(
) is a keystone periodontal pathogen associated with various digestive cancers. However, whether
can promote colorectal cancer and the underlying mechanism associated with such promotion remains ...unclear. In this study, we found that
was enriched in human feces and tissue samples from patients with colorectal cancer compared with those from patients with colorectal adenoma or healthy subjects. Cohort studies demonstrated that
infection was associated with poor prognosis in colorectal cancer.
increased tumor counts and tumor volume in the
mouse model and increased tumor growth in orthotopic rectal and subcutaneous carcinoma models. Furthermore, orthotopic tumors from mice exposed to
exhibited tumor-infiltrating myeloid cell recruitment and a proinflammatory signature.
promoted colorectal cancer via NLRP3 inflammasome activation
and
. NLRP3 chimeric mice harboring orthotopic tumors showed that the effect of NLRP3 on
pathogenesis was mediated by hematopoietic sources. Collectively, these data suggest that
contributes to colorectal cancer neoplasia progression by activating the hematopoietic NLRP3 inflammasome. SIGNIFICANCE: This study demonstrates that the periodontal pathogen
can promote colorectal tumorigenesis by recruiting myeloid cells and creating a proinflammatory tumor microenvironment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2745/F1.large.jpg.
Oncogenic KRAS has been previously identified to act in a cell-intrinsic manner to modulate multiple biological functions of colorectal cancer (CRC). Here, we demonstrate a cell-extrinsic role of ...KRAS, where KRAS engages with the tumor microenvironment by functional reprogramming of tumor-associated macrophages (TAMs). In human CRC specimens, mutant KRAS positively correlates with the presence of TAMs. Mutationally activated KRAS in tumor cells reprograms macrophages to a TAM-like phenotype via a combination effect of tumor-derived CSF2 and lactate. In turn, KRAS-reprogrammed macrophages were shown to not only promote tumor progression but also induce the resistance of tumor cells to cetuximab therapy. Mechanistically, KRAS drives the production of CSF2 and lactate in tumor cells by stabilizing hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls the expression of CSF2 and glycolytic genes. Mutant KRAS increased the production of reactive oxygen species, an inhibitor of prolyl hydroxylase activity which decreases HIF-1α hydroxylation, leading to enhanced HIF-1α stabilization. This cell-extrinsic mechanism awards KRAS a critical role in engineering a permissive microenvironment to promote tumor malignancy, and may present new insights on potential therapeutic defense strategies against mutant KRAS tumors.
Exosomes from extracellular vesicles can activate or inhibit various signaling pathways by transporting proteins, lipids, nucleic acids and other substances to recipient cells. In addition, exosomes ...are considered to be involved in the development and progression of tumors from different tissue sources in numerous ways, including remodeling of the tumor microenvironment, promoting angiogenesis, metastasis, and invasion, and regulating the immune escape of tumor cells. However, the precise molecular mechanisms by which exosomes participate in these different processes remains unclear. In this review, we describe the research progress of tumor cell-derived exosomes in cancer progression. We also discuss the prospects of the application of exosomes combined with nanoengineered chemotherapeutic drugs in the treatment of cancer.
Screening for early‐stage disease is vital for reducing colorectal cancer (CRC)‐related mortality. Methylation of circulating tumor DNA has been previously used for various types of cancer screening. ...A novel cell‐free DNA (cfDNA) methylation‐based model which can improve the early detection of CRC is warranted. For our study, we collected 313 tissue and 577 plasma samples from patients with CRC, advanced adenoma (AA), non‐AA and healthy controls. After quality control, 187 tissue DNA samples (91 non‐malignant tissue from CRC patients, 26 AA and 70 CRC) and 489 plasma cfDNA samples were selected for targeted DNA methylation sequencing. We further developed a cfDNA methylation model based on 11 methylation biomarkers for CRC detection in the training cohort (area under curve AUC = 0.90 (0.85–0.94) and verified the model in the validation cohort (AUC = 0.92 0.88–0.96). The cfDNA methylation model robustly detected patients pre‐diagnosed with early‐stage CRC (AUC = 0.90 0.86–0.95) or AA (AUC = 0.85 0.78–0.91). Here we established and validated a non‐invasive cfDNA methylation model based on 11 DNA methylation biomarkers for the detection of early‐stage CRC and AA. The utilization of the model in clinical practice may contribute to the early diagnosis of CRC.
Cell‐free DNA (cfDNA) methylation is promising for colorectal cancer (CRC) screening. In this study, after DNA methylation sequencing of tissue and plasma samples, we established a cfDNA methylation model based on 11 DNA methylation biomarkers for the detection of early‐stage CRC and advanced adenoma. The utilization of the model may contribute to the non‐invasive early diagnosis of CRC.
Adipose‐derived stem cells (ADSCs) play a vital role in colorectal cancer (CRC) progression, but the mechanism remains largely unknown. Herein, we found that ADSCs isolated from CRC patients produced ...more cysteine‐rich 61 (Cyr61) than those from healthy donors, and the elevated serum Cyr61 levels were associated with advanced TNM stages. Moreover, serum Cyr61 displayed a better diagnostic value for CRC compared to carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19‐9). Mechanistically, integrin αVβ5 was identified as the functional receptor by which Cyr61 promotes CRC cell metastasis in vitro and in vivo by activating the αVβ5/FAK/NF‐κB signaling pathway. In addition, Cyr61 promotes vasculogenic mimicry (VM) formation, thereby promoting tumor growth and metastasis through a αVβ5/FAK/HIF‐1α/STAT3/MMP2 signaling cascade. Histologically, xenografts and clinical samples of CRC both exhibited VM, which was correlated with HIF‐1α and MMP2 activation. Notably, we demonstrated the synergistic effect of combined anti‐VM therapy (integrin αVβ5 inhibitor) and anti‐VEGF therapy (bevacizumab) in patient‐derived xenograft models. Further investigation showed that CRC cell‐derived exosomal STAT3 promoted Cyr61 transcription in ADSCs. These findings indicate that Cyr61 derived from ADSCs plays a critical role in promoting CRC progression via integrin αVβ5 and provides a novel antitumor strategy by targeting Cyr61/αVβ5.
Cysteine‐rich 61 (Cyr61) derived from adipose‐derived stem cells (ADSCs) promotes colorectal cancer (CRC) metastasis and vasculogenic mimicry via binding to the integrin αVβ5 receptor and activating the FAK signaling pathway. In turn, CRC cell‐derived exosomal STAT3 and p‐STAT3 promote Cyr61 transcription in ADSCs. These findings suggest that targeting of Cyr61/αVβ5 may serve as a novel antitumor strategy in patients with CRC.
Mutant KRAS (KRAS
) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) ...from KRAS
cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRAS
tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8
T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.
Background
The aim of this study was to evaluate the experience of surgery in IBD patients during the COVID pandemic.
Methods
A survey was distributed among patients undergoing IBD-related surgeries ...from January 2020 to March 2020 via an online platform. The response was submitted anonymously.
Results
A total of 78 patients responded to the survey. COVID-19 testing was conducted in 60 (76.9%) patients, and they were all tested negative. Emergent surgery was performed in 12 (15.4%) patients and postponed surgery in 18 (23.1%) patients. The surgical indications were mainly bowel obstruction (
N
= 21, 26.9%) and perianal abscess (
N
= 18, 23.1%). Postoperative complications were noted in 5.1% of cases, but no re-operation was required. Due to the ongoing COVID pandemic, 58 (74.4%) patients reported various levels of concern and anxiety for surgery.
Conclusions
Common surgical indications were for bowel obstruction and perianal abscess. Surgery can be postponed, but disease progression should be monitored closely and surgically intervened as needed. Most patients expressed anxiety resulting from the pandemic. The overall experience was satisfactory.
We aimed to identify a signature comprising N6-methyladenosine (m6A)-related long non-coding RNAs (lncRNAs) and molecular subtypes associated with breast cancer (BRCA). We obtained data of BRCA ...samples from The Cancer Genome Atlas database. The m6A-related lncRNA prognostic signature (m6A-LPS) included 10 lncRNAs previously identified as prognostic m6A-related lncRNAs and was constructed using integrated bioinformatics analysis and validated. Accordingly, a risk score based on the m6A-LPS signature was established and shown to confirm differences in survival between high-risk and low-risk groups. Three distinct genotypes were identified, whose characteristics included features of the tumor immune microenvironment in each subtype. Our results indicated that patients in Cluster 2 might have a worse prognostic outcome than those in other clusters. The three genotypes and risk subgroups were enriched in different biological processes and pathways, respectively. We then constructed a competing endogenous RNA network based on the prognostic m6A-related lncRNAs. Finally, we validated the expression levels of target lncRNAs in 72 clinical samples. In summary, the m6A-LPS and the potentially novel genotype may provide a theoretical basis for further study of the molecular mechanism of BRCA and may provide novel insights into precision medicine.
With the growing popularity of portable and wearable smart electronics, the electromagnetic shielding materials with high shielding effectiveness (SE) as well as light weight and excellent mechanical ...strength are in high. In this work, the PEDOT:PSS‐based free‐standing conducting film with superior conductivity and mechanical strength is prepared through a facile fabrication. The cellulose nanofibers (CNFs) are first introduced to induce an orderly grow and stack of the PEDOT grains. A phosphoric acid immersion process is then employed to remove the insulating CNF and PSS in the film. The obtained free‐standing conducting film shows a record conductivity of 3508 S cm−1 and its elongation at break reaches 3.75%. Encouragingly, the film delivers an excellent electromagnetic interference (EMI) shielding behavior with a SE of 49 dB in the X‐band (8.2–12.4 GHz) at a thickness of 4 µm. The superior conductivity, mechanical strength, and high SE as well as its facile solution processability make this free‐standing conducting film to be an attractive EMI material for portable and wearable smart electronics.
A densely packed free‐standing PEDOT:PSS film with superior conductivity and mechanical strength is prepared. The free‐standing film exhibits an excellent electromagnetic interference shielding behavior with a shielding effectiveness of 49 dB in the X‐band and is envisioned to bwoven into clothing to protect the human body from electromagnetic damage.
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