The dynamic cell–cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are ...extracellular vesicles that actively participate in cell–cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the β‐catenin/Tcf‐4‐activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA‐146a‐5p (miR‐146a) is the major miRNA in CRCSC exosomes and exosomal miR‐146a promotes stem‐like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR‐146a expression in serum exhibits higher miR‐146aHigh/NumbLow CRCSC traits, an increased number of tumor‐filtrating CD66(+) neutrophils and a decreased number of tumor‐infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome‐mediated stemness expansion.
What's new?
The tumor microenvironment (TME) is composed of heterogeneous tumor cells and host cells interacting with each other to promote disease progression. However, diagnostic and prognostic biomarkers to monitor the cancer stem cells (CSCs)‐host interplay are lacking. Here, the authors explore the role of tumor exosomes in cancer stemness and demonstrate that RAB27B‐assisted secretion of miRNA‐dominant exosomes is one critical feature of CSCs. Importantly, they show that colorectal cancer stem cells release miR‐146a‐loaded oncogenic exosomes for reprogramming non‐CSC cells and demonstrate the clinical relevance of exosomal miR‐146a in predicting the TME of CRC patients.
Colorectal cancer (CRC) is a major global health concern, with microsatellite instability-high (MSI-H) being a defining characteristic of hereditary nonpolyposis colorectal cancer syndrome and ...affecting 15% of sporadic CRCs. Tumors with MSI-H have unique features and better prognosis compared to MSI-L and microsatellite stable (MSS) tumors. This study proposed establishing a MSI prediction model using more available and low-cost colonoscopy images instead of histopathology. The experiment utilized a database of 427 MSI-H and 1590 MSS colonoscopy images and vision Transformer (ViT) with different feature training approaches to establish the MSI prediction model. The accuracy of combining pre-trained ViT features was 84% with an area under the receiver operating characteristic curve of 0.86, which was better than that of DenseNet201 (80%, 0.80) in the experiment with support vector machine. The content-based image retrieval (CBIR) approach showed that ViT features can obtain a mean average precision of 0.81 compared to 0.79 of DenseNet201. ViT reduced the issues that occur in convolutional neural networks, including limited receptive field and gradient disappearance, and may be better at interpreting diagnostic information around tumors and surrounding tissues. By using CBIR, the presentation of similar images with the same MSI status would provide more convincing deep learning suggestions for clinical use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Altered metabolism is one of the hallmarks of cancers. Deregulation of ribose-5-phosphate isomerase A (RPIA) in the pentose phosphate pathway (PPP) is known to promote tumorigenesis in liver, lung, ...and breast tissues. Yet, the molecular mechanism of RPIA-mediated colorectal cancer (CRC) is unknown. Our study demonstrates a noncanonical function of RPIA in CRC. Data from the mRNAs of 80 patients' CRC tissues and paired nontumor tissues and protein levels, as well as a CRC tissue array, indicate RPIA is significantly elevated in CRC. RPIA modulates cell proliferation and oncogenicity via activation of β-catenin in colon cancer cell lines. Unlike its role in PPP in which RPIA functions within the cytosol, RPIA enters the nucleus to form a complex with the adenomatous polyposis coli (APC) and β-catenin. This association protects β-catenin by preventing its phosphorylation, ubiquitination, and subsequent degradation. The C-terminus of RPIA (amino acids 290 to 311), a region distinct from its enzymatic domain, is necessary for RPIA-mediated tumorigenesis. Consistent with results in vitro, RPIA increases the expression of β-catenin and its target genes, and induces tumorigenesis in gut-specific promotor-carrying RPIA transgenic zebrafish. Together, we demonstrate a novel function of RPIA in CRC formation in which RPIA enters the nucleus and stabilizes β-catenin activity and suggests that RPIA might be a biomarker for targeted therapy and prognosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Interleukin‐17 (IL‐17) is a pro‐inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current ...evidence, IL‐17 binds to interleukin‐17 receptor A (IL‐17RA); however, the role of IL‐17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL‐17RA in human CRC tissues and the progression of CRC in humans and mice.
Methods
The expressions of IL‐17RA and epithelial‐mesenchymal transition (EMT)‐related genes were examined in CRC cells and tissue samples by quantitative real‐time polymerase chain reaction. The role of IL‐17RA in pathogenesis and prognosis was evaluated using a Chi‐squared test, Kaplan–Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor‐bearing mice model was executed to evaluate the role of IL‐17RA in tumor growth, vascularity and population of infiltrating immune cells.
Results
IL‐17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL‐17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL‐17RA expression exhibited significantly worse overall and CRC‐specific survival than those with low IL‐17RA expression. Functional assessment suggested that the knockdown of IL‐17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT‐related gene expression. In a tumor‐bearing mouse model, decreased IL‐17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid‐derived suppressor cells (MDSCs).
Conclusion
Reduced IL‐17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL‐17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL‐17RA expression was identified to be independently associated with the prognosis of patients with CRC.
Abstract
Colorectal cancer (CRC) is one of the most well-known malignancies with high prevalence and poor 5-year survival. Previous studies have demonstrated that a high-fat diet (HFD) is capable of ...increasing the odds of developing CRC. Acrolein, an IARC group 2A carcinogen, can be formed from carbohydrates, vegetable oils, animal fats, and amino acids through the Maillard reaction during the preparation of foods. Consequently, humans are at risk of acrolein exposure through the consumption of foods rich in fat. However, whether acrolein contributes to HFD-induced CRC has not been determined. In this study, we found that acrolein induced oncogenic transformation, including faster cell cycling, proliferation, soft agar formation, sphere formation and cell migration, in NIH/3T3 cells. Using xenograft tumorigenicity assays, the acrolein-transformed NIH/3T3 clone formed tumors. In addition, cDNA microarray and bioinformatics studies by Ingenuity Pathway Analysis pointed to the fact that RAS/MAPK pathway was activated in acrolein-transformed clones that contributed to colon tumorigenesis. Furthermore, acrolein-induced DNA damages (Acr-dG adducts) were higher in CRC tumor tissues than in normal epithelial cells in CRC patients. Notably, CRC patients with higher levels of Acr-dG adducts appeared to have better prognosis. The results of this study demonstrate for the first time that acrolein is important in oncogenic transformation through activation of the RAS/MAPK signaling pathway, contributing to colon tumorigenesis.
Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress ...transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogene, and its expression has been correlated with the prognosis of patients with cancer. In this study, we aimed to explore the relationship between ER stress‐related ATF signaling and CIP2A. We found that CIP2A expression was positively correlated with ATF6 expression by analyzing publicly available RNA sequence data of patients with colorectal cancer (The Cancer Genome Atlas, TCGA). In addition, we demonstrated that tunicamycin‐induced ER stress in vitro upregulated ATF6 and CIP2A. Mechanistically, we found that ATF6 directly bound to the CIP2A promoter and induced CIP2A gene expression, which contributed to colon cancer cell survival. Furthermore, knockdown of CIP2A reduced the viability of cells under ER stress. Most importantly, immunohistochemical analysis of a tissue microarray from a colon cancer patient cohort showed that higher expression levels of ATF6 and CIP2A were associated with a trend toward poor prognosis. Taken together, our results show that ER stress‐related ATF6 upregulates CIP2A and contributes to the prognosis of colon cancer. Targeting CIP2A may disrupt ER stress‐mediated colon cancer cell survival and thus improve the prognosis of patients with colon cancer.
Endoplasmic reticulum (ER) stress induces activating transcription factor 6 (ATF6) that translocates from the ER to the Golgi membrane to release active form of ATF6. The active ATF6 directly binds to the cancerous inhibitor of protein phosphatase 2A (CIP2A) promoter and elicits CIP2A gene expression, which contributes to colon cancer cell survival and the prognosis of colon cancer.
Objectives
Computer-aided diagnosis (CAD)-based artificial intelligence (AI) has been shown to be highly accurate for detecting and characterizing colon polyps. However, the application of AI to ...identify normal colon landmarks and differentiate multiple colon diseases has not yet been established. We aimed to develop a convolutional neural network (CNN)-based algorithm (GUTAID) to recognize different colon lesions and anatomical landmarks.
Methods
Colonoscopic images were obtained to train and validate the AI classifiers. An independent dataset was collected for verification. The architecture of GUTAID contains two major sub-models: the Normal, Polyp, Diverticulum, Cecum and CAncer (NPDCCA) and Narrow-Band Imaging for Adenomatous/Hyperplastic polyps (NBI-AH) models. The development of GUTAID was based on the 16-layer Visual Geometry Group (VGG16) architecture and implemented on Google Cloud Platform.
Results
In total, 7838 colonoscopy images were used for developing and validating the AI model. An additional 1273 images were independently applied to verify the GUTAID. The accuracy for GUTAID in detecting various colon lesions/landmarks is 93.3% for polyps, 93.9% for diverticula, 91.7% for cecum, 97.5% for cancer, and 83.5% for adenomatous/hyperplastic polyps.
Conclusions
A CNN-based algorithm (GUTAID) to identify colonic abnormalities and landmarks was successfully established with high accuracy. This GUTAID system can further characterize polyps for optical diagnosis. We demonstrated that AI classification methodology is feasible to identify multiple and different colon diseases.
Abstract Background The clinicopathological features and frequency of KRAS mutations in colorectal (CRC) patients have been reported; however, the characteristics and impact of NRAS and HRAS ...mutations on the survival of CRC patients has seldom been addressed. Methods Under Institutional Review Board approval, 1519 CRC patients who underwent surgery were enrolled. Mutation status of RAS was determined by polymerase chain reaction and mass spectrophotometry. Results The frequency of KRAS , NRAS , and HRAS mutations was 39.6%, 4.3%, and 1.7%, respectively. The KRAS mutation was associated with fewer left-sided tumors, fewer poor differentiated tumors, more mucin component, and less lymphovascular invasion. The NRAS or HRAS mutations were not associated with any of the clinicopathological features examined. After univariate analysis, only NRAS mutation was associated with patients’ overall and disease-free survival. However, the association of NRAS with patients’ overall and disease-free survival disappeared after stepwise elimination. Conclusions This study demonstrates the clinicopathological characteristics of CRC patients with RAS mutations. Patients with NRAS mutation tended to have worse outcomes.
Background
Taiwan has witnessed a surge in the incidence of colorectal cancer (CRC), of which 40–60% metastasize. Continuous updating of cytoreductive strategies in metastatic CRC (mCRC) has ...contributed to median overall survival reaching 40 months. In this changing scenario, to standardize the approaches across Taiwan, a group of experts from the Taiwan Society of Colon and Rectal Surgeons (TSCRS) convened to establish evidence- and opinion-based recommendations for defining the criteria of “resectability” in mCRC.
Methods
Over the course of one-on-one consultations, lasting 30–40 min each, with 30 medical specialists (19 colorectal surgeons, 4 general surgeons, and 7 medical oncologists) from 16 hospitals in Taiwan followed by a 2-h meeting with 8 physician experts (3 general surgeons, 4 colorectal surgeons, and 1 thoracic surgeon), 12 key questions on cytoreduction were addressed. This was further contextualized based on published literature.
Results
The final consensus includes eight recommendations regarding the criteria for metastasis resection, role of local control treatment in liver potentially resectable patients, management of synchronous liver metastases, approach for peritoneal metastasis, place for resection in multiple-organ metastasis, and general criteria for resectability.
Conclusions
mCRC patients undergoing R0 resection have the greatest survival advantage following surgery. Our role as a multidisciplinary team (MDT) should be to treat potentially resectable mCRC patients as rapidly and safely as possible, and achieve R0 resection as far as possible and for as long as possible (continuum of care). This TSCRS consensus statement aims to help build clinical capacity within the MDTs, while making better use of existing healthcare resources.
Carcinoembryonic antigen (CEA) levels and imaging are used to guide treatment for metastatic colorectal cancer (mCRC). This study evaluated changes in CEA and imaging findings in mCRC patients ...following systemic therapy and their clinical significance, especially the ones with inconsistent results of CEA and image findings. We enrolled 330 stage IV CRC patients who systemic therapy. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) and a modification for CEA, patients were stratified into consistent and inconsistent response groups. Clinicopathological features and prognoses were compared between each groups. Different CEA/IMG groups showed no significant differences in terms of tumor location, initial CEA level, mucinous component, tumor differentiation and further surgical treatment rate. Inconsistent responses were observed in half of the patients (n = 165, 50%). The prognosis in the inconsistent groups with either CEA-SD or IMG-SD was dependent on the result of the other evaluation method (PR or PD). Cases with conflicting results between CEA and image groups (CEA-RD/IMG-PD, CEA-PD/IMG-PR) had an OS close to that of CEA-SD/IMG-SD (18.2 m, 16.2 m vs. 18.8 m, P = 0.620). The overall survival (OS) in the consistent (PR/PR ro PD/PD) groups were significantly different (P < 0.001). Combining CEA and imaging provides more information about mCRC patients who have undergone systemic therapy. Approximately half the patients have inconsistent responses, which is still valuable in predicting the prognosis.
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