Corrigendum: Intratumor tertiary lymphatic structure evaluation predicts the prognosis and immunotherapy response of patients with colorectal cancer.

[This corrects the article DOI: 10.3389/fimmu.2024.1302903.].

Prognostic impact of myosteatosis in patients with colorectal cancer undergoing curative surgery: an updated systematic review and meta-analysis.

Background: Colorectal cancer (CRC) is a global health concern, and identifying prognostic factors can improve outcomes. Myosteatosis is fat infiltration into muscles and is a potential predictor of the survival of patients with CRC. Methods: This systematic review and meta-analysis aimed to assess the prognostic role of myosteatosis in CRC. PubMed, Embase, and Cochrane CENTRAL were searched up to 1 August 2023, for relevant studies, using combinations of the keywords CRC, myosteatosis, skeletal muscle fat infiltration, and low skeletal muscle radiodensity. Case-control, prospective, and retrospective cohort studies examining the association between myosteatosis and CRC outcomes after curative intent surgery were eligible for inclusion. Primary outcomes were overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). Results: A total of 10 studies with a total of 9,203 patients were included. The pooled hazard ratio (HR) for OS (myosteatosis vs. no myosteatosis) was 1.52 [95% confidence interval (CI), 1.38-1.67); for CSS, 1.67 (95% CI, 1.40-1.99); and for DFS, 1.89 (95% CI, 1.35-2.65). Conclusion: In patients with CRC undergoing curative intent surgery, myosteatosis is associated with worse OS, CSS, and DFS. These findings underscore the importance of evaluating myosteatosis in patients with CRC to improve outcomes.

M6A-modified lncRNA FAM83H-AS1 promotes colorectal cancer progression through PTBP1.

LncRNA plays a crucial role in cancer progression and targeting, but it has been difficult to identify the critical lncRNAs involved in colorectal cancer (CRC) progression. We identified FAM83H-AS1 as a tumor-promoting associated lncRNA using 21 pairs of stage IV CRC tissues and adjacent normal tissues. In vitro and in vivo experiments revealed that knockdown of FAM83H-AS1 in CRC cells inhibited tumor proliferation and metastasis, and vice versa. m6A modification is critical for FAM83H-AS1 RNA stability through the writer METTL3 and the readers IGF2BP2/IGFBP3. PTBP1-an RNA binding protein-is responsible for the FAM83H-AS1 function in CRC. T4 (1770-2440nt) and T5 (2440-2743nt) on exon 4 of FAM83H-AS1 provide a platform for PTBP1 RRM2 interactions. Our results demonstrated that m6A modification dysregulated the FAM83H-AS1 oncogenic role by phosphorylated PTBP1 on its RNA splicing effect. In patient-derived xenograft models, ASO-FAM83H-AS1 significantly suppressed the growth of gastrointestinal (GI) tumors, not only CRC but also GC and ESCC. The combination of ASO-FAM83H-AS1 and oxaliplatin/cisplatin significantly suppressed tumor growth compared with treatment with either agent alone. Notably, there was pathological complete response in all these three GI cancers. Our findings suggest that FAM83H-AS1 targeted therapy would benefit patients primarily receiving platinum-based therapy in GI cancers.

Chemotherapy Rechallenge or Reintroduction Compared to Regorafenib or Trifluridine/Tipiracil for Pretreated Metastatic Colorectal Cancer Patients: A Propensity Score Analysis of Treatment Beyond Second Line (Proserpyna Study).

BACKGROUND: The optimal treatment for metastatic colorectal cancer (mCRC) beyond second line is still questioned. Besides the standard of care agents (regorafenib, REG, or trifluridine/tipiracil, FTD/TPI), chemotherapy rechallenge or reintroduction (CTr/r) are commonly considered in clinical practice, despite weak supporting evidence. The prognostic performance of CTr/r, REG and FTD/TPI in this setting are herein evaluated. PATIENTS AND METHODS: PROSERpYNa is a multicenter, observational, retrospective study, in which patients with refractory mCRC, progressing after at least 2 lines of CT, treated with CTr/r, REG or FTD/TPI, are considered eligible and were enrolled in 2 independent data sets (exploratory and validation). Primary endpoint was overall survival (OS); secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (RR) and safety. A propensity score adjustment was accomplished for survival analyses. RESULTS: Data referring to patients treated between Jan-10 and Jan-19 from 3 Italian institutions were gathered (341 and 181 treatments for exploratory and validation data sets respectively). In the exploratory cohort, median OS (18.5 vs. 6.5 months), PFS (6.1 vs. 3.5 months) and RR (28.6% vs. 1.4%) were significantly longer for CTr/r compared to REG/FTD/TPI. Survival benefits were retained at the propensity score analysis, adjusted for independent prognostic factors identified at multivariate analysis. Moreover, these results were confirmed within the validation cohort analyses. CONCLUSIONS: Although the retrospective fashion, CTr/r proved to be a valuable option in this setting in a real-world context, providing superior outcomes compared to standard of care agents at the price of a moderate toxicity.

Research progress of DNA methylation in colorectal cancer (Review).

DNA methylation is one of the earliest and most significant epigenetic mechanisms discovered. DNA methylation refers, in general, to the addition of a methyl group to a specific base in the DNA sequence under the catalysis of DNA methyltransferase, with S­adenosine methionine as the methyl donor, via covalent bonding and chemical modifications. DNA methylation is an important factor in inducing cancer. There are different types of DNA methylation, and methylation at different sites plays different roles. It is well known that the progression of colorectal cancer (CRC) is affected by the methylation of key genes. The present review did not only discuss the potential relationship between DNA methylation and CRC but also discussed how DNA methylation affects the development of CRC by affecting key genes. Furthermore, the clinical significance of DNA methylation in CRC was highlighted, including that of the therapeutic targets and biomarkers of methylation; and the importance of DNA methylation inhibitors was discussed as a novel strategy for treatment of CRC. The present review did not only focus upon the latest research findings, but earlier reviews were also cited as references to older literature.

Abdominal wound length influences the postoperative serum level of interleukin-6 and recovery of flatus passage among patients with colorectal cancer.

Introduction: A mini-laparotomy for colorectal cancer (CRC) has been reported to shorten postoperative ileus (POI) and hospital stay. Interleukin-6 (IL-6) plays a role in intestinal tissue inflammation, leading to POI. This study investigated the effects of abdominal wounds and IL-6 levels on POI in patients having CRC surgery. Materials and methods: Forty-three patients with CRC underwent bowel resection. Serum samples were collected preoperatively and at 2, 24, and 48 h after surgery for cytokine quantification by ELISA. Clinical data, including time from surgery to first passage of flatus and postoperative hospital stay, demographic and pathological data, and routine blood tests, were compared statistically with abdominal wound length and the postoperative increments of cytokines (designated as Δ). Results: The length of the abdominal wound showed a significant correlation with clinical variables (length of operation time, time of first flatus passage, and length of postoperative hospital stay) and cytokine variables (IL-6(Δ2 h), IL-8(Δ2 h) and IL-10(Δ2 h). Linear regression analysis showed that the abdominal wound length significantly influenced the operation time, time of first flatus passage, and length of postoperative hospital stay (p < 0.001). The length of the abdominal wound showed a significant influence on the IL-6(Δ2 h) and IL-8(Δ2 h) (p < 0.001, respectively) but no influence on IL-10(Δ2 h). IL-6(Δ2 h), but not IL-8(Δ2 h), significantly influenced the time to first flatus passage and length of hospital stay (p = 0.007, p = 0.006, respectively). The mini-laparotomy approach (wound length <7 cm) led to significantly shortened operation time, time of first flatus passage, length of postoperative stay (p = 0.004, p = 0.003, p = 0.006, respectively) as well as reduced postoperative increment of IL-6(Δ2 h) (p = 0.015). The mini-laparotomy for anterior resection surgery significantly influenced operation time, time of first passage of flatus, length of postoperative stay, and IL-6(Δ2 h). Conclusion: Our study is the first to report the complex interaction among the length of the abdominal wound, IL-6 serum level, recovery of the first passage of flatus, and postoperative hospital stay. These results suggest that smaller abdominal wounds and smaller postoperative IL-6 increments were associated with faster recovery of flatus passage and shorter hospital stays.

Decoding immune-related gene-signatures in colorectal neoplasia.

Background: Colorectal cancer (CRC) is a significant health issue, with notable incidence rates in Norway. The immune response plays a dual role in CRC, offering both protective effects and promoting tumor growth. This research aims to provide a detailed screening of immune-related genes and identify specific genes in CRC and adenomatous polyps within the Norwegian population, potentially serving as detection biomarkers. Methods: The study involved 69 patients (228 biopsies) undergoing colonoscopy, divided into CRC, adenomatous polyps, and control groups. We examined the expression of 579 immune genes through nCounter analysis emphasizing differential expression in tumor versus adjacent non-tumorous tissue and performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) across patient categories. Results: Key findings include the elevated expression of CXCL1, CXCL2, IL1B, IL6, CXCL8 (IL8), PTGS2, and SPP1 in CRC tissues. Additionally, CXCL1, CXCL2, IL6, CXCL8, and PTGS2 showed significant expression changes in adenomatous polyps, suggesting their early involvement in carcinogenesis. Conclusions: This study uncovers a distinctive immunological signature in colorectal neoplasia among Norwegians, highlighting CXCL1, CXCL2, IL1B, IL6, CXCL8, PTGS2, and SPP1 as potential CRC biomarkers. These findings warrant further research to confirm their role and explore their utility in non-invasive screening strategies.

The survival prediction of advanced colorectal cancer received neoadjuvant therapy-a study of SEER database.

PURPOSE: The aim of study was to screen factors associated with the overall survival of colorectal cancer patients with lymph nodes metastasis who received neoadjuvant therapy and construct a nomogram model. METHODS: All enrolled subjects of the SEER database were randomly assigned to the training and testing group in a ratio of 3:2. The patients of Tangdu Hospital were seemed as validation group. Univariate cox regression analysis, lasso regression and random forest survival were used to screen variables related to the survival of advanced CRC patients received neoadjuvant therapy in the training group. Area under curves were adopted to evaluate the 1,3,5-year prediction value of the optimal model in three cohorts. Calibration curves were drawn to observe the prediction accuracy of the nomogram model. Decision curve analysis was used to assess the potential clinical value of the nomogram model. RESULTS: A total of 1833 subjects were enrolled in this study. After random allocation, 1055 cases of the SEER database served as the training group, 704 cases as the testing group and 74 patients from our center as the external validation group. Variables were screened by univariate cox regression used to construct a nomogram survival prediction model, including M, age, chemotherapy, CEA, perineural invasion, tumor size, LODDS, liver metastasis and radiation. The AUCs of the model for predicting 1-year OS in the training group, testing and validation group were 0.765 (0.703,0.827), 0.772 (0.697,0.847) and 0.742 (0.601,0.883), predicting 3-year OS were 0.761 (0.725,0.780), 0.742 (0.699,0.785), 0.733 (0.560,0.905) and 5-year OS were 0.742 (0.711,0.773), 0.746 (0.709,0.783), 0.838 (0.670,0.980), respectively. The calibration curves showed the difference between prediction probability of the model and the actual survival was not significant in three cohorts and the decision curve analysis revealed the practice clinical application value. And the prediction value of model was better for young CRC than older CRC patients. CONCLUSION: A nomogram model including LODDS for the prognosis of advanced CRC received neoadjuvant therapy was constructed and verified based on the SEER database and single center practice. The accuracy and potential clinical application value of the model performed well, and the model had better predictive value for EOCRC than LOCRC.

Increase in GPIHBP1 expression in advanced stage colorectal cancer indicates poor immune surveillance.

Background: Glycosylphosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) plays a crucial role in fatty acid metabolism, which is involved in the progression of colorectal cancer (CRC). The aim of this study was to determine the expressional variations of GPIHBP1 in CRC at different stages and to verify whether this protein affects the shaping of the immune microenvironment of cancer cells. Methods: Variations of GPIHBP1 messenger RNA (mRNA) levels were first analysed using The Cancer Genome Atlas (TCGA) database. Protein levels of GPIHBP1 in cancer nest cells, stromal cells or surrounding normal tissues from 68 patients with CRC were checked by immunohistochemistry. Infiltration of immune cells such as macrophages, myeloid-derived suppressor cells (MDSCs), CD8+ and CD56+ cells was parallelly stained in the same tissues. Ectopic GPIHBP1 expressed colonic tumour cells were transplanted into the back of mice. Tumour growth and immune cell infiltrations were also observed. Results: Compared with those in healthy tissues, GPIHBP1 mRNA and protein levels decreased in the patients with CRC at Dukes A-B stage but gradually increased in the patients at Dukes C-D stage. GPIHBP1 in foci or stroma was positively correlated with recruited macrophages or MDSCs and negatively correlated with recruited CD8+, CD56+ or granzyme+ cells. The mice injected with GPIHBP1 overexpression cells bore large tumours. Histological analysis confirmed the infiltration of many macrophages and MDSCs but less CD8+ T or CD56+ cells. Conclusions: The increased expression of GPIHBP1 is involved in the progression of CRC. High GPIHBP1 level of advanced CRC indicates efficient immune evasion in tumour microenvironment.

Construction of a new prognostic model for colorectal cancer based on bulk RNA-seq combined with The Cancer Genome Atlas data.

Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths, and improving the prognosis of CRC patients is an urgent concern. The aim of this study was to explore new immunotherapy targets to improve survival in CRC patients. Methods: We analyzed CRC-related single-cell data GSE201348 from the Gene Expression Omnibus (GEO) database, and identified differentially expressed genes (DEGs). Subsequently, we performed differential analysis on the rectum adenocarcinoma (READ) and colon adenocarcinoma (COAD) transcriptome sequencing data [The Cancer Genome Atlas (TCGA)-CRC queue] and clinical data downloaded from TCGA database. Subgroup analysis was performed using CIBERSORTx and cluster analysis. Finally, biomarkers were identified by one-way cox regression as well as least absolute shrinkage and selection operator (LASSO) analysis. Results: In this study, we analyzed CRC-related single-cell data GSE201348, and identified 5,210 DEGs. Subsequently, we performed differential analysis on the TCGA-CRC queue database, and obtained 4,408 DEGs. Then, we categorized the cancer samples in the sequencing data into three groups (k1, k2, and k3), with significant differences observed between the k1 and k2 groups via survival analysis. Further differential analysis on the samples in the k1 and k2 groups identified 1,899 DEGs. A total of 77 DEGs were selected among those DEGs obtained from three differential analyses. Through subsequent Cox univariate analysis and LASSO analysis, seven biomarkers (RETNLB, CLCA4, UGT2A3, SULT1B1, CCL24, BMP5, and ATOH1) were identified and selected to establish a risk score (RS). Conclusions: To sum up, this study demonstrates the potential of the seven-gene prognostic risk model as instrumental variables for predicting the prognosis of CRC.

Value analysis of ITLN1 in the diagnostic and prognostic assessment of colorectal cancer.

Background: Colorectal cancer (CRC) remains the leading cause of cancer death worldwide. Less than half of the patients are diagnosed when the cancer is locally advanced. Several studies have shown that intelectin-1 (ITLN1) can serve as a key prognostic and therapeutic target for CRC. The purpose of this study was to investigate the clinical value of ITLN1 in CRC and to analyse its potential as a predictive biomarker for CRC. Methods: Colon adenocarcinoma (COAD) is the main type of CRC. COAD project in The Cancer Genome Atlas (TCGA) database served as the training cohort, and GSE39582 series in the Gene Expression Omnibus (GEO) database served as the external independent validation cohort. First, the difference in the expression level of ITLN1 between COAD tissue and normal tissue was analysed, and the results were verified via immunohistochemistry. The relationship between ITLN1 expression and the prognosis of COAD patients was evaluated via the heatmap and the Kaplan-Meier (KM) curve. The ITLN1 coexpressed gene set obtained by Pearson correlation analysis was used. The prognostic signatures that were significantly correlated with survival status were screened by Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Finally, a nomogram related to ITLN1 was constructed based on the risk score of the prognostic signature and routine clinicopathological variables. Results: ITLN1 is significantly underexpressed in tumour tissues and can be used as a valuable tool to distinguish COAD. The high-expression group of ITLN1 was verified to have a greater survival rate. ITLN1 is significantly associated with a good prognosis in COAD patients. Six candidate genes (ITLN1 and MORC2, SH2D7, LGALS4, ATOH1, and NAT2) were selected for use in the Cox-LASSO regression analysis to calculate the risk score. Finally, a nomogram was constructed with a comprehensive risk score and clinicopathologic factors to successfully predict and verify the 1-year, 3-year, and 5-year survival probability. Conclusions: Our study established ITLN1 as an effective tool for CRC screening, diagnosis, and prognostic assessment, provided a basis for further study of the molecular function of ITLN1, and provided new insights for the mechanistic exploration and treatment of CRC.

Minimal residual disease monitoring via ctDNA: a case report of Lynch syndrome with synchronous colorectal cancer and review of literature.

Background: The investigation of circulating tumor DNA (ctDNA) as a substitute for minimal residual disease (MRD) has been a central focus in various clinical trials, with findings highlighting its effectiveness as a sensitive marker for detecting recurrence. In 2018, a joint review by the American Society of Clinical Oncology and the College of American Pathologists acknowledged a lack of current evidence guiding clinical decisions regarding ctDNA. Nevertheless, there are a multitude of ongoing studies exploring the future applications of ctDNA and its role in clinical decision making for select patient populations. Case Description: The case presented involves a patient with Lynch syndrome who developed synchronous left-sided colorectal cancers (CRC). Each primary malignancy exhibited a distinct mutational profile, introducing complexity to the personalized tumor-informed assays used for quantifying ctDNA levels. Initial ctDNA levels were negative until the assay was calibrated to the transverse colon primary tumor. Unfortunately, surveillance imaging showed radiographic recurrence coinciding with positive ctDNA findings. Treatment with the anti-PD-1 inhibitor pembrolizumab was initiated, resulting in the clearance of ctDNA after just four cycles. As of now, there is no radiographic or biologic evidence indicating disease recurrence. Conclusions: This case study sheds light on the evolving landscape and current limitations of ctDNA as a surrogate for MRD. We describe a patient with synchronous CRC who had radiographic recurrence and a negative MRD assay. Current tumor-informed assays are limited in their capacity to detect a single tumor, and by nature can miss both synchronous and metachronous malignancies. Assays tailored to multiple tumors or utilizing tumor agnostic methods should be a part of clinical decision making in this patient population.

The roles and mechanisms of APOL1 in the development of colorectal cancer.

Background: Research has demonstrated that apolipoprotein L1 (APOL1) has a role in the emergence and progression of a number of malignant cancers. It is unclear, however, how APOL1 functions in colorectal cancer (CRC). In this study, we examined the possible molecular processes underlying APOL1's biological role in CRC. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to identify APOL1 expression in patients with CRC and the cell line of cancer tissue. Following transfection of human colon carcinoma cells (HCT116) and human colon adenocarcinoma cells (SW1116) with sh-APOL1, the effects of APOL1 on the biological behavior of CRC cell lines were examined. In nude mice, the effect of APOL1 on tumor growth was noted. The protein interaction between APOL1 and RUNX1 was detected via coimmunoprecipitation. The expression of relevant proteins and cell biological behaviors were examined to confirm the APOL1-RUNX1 pathway in CRC cell lines. Results: The CRC tissues and cells exhibited elevated expression of APOL1. HCT116 and SW1116 cells' proliferation, migration, and invasion were suppressed by sh-APOL1, and sh-APOL1 also increased the expression of E-cadherin and decreased the expression of RUNX1, cyclin D1, ß-catenin, N-cadherin, and vimentin. APOL1 bound to the RUNX1 protein and regulated its protein levels. The counteractive effect of sh-APOL1 epithelial-mesenchymal transition (EMT), proliferation, migration, and invasion of CRC cells was counteracted by the overexpression of RUNX1. By silencing APOL1, the Wnt-ß-catenin pathway was able to restrain EMT and regulate the biological behavior processes in CRC cells. Conclusions: APOL1 has potential as a diagnostic biomarker for CRC. By preventing the Wnt-ß-catenin pathway from being activated, the sh-APOL1-binding protein RUNX1 inhibited the EMT and biological behavior of CRC cells.

Senescence-related signatures predict prognosis and response to immunotherapy in colon cancer.

Background: Colorectal cancer (CRC) is one of the most common cancers. Cellular senescence plays a vital role in carcinogenesis by activating many pathways. In this study, we aimed to identify biomarkers for predicting the survival and recurrence of CRC through cellular senescence-related genes. Methods: Utilizing The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, RNA-sequencing data and clinical information for CRC were collected. A risk model for predicting overall survival was established based on five differentially expressed genes using least absolute shrinkage and selection operator-Cox regression (LASSO-Cox regression), receiver operating characteristic (ROC), and Kaplan-Meier analyses. The study also delved into both the tumor microenvironment and the response to immunotherapy. Moreover, we gathered clinical sample data from our center in order to confirm the findings of public database analysis. Results: Through ROC and Kaplan-Meier analyses, a risk model was developed using five cellular senescence-related genes [i.e., CDKN2A, SERPINE1, SNAI1, CXCL1, and ETS2] to categorize patients into high- and low-risk groups. In the TCGA-colon adenocarcinoma (COAD) and GEO-COAD cohorts, the high-risk group was associated with a bleaker forecast (P<0.05), immune cell inactivation, and insensitivity to immunotherapy in IMvigor210 database (http://research-pub.gene.com/IMvigor210CoreBiologies/). Clinical samples were then used to confirm that ETS2 and CDKN2A could serve as independent prognostic biomarkers in CRC. Conclusions: Gene signatures related to cellular senescence, specifically involving CDKN2A and ETS2, are emerging as promising biomarkers for predicting CRC prognosis and guiding immunotherapy.

B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α.

Background: B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC. Methods: Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected. Results: B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well. Conclusions: B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.

The application of graphene oxide and ferroptosis in the diagnosis and treatment of colorectal cancer: a narrative review.

Background and Objective: Colorectal cancer (CRC), a leading global malignancy, continues to challenge the medical community. Despite advancements in surgical, chemotherapeutic, radiation, targeted, and immunotherapeutic strategies, issues like resistance and side effects persist. This review illuminates the potential of ferroptosis, an emerging non-apoptotic cell death form, and graphene oxide (GO), with its distinctive physicochemical properties, in CRC therapy. Methods: The databases search included PubMed, Medline and Web of Science. Search terms focused on CRC, graphene, GO, ferroptosis, and related aspects in therapy and drug delivery. The time frame for literature retrieval was up to April 2024. Studies in languages other than English were excluded. Key Content and Findings: Ferroptosis has been recognized for its role in addressing treatment resistance, a notable hurdle in effective CRC management. This form of cell death offers a promising avenue for enhancing the effectiveness of existing treatments. However, understanding its mechanisms and clinical implications in CRC remains an area of active research, with significant progress required for its practical application. Simultaneously, GO, a versatile two-dimensional material, has demonstrated substantial potential in biomedical applications, especially in cancer therapy. Its high specific surface area and unique π-electron domains facilitate the effective binding of chemotherapy drugs, target genes, and photosensitizers. This makes GO a promising candidate in cancer diagnosis and treatment, particularly through tumor photothermal and photodynamic therapy (PDT). Despite these advancements, GO's clinical application faces challenges, including in vitro cytotoxicity and decreased biodegradability, necessitating further research. Conclusions: This review focuses on the characteristics of GO and ferroptosis, as well as their applications in tumor diagnosis and treatment, with a particular emphasis on their potential in CRC.

An unusual presentation of solitary ovarian metastasis from colorectal cancer in an elderly woman: a case report.

Background: There have been cases of colorectal cancer (CRC) metastasizing into the ovary. This study reports a case involving solitary ovarian metastasis (OM) from CRC, which is very rare in the absence of other pelvic and peritoneal metastases. This atypical clinical presentation added to the complexity of the diagnosis. Case Description: We report a case of solitary OM-CRC in a 48-year-old woman. The patient underwent CRC surgery and refused follow-up after three rounds of chemotherapy. Approximately 14 months later, the patient presented with vaginal bleeding for 2 months. The magnetic resonance imaging (MRI) showed a huge solid cystic mass in the right adnexa. Intraoperatively, the right ovary was found to be enlarged and smooth without adhesions. By careful examination of the abdominal cavity, no metastatic lesions were found in the left ovary and uterus, and no seedings were found in the rest of the pelvis and abdomen. After removal of the uterus and bilateral adnexa, the histologic examination revealed metastatic adenocarcinoma of the right ovary with a considered rectal carcinoma of origin. Positive staining for multiple tumor-associated markers, which further established the primary nature of CRC. These findings support a possible diagnosis of primary CRC and ovarian metastases. The patient recovered well after the operation and no recurrence or metastasis was seen 18 months after the operation. Conclusions: Solitary ovarian metastases from CRC can be better managed and treated by increasing clinicians' vigilance for this rare condition. This helps to improve the patient's prognosis and quality of life.

Gasdermin E benefits CD8+T cell mediated anti-immunity through mitochondrial damage to activate cGAS-STING-interferonß axis in colorectal cancer.

BACKGROUND: Pyroptosis belongs to a unique type of programmed cell death among which GSDME is reported to exert anti-tumor immunity. However, the underlying mechanisms of how to boost tumor-infiltrating lymphocytes and whether it could benefit the efficacy of ICIs are still unknown. METHODS: CRC samples were used to analyze its relationship with CD8+T cells. GSDME in mouse CRC cell lines CT26/MC38 was overexpressed. The infiltration of CD8+T cells in grafted tumors was determined by multiplex flow cytometric analysis and immunohistochemistry. Transcriptomic analysis was performed in cell lines to define key signatures related to its overexpression. The mechanism of how mtDNA was released by GSDME-induced mitochondrial damage and activated cGAS-STING pathway was observed. Whether GSDME benefited ICIs and the relationships with the genotypes of CRC patients were investigated. RESULTS: It had favorable prognostic value in CRC and was positively associated with increased number and functionality of CD8+T cells both in human samples and animal models. This was due to mitochondrial damage and activation of cGAS-STING-IFNß pathway for the recruitment of CD8+T cells. Mechanically, GSDME overexpression enhanced N-GSDME level, leading to the mitochondrial damage and mtDNA was released into cytosol. Finally, GSDME benefited with ICIs and exhibited positive relationships with MSI in CRC patients. CONCLUSION: We presented the mechanism of GSDME in anti-tumor immunity through activating cGAS-STING-IFNß axis mediated by mitochondrial damage, leading to more infiltration of CD8+T cells with synergistic efficacy with ICIs.

The salvage lenvatinib-based regimen provides survival benefit in patients with refractory metastatic colorectal cancer.

Salvage treatment for refractory metastatic colorectal cancer (mCRC) has yet to be identified. We aimed to evaluate the efficacy of a salvage lenvatinib-based regimen for refractory mCRC. In total, 371 patients were categorized into lenvatinib-based and non-lenvatinib-based groups. In the lenvatinib-based group, patients who received lenvatinib at a dosage of 10 mg/day were categorized into lenvatinib/chemotherapy and lenvatinib/immunotherapy subgroups. We reported overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. OS1 was used to measure the time from disease progression after TAS-102 and regorafenib treatment to death, while OS2 was used to measure the time from TAS-102 or regorafenib treatment to death. Propensity score matching analysis was employed to compare the characteristics between the lenvatinib-based and non-lenvatinib-based groups. Next-generation sequencing (NGS) information was analyzed using R software. The lenvatinib-based group exhibited longer OS than did the non-lenvatinib-based group (OS1, 11.4 vs. 3.7 months; OS2, 27.2 vs. 8.2 months). The disease control rate (DCR) and objective response rate (ORR) of the lenvatinib-based regimens were 69.4% and 6.1%, respectively. Lenvatinib/chemotherapy and lenvatinib/immunotherapy had similar PFS, OS, DCR, and ORR. The adverse effects were manageable. After propensity score matching, the lenvatinib-based group continued to exhibit significantly longer OS1 and OS2 than did the non-lenvatinib-based group. NGS analysis revealed that GNAS and KRAS alterations were associated with a worse treatment response and prolonged survival, respectively. In conclusion, a moderate-dose salvage lenvatinib-based regimen demonstrated promising clinical activity and tolerability in treating refractory mCRC.

LNA-i-miR-221 activity in colorectal cancer: A reverse translational investigation.

Colorectal cancer (CRC) is one of the most common malignancies and a relevant cause of cancer-related deaths worldwide. Dysregulation of microRNA (miRNA) expression has been associated with the development and progression of various cancers, including CRC. Among them, miR-221 emerged as an oncogenic driver, whose high expression is associated with poor patient prognosis. The present study was conceived to investigate the anti-CRC activity of miR-221 silencing based on early clinical data achieved from a first-in-human study by our group. Going back from bedside to bench, we demonstrated that LNA-i-miR-221 reduces cell viability, induces apoptosis in vitro, and impairs tumor growth in preclinical in vivo models of CRC. Importantly, we disclosed that miR-221 directly targets TP53BP2, which, together with TP53INP1, is known as a positive regulator of the TP53 apoptotic pathway. We found that (1) both these genes are overexpressed following miR-221 inhibition, (2) the strong anti-tumor activity of LNA-i-miR-221 was selectively observed on TP53 wild-type cells, and (3) this activity was reduced in the presence of the TP53-inhibitor Pifitrin-α. Our data pave the way to further investigations on TP53 functionality as a marker predictive of response to miR-221 silencing, which might be relevant for clinical applications.