpectedly long OS for the SoC arm.
The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). ...However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN.
Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m2, followed by 250mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients.
Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7months and progression-free survival was 5.2months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia.
The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population.
UMIN000010507.
Cancer contains tumor-initiating stem-like cells (TICs) that are resistant to therapies. Hepatocellular carcinoma (HCC) incidence has increased twice over the past few decades, while the incidence of ...other cancer types has trended downward globally. Therefore, an understanding of HCC development and therapy resistance mechanisms is needed for this incurable malignancy. This review article describes links between immunotherapies and microbiota in tumor-initiating stem-like cells (TICs), which have stem cell characteristics with self-renewal ability and express pluripotency transcription factors such as NANOG, SOX2, and OCT4. This review discusses (1) how immunotherapies fail and (2) how gut dysbiosis inhibits immunotherapy efficacy. Gut dysbiosis promotes resistance to immunotherapies by breaking gut immune tolerance and activating suppressor immune cells. Unfortunately, this leads to incurable recurrence/metastasis development. Personalized medicine approaches targeting these mechanisms of TIC/metastasis-initiating cells are emerging targets for HCC immunotherapy and microbiota modulation therapy.
ABSTRACT In our previous works, we found absorbed thermal X-ray plasma with kT 0.3 keV observed ubiquitously near the edges of the Fermi bubbles and interpreted this emission as weakly shock-heated ...Galactic halo gas. Here we present a systematic and uniform analysis of archival Suzaku (29 pointings; 6 newly presented) and Swift (68 pointings; 49 newly presented) data within Galactic longitudes < 20° and latitude 5° < 60°, covering the whole extent of the Fermi bubbles. We show that the plasma temperature is constant at kT 0.30 0.07 keV, while the emission measure (EM) varies by an order of magnitude, increasing toward the Galactic center (i.e., low ) with enhancements at the North Polar Spur (NPS), SE-claw, and NW-clump features. Moreover, the EM distribution of kT 0.30 keV plasma is highly asymmetric in the northern and southern bubbles. Although the association of the X-ray emission with the bubbles is not conclusive, we compare the observed EM properties with simple models assuming (i) a filled halo without bubbles, whose gas density follows a hydrostatic isothermal model (King profile), and (ii) a bubble-in-halo in which two identical bubbles expand into the halo, forming thick shells of swept halo gas. We argue that the EM profile in the north (b > 0°) favors (ii), whereas that of the south (b < 0°) is rather close to (i), but a weak excess signature is clearly detected also in the south like NPS (South Polar Spur). Such an asymmetry, if due to the bubbles, cannot be fully understood only by the inclination of bubbles' axis against the Galactic disk normal, thus suggesting asymmetric outflow due to different environmental/initial conditions.
We present Suzaku X-ray observations along two edge regions of the Fermi Bubbles, with eight Asymptotically = to 20 ks pointings across the northern part of the North Polar Spur (NPS) surrounding the ...north bubble and six across the southernmost edge of the south bubble. After removing compact X-ray features, diffuse X-ray emission is clearly detected and is well reproduced by a three-component spectral model consisting of unabsorbed thermal emission (temperature kT Asymptotically = to 0.1 keV) from the Local Bubble, absorbed kT Asymptotically = to 0.3 keV thermal emission related to the NPS and/or Galactic halo (GH), and a power-law component at a level consistent with the cosmic X-ray background. We also derived an upper limit for any non-thermal X-ray emission component associated with the bubbles and demonstrate that, in agreement with the aforementioned findings, the non-thermal pressure and energy estimated from a one-zone leptonic model of its broadband spectrum, are in rough equilibrium with that of the surrounding thermal plasma.
The effect of cyclic deformation on superelasticity was investigated in a Ti–26 at.% Nb alloy. Loading and unloading tensile tests with a constant maximum applied strain of 2.5% were carried out ...until the 500th cycle. The critical stress for inducing the martensitic transformation and superelastic strain decreased, while the accumulated residual strain increased with increasing number of cycles. The increase in the residual strain during cyclic deformation was due mainly to α′′ martensite phase stabilization. Both the residual strain and the residual α′′ martensite phase increased with increasing number of cycles. The stability of superelasticity was improved, i.e. the residual strain decreased and the superelastic strain increased, by intermediate-temperature annealing and/or aging. The specimen annealed at 873
K for 0.6
ks followed by aging at 573
K for 3.6
ks exhibited the most stabilized superelasticity, owing to the combination effect of work hardening and fine ω-phase precipitation.
Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) ...is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.
B-cell infection by hepatitis C virus (HCV) has been a controversial topic. To examine whether HCV has a genetically determined lymphotropism through a co-receptor specific for the infection by ...lymphotropic HCV, we established an infectious clone and chimeric virus of hepatotropic and lymphotropic HCV strains derived from an HCV-positive B-cell lymphoma. The viral envelope and 5'-UTR sequences of the lymphotropic HCV strain were responsible for the lymphotropism. Silencing of the virus sensor, RIGI, or overexpression of microRNA-122 promoted persistent viral replication in B cells. By cDNA library screening, we identified an immune cell-specific, co-stimulatory receptor B7.2 (CD86) as a co-receptor of lymphotropic HCV. Infection of B cells by HCV inhibited the recall reaction to antigen stimulation. Together, a co-receptor B7.2 enabled lymphotropic HCV to infect memory B cells, leading to inhibition of memory B-cell function and persistent HCV infection in HCV-infected hosts.
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