The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to ...highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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•Epithelial NOTCH1 signaling drives metastasis in serrated CRC•Poor-prognosis CRC subtypes CMS4/CRIS-B are controlled by NOTCH1•TGF-β-mediated neutrophil infiltration is critical for NOTCH1-driven metastasis•Neutrophil targeting provides therapeutic opportunity in metastatic CRC
In a genetically engineered mouse model, Jackstadt et al. show that NOTCH1 activation drives metastasis in KRASG12D-driven serrated colorectal cancer (CRC) through TGFβ-dependent neutrophil recruitment. Thus, targeting neutrophil recruitment is a potential therapeutic approach in metastatic CRC.
Colorectal cancer (CRC) is the third most common cancer with the second most frequent cause of death worldwide. One fourth to one fifth of the CRC cases are detected at advance stage. Early detection ...of colorectal cancer might help in decreasing mortality and morbidity worldwide. CRC being a heterogeneous disease, new non-invasive approaches are needed to complement and improve the screening and management of CRC. Reliable and early detectable biomarkers would improve diagnosis, prognosis, therapeutic responses, and will enable the prediction of drug response and recurrence risk. Over the past decades molecular research has demonstrated the potentials of CTCs, ctDNAs, circulating mRNAs, ncRNAs, and exosomes as tumor biomarkers. Non-invasive screening approaches using fecal samples for identification of altered gut microbes in CRC is also gaining attention. Exosomes can be potential candidates that can be employed in the drug delivery system. Further, the integration of in vitro, in vivo and in silico models that involve CRC biomarkers will help to understand the interactions occurring at the cellular level. This review summarizes recent update on CRC biomarkers and their application along with the nanoparticles followed by the application of organoid culture in CRC.
•CRC being heterogeneous disease new biomarkers which would improve diagnosis, prognosis, therapeutic responses, and enable the prediction of drug response and recurrence risk is warranted.•Over the past decades molecular research has demonstrated the potentials of CTCs, ctDNAs, circulating mRNA, ncRNAs, exosomes, and gut microbiota as tumor biomarkers (summarized in Fig. 1).•Exosomes can be potential candidates that can be employed in the drug delivery system.•Advances in molecular research have made the screening of KRAS, BRAF, and MSI status as part of of therapeutic planning especially in mCRC patients.•The advances like organoid culture have made advancement for drug screening before giving it to the patients.
Despite their lethality and ensuing clinical and therapeutic relevance, circulating tumor cells (CTCs) from colorectal carcinoma (CRC) remain elusive, poorly characterized biological entities.
We ...perfected a cell system of stable, primary lines from human CRC showing that they possess the full complement of ex- and in-vivo, in xenogeneic models, characteristics of CRC stem cells (CCSCs). Here we show how tumor-initiating, CCSCs cells can establish faithful orthotopic phenocopies of the original disease, which contain cells that spread into the circulatory system. While in the vascular bed, these cells retain stemness, thus qualifying as circulating CCSCs (cCCSCs). This is followed by the establishment of lesions in distant organs, which also contain resident metastatic CCSCs (mCCSCs).
Our results support the concept that throughout all the stages of CRC, stemness is retained as a continuous property by some of their tumor cells. Importantly, we describe a useful standardized model that can enable isolation and stable perpetuation of human CRC's CCSCs, cCCSCs and mCCSCs, providing a useful platform for studies of CRC initiation and progression that is suitable for the discovery of reliable stage-specific biomarkers and the refinement of new patient-tailored therapies.
This work was financially supported by grants from “Ministero della Salute Italiano”(GR-2011-02351534, RC1703IC36 and RC1803IC35) to Elena Binda and from “Associazione Italiana Cancro” (IG-14368) Angelo L. Vescovi. None of the above funders have any role in study design, data collection, data analysis, interpretation, writing the project.
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•This study delves into key genes that contribute to 5-FU resistance in colorectal cancer, as well as potential therapeutic agents.•A risk signature model (ACOX1 and ITGA2) associated ...with 5-FU resistance constructed using machine learning have diagnostic value in predicting 5-FU resistance.•ITGA2 was expressed in malignant cells and promoted 5-FU resistance and cell growth in CRC cells.•ITGA2 expression was nagetively associated with selumetinib treatment.
Colorectal cancer (CRC) is the third most malignant tumor in the world. 5-fluorouracil (5‑FU) -based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. Therefore, identification of genes associated with 5‑FU chemotherapy and seeking second-line treatment are necessary means to improve survival and prognosis of patients with CRC.
The Cancer Therapeutics Response Portal (CTRP) database and Genomics of Drug Sensitivity in Cancer (GDSC) database were used to identify CRC-related genes and potential second-line therapies for 5-FU-resistant CRC. The single-cell RNA sequencing data for CRC tissues were obtained from a GEO dataset. The relationship between ITGA2 and 5-FU-resistant was investigated in vitro and in vivo models.
ACOX1 and ITGA2 were identified as risk biomarkers associated with 5-FU-resistance. We developed a risk signature, consisting of ACOX1 and ITGA2, that was able to distinguish well between 5-FU-resistance and 5-FU-sensitive. The single-cell sequencing data showed that ITGA2 was mainly enriched in malignant cells. ITGA2 was negatively correlated with IC50 values of most small molecule inhibitors, of which selumetinib had the highest negative correlation. Finally, knocking down ITGA2 can make 5-FU-resistant CRC cells sensitive to 5-FU and combining with selumetinib can improve the therapeutic effect of 5-FU resistant cells.
In summary, our findings demonstrated the critical role of ITGA2 in enhancing chemotherapy resistance in CRC cells and suggested that selumetinib can restore the sensitivity of chemotherapy-resistant CRC cells to 5-FU by inhibiting ITGA2 expression.
Background: Colorectal cancer (CRC) is the third common diagnosed. cancer in the world, so that colonic polyp detection is important because colonic polyp is a precursor to CRC.
Objective: To ...detect the prevalence of polyp and adenoma.
Patients and Methods: A retrospective study was done using reports of endoscopic examination done previously for patients seen at gasteroenterology and hepatology hospital in Baghdad.
Results: The study included 924 examination of colon, mean age of patients was 48.1 years. Polyps was detected in 128 colonoscopies. (PDR) was 16.7 %. The PDR was higher in patients ≥ 60 years old (25 %), while polyp detection rate was ( 17.7 % ) in those 50 – 59 years age group. Adenoma was found in 7.9 % of those with completed colonoscopies. It was higher in male patients (9.2 % ) than female patients (6.2%). It was highest in age group ≥ 60 years old (15.9%), while adenoma was found in (8.2 %) of those with age group of 50 – 59 years old.
Conclusion: This study highlight on the prevalence of polyp (16.7%) and adenomas (7.9%) in patients underwent endoscopy for different indications, and give us an idea about screening for CRC in Iraq and at which age it should be started.
Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in ...mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.
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•mutp53 R248Q, the most common p53 mutant in human CRC, promotes CRC in mice•mutp53 R248Q binds to and deregulates Stat3, correlating with poor patient survival•Genetic ablation of mutp53 R248Q reduces growth and invasion of established CRCs•Hsp90 inhibition reduces the mutp53 R248Q level and inhibits CRC progression
Schulz-Heddergott et al. show that the most common p53 mutant R248Q (mutp53) enhances Stat3 activation by binding to Stat3 and displacing SHP2 in colorectal cancer cells. Reduction of mutp53 genetically or by using the HSP90 inhibitor 17AAG reduces Stat3 signaling and the growth of mutp53-driven tumors.
Colorectal cancer has served as a genetic and biological paradigm for the evolution of solid tumors, and these insights have illuminated early detection, risk stratification, prevention, and ...treatment principles. Employing the hallmarks of cancer framework, we provide a conceptual framework to understand how genetic alterations in colorectal cancer drive cancer cell biology properties and shape the heterotypic interactions across cells in the tumor microenvironment. This review details research advances pertaining to the genetics and biology of colorectal cancer, emerging concepts gleaned from immune and single-cell profiling, and critical advances and remaining knowledge gaps influencing the development of effective therapies for this cancer that remains a major public health burden.
As technology scales down, circuits are more prone to incur in faults and fault detection is necessary to ensure the system reliability. However, fault-detection circuits are also vulnerable to ...stuck-at faults due to, for example, manufacturing defects or ageing; a fault can cause an incorrect output in the fault-detection scheme; so concurrent fault detection is, therefore, needed. Cyclic redundancy checks (CRCs) are widely used to detect errors in many applications, for example, they are used in communication to detect errors on transmitted frames. In this study, an efficient method to implement concurrent fault detection for parallel CRC computation is proposed. The scheme relies on using a serial CRC computation circuit that is used to periodically check the results obtained from the main module to detect the faults. This introduces a lower circuit overhead than existing schemes. All CRC encoders and decoders that implement the CRC computation in parallel can employ the proposed scheme to detect faults.
Predicting the prognosis of colorectal cancer (CRC) is challenging since these tumors exhibit a wide range of biological behaviors. It has been hypothesized that caudal-related homeobox gene 2 ...(CDX2), which is vital for intestinal growth and maintenance, has a tumor-suppressing effect and promising role in CRC prognosis but studies are still controversial. This study used the immunohistochemical (IHC) staining method to determine the expression of the CDX2 protein in mucinous and non-mucinous CRC adenocarcinoma, as well as in normal colorectal tissues as a control, and correlate this expression with clinicopathological features such as grade, tumor distant metastasis, tumor site, histological type, lymph node metastasis, tumor invasion, sex, age, and rate of 4 years Overall survival (OS) after diagnosis. A total of sixty three tissue samples were obtained from CRC patients (58.90±14.94) years and embedded in wax and thirty-seven normal non-tumoural colorectal tissue samples with (56.43±12.28) years as a control group. CDX2 protein expression decreased significantly (p<0.05) in CRC patients than control, advanced age, mucinous pattern of CRC, moderate and poorly differentiated grades, lymph node metastasis, advanced tumor invasion (T3, T4), and organs metastasis. Moreover, the (OS) for patients with low CDX2 expression was (17.943±1.7) months compared to (33.431±2.7) months for those with high CDX2 expression (p = 0.0001). This study concluded that protein expression of CDX2 is regarded as a prognostic and diagnostic marker for CRC patients.
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