Treatment Of Colorectal Cancer Research Articles

Glucocorticoid promotes metastasis of colorectal cancer via co-regulation of glucocorticoid receptor and TET2.

Glucocorticoids (GCs), commonly used for anti-inflammatory and cancer treatments, have been linked to the promotion of cancer metastasis. Yet, the molecular mechanisms behind this potential remain poorly understood. Clarifying these mechanisms is crucial for a nuanced understanding and potential refinement of GC therapies in the context of cancer treatment. In HEK293T cells, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation sequencing (ChIP-seq) were used with antibodies of glucocorticoid receptor (GR) and ten-eleven translocation enzymes (TET) family proteins (TET1, TET2, TET3). Drug repositioning was performed through the Connectivity Map database, using common target genes of GR and TET2 in HEK293 and HCT116 cell lines and differentially expressed genes (DEGs) of colorectal cancer (CRC). Cell migration and invasion were tested in CRC cell lines with varying GR expression, that is, HCT116 and HT29 cell lines. Dexamethasone (Dex) treatment resulted in a significant difference in cell migration rates in two CRC cell lines with disparate GR expression levels. Co-IP and ChIP-seq analyses substantiated the interaction between GR and TET family proteins in HEK293T cells. Belinostat, the selected compound, was successfully validated for its potential to counteract the effects of GC-induced invasion in CRC cells in vitro. Transcriptomic analyses of Belinostat-treated HCT116 cells revealed down-regulation of target genes associated with cancer metastasis. This study provides valuable insights into the molecular mechanisms underlying GC-induced metastasis, introducing newly repositioned compounds that could serve as potential adjuvant therapy to GC treatment. Furthermore, it opens avenues for exploring novel drug candidates for CRC treatment.

Robotic and laparoscopic minimally invasive surgery for colorectal cancer in Africa: an outcome comparison endorsed by the Nigerian society for colorectal disorders.

Minimally invasive surgery for colorectal cancer (CRC) offer superior outcomes compared to open surgery. This study aimed to review the robotic and laparoscopic procedures for CRCperformed in Africa, and compare the mean surgery duration, blood loss, hospital stay, rate of conversion, and prevalence of morbidity and mortality. This is the first study to compare the outcomes of robotic and laparoscopic surgeries for CRC in Africa. A systematic review following the PRISMA guidelines was conducted. PubMed, Google Scholar, Web of Science, AJOL, EMBASE, and CENTRAL were searched, identifying 2,259 publications, 33 of which were deemed eligible. Statistical analysis of outcomes was performed using "R". Methodological quality of the included studies was assessed using the Cochrane ROBINS-I tool. The minimally invasive approach has been applied for CRC treatment in seven African countries: Algeria, Cameroon, Egypt, Morocco, Nigeria, Senegal, and South Africa. Laparoscopic surgeries accounted for 1,485 (95%) of cases, while 71 (5%) were robotic. Robotic procedures were associated with a longer surgery duration (256.41min vs. 190.45min, p < 0.0001), higher blood loss (226.48mL vs. 141.55mL, p < 0.0001), and a shorter hospital stay (4.52days vs. 6.06days, p = 0.85). Robotic procedures had a lower rate of conversion (3% vs. 8%, p = 0.29) and a lower prevalence of morbidity (19% vs. 26%, p = 0.26). Wound infection (24.49%) and ileus (57.14%) were the most common complications following laparoscopic and robotic procedures, respectively. There was no mortality from robotic surgeries; however, a prevalence of 0.39% (95% CI: 0;1.19) was recorded from laparoscopy. This study establishes and compares the outcomes of advances in the treatment of CRC in the African setting, providing insights for policymakers, healthcare providers, and international organizations to make decisions regarding optimizing care for CRC patients in Africa.

Screen-printed electrode for electrochemical detection of sunitinib malate for therapeutic drug monitoring

Sunitinib is a targeted therapy for colorectal cancer, which needs a precise dosage due to potential severe side effects from overdose. Therapeutic drug monitoring is crucial for maintaining optimal drug levels in body fluids. Traditional anticancer drug dose evalua­tion methods such as high-pressure liquid chromatography, liquid chromatography with mass spectrophotometry, and immunoassays are cumbersome. This study explores the utilization of electrochemical sensors on indigenously developed screen-printed electrodes for sunitinib malate monitoring. Differential pulse voltammetry, cyclic voltam­metry and chrono-amperometric studies were conducted in a conventional three-elec­trode system. An anodic peak current, indicative of sunitinib malate electro­oxi­dation, was observed around +0.45 V vs. Ag/AgCl reference electrode in 0.1 M PB of pH 7.4. Sen­sitivity, the limit of detection and method detection limit were determined as 0.386 µA µM-1 cm-2, 0.009 and 0.0108 µM, respectively. The response exhibited linearity (R2 = 0.990) with sunitinib concentration ranging from 0.08 to 88 μM with good reproducibility. DPV studies on real samples yielded acceptable recovery values. Electro­chemical sensors based on the screen-printed electrode present a promising approach for sunitinib monitoring, offering sensitivity, low limit of detection, and a wide linear range. Since the expected plasma concentration of sunitinib is much higher than the sensor detection range, it can be used for real sample analysis. Here developed methods could simplify and improve therapeutic drug monitoring in colorectal cancer treatment.

Villin-1 regulates ferroptosis in colorectal cancer progression.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanistic underpinnings driving CRC progression remain largely unknown. As a fundamental component of the brush border cytoskeleton, villin-1 (VIL1) acts as a marker for intestinal cell differentiation and maturation. Through a comprehensive transcriptomics analysis of eight studies (total sample: n = 1952), we consistently observed significant upregulation of VIL1 expression in CRC tumors compared with adjacent normal tissue. In our independent cohort, this notable upregulation has been further validated at both mRNA and protein levels in colon tumor tissues, relative not only to adjacent normal tissue but also to normal controls. Our data show that VIL1 promotes proliferation and migration while inhibiting apoptosis. Conversely, knockout of VIL1 suppresses proliferation and migration while inducing apoptosis. Mechanistically, we reveal that knocking out VIL1 activates ferroptosis and inhibits the migration of CRC cells, while overexpressing VIL1 yields the opposite effects, and vice versa. Additionally, VIL1 binds to Nuclear factor NF-kappa-B p105 subunit (NF-κB) and controls NF-κB expression. In vivo, overexpressing VIL1 inhibits ferroptosis, and induces the expression of NF-κB and lipocalin 2 (LCN2), thereby promoting CRC tumor growth. Thus, we have identified the VIL1/NF-κB axis as a pivotal regulator of CRC progression through ferroptosis modulation, unveiling VIL1 as a promising therapeutic target for CRC treatment via ferroptosis. Our study offers novel avenues for exploring the therapeutic potential of ferroptosis in CRC management, emphasizing the high potential of VIL1 in regulating colorectal tumorigenesis.

TIPE Inhibits Ferroptosis in Colorectal Cancer Cells by Regulating MGST1/ALOX5.

TIPE is a protein highly expressed in various cancers that promotes ferroptosis in colorectal cancer cells. Ferroptosis is a nonapoptotic cell death caused by lipid peroxidation, and microsomal glutathione transferase 1 (MGST1) is a critical enzyme that resists lipid peroxidation. This study explored how TIPE regulates MGST1 expression to inhibit ferroptosis and promote colorectal cancer proliferation. TIPE was highly expressed in colorectal cancer tissues and positively correlated with the proliferation of human colorectal cancer cells. We measured levels of reactive oxygen species and lipid reactive oxygen species in colorectal cancer cells with differential expression of TIPE and detected ferroptosis using transmission electron microscopy. Bioinformatics analysis revealed a positive correlation of expression patterns between TIPE and MGST1 in colorectal cancer. TIPE regulated the expression of MGST1 by activating the phosphorylation of ERK1/2. Coimmunoprecipitation revealed binding between MGST1 and ALOX5. This binding inhibited the phosphorylation of ALOX5, inhibiting ferroptosis and promoting the proliferation of colorectal cancer cells. A tumor formation experiment in nude mice supported our findings that TIPE regulates the proliferation of colorectal cancer by regulating ferroptosis. Implications: TIPE inhibits colorectal cancer ferroptosis via an MGST1-ALOX5 interaction to promote colorectal cancer proliferation. These findings suggest future colorectal cancer treatment strategies.

Targeting Arachidonic Acid Metabolism Enhances Immunotherapy Efficacy in ARID1A-Deficient Colorectal Cancer.

ARID1A, a core constituent of SWI/SNF complex, is mutated in approximately 10% of colorectal cancers (CRC). While ARID1A deficiency corresponds to heightened immune activity in CRC, immune checkpoint inhibitors (ICIs) have shown limited efficacy in these tumors. The discovery of targetable vulnerabilities associated with ARID1A deficiency in CRC could expand treatment options for patients. In this study, we demonstrated that arachidonic acid metabolism inhibitors synergize with ICIs in ARID1A-deficient CRC by enhancing the activity of CD8+ T cells and inhibiting vasculogenic mimicry (VM). Epigenetic analysis using ATAC-seq and ChIP-qPCR revealed that the lack of ARID1A results in reduced levels of PTGS1 and PTGS2, the key enzymes that control the arachidonic acid pathway. Low PTGS1 and PTGS2 expression generated a reliance on the remaining functionality of the arachidonic acid pathway in ARID1A-deficient cells. The arachidonic acid pathway inhibitor aspirin selectively inhibited the growth of ARID1A-deficient CRC, and aspirin sensitized tumors lacking ARID1A to immunotherapy. Together, these findings suggest that blocking arachidonic acid metabolism can enhance immune responses against tumors by activating CD8+ T cells and inhibiting VM, which synergizes with ICIs to improve treatment of ARID1A-deficient CRC.

The Novel Elemene Derivative, OMe-Ph-Elemene, Attenuates Oxidative Phosphorylation and Facilitates Apoptosis by Inducing Intracellular Reactive Oxygen Species.

The incidence and mortality rates of colorectal cancer have been steadily increasing, making it one of the most prevalent cancers globally. Although current chemotherapy drugs have shown some efficacy in treating this disease, their associated side effects necessitate the development of more effective treatments and medications. The clinical application of elemene is widely utilized in tumor treatment; however, its efficacy is hindered by the requirement for high dosage and suboptimal anticancer effects. Thus, we have made modifications and enhancements to elemene, resulting in the development of a novel compound named (E)-8-(3,4,5-OMe-Ph)-β-Elemene (abbreviated as OMe-Ph-Elemene) that demonstrates significantly enhanced efficacy in suppressing colorectal cancer. We conducted an in vivo study and demonstrated the potential of OMe-Ph-Elemene in suppressing the growth of colorectal cancer xenograft tumors in zebrafish. The in vitro experiments revealed that OMe-Ph-Elemene effectively inhibited the proliferation and migration of colorectal cancer SW480 and HT-29 cells by inducing reactive oxygen species (ROS)-caused apoptosis and inhibiting mitochondrial oxidative phosphorylation. The mechanism was elucidated through high-throughput proteomic analysis and molecular biological analysis, revealing that OMe-Ph-Elemene induced cellular oxidative stress by downregulating CISD3 and promoted cell apoptosis by downregulating TRIAP1 and upregulating HMOX1. Furthermore, OMe-Ph-Elemene suppressed colorectal cancer cells' mitochondrial oxidative phosphorylation by downregulating NDUFA7. In summary, the utilization of the elemene parent nucleus structure has led to the derivation of a novel tumor suppressor compound characterized by high efficacy and low toxicity, thereby providing a significant reference for the development of innovative drugs for colorectal cancer treatment.

Evaluation of the Leaves and Seeds of Cucurbitaceae Plants as a New Source of Bioactive Compounds for Colorectal Cancer Prevention and Treatment.

The Cucurbitaceae family represents an important source of bioactive compounds with antioxidant, antimicrobial, anti-inflammatory and antitumor activities. This study aims to investigate the potential application of Cucurbitaceae leaves and seed extracts to prevent and treat colorectal cancer (CRC). Four extracts (ethanol extracts and protein extracts and hydrolysates) from the leaves and seeds of cucurbits were tested in T-84, HCT-15 and HT-29 CRC cells. The antitumor, antiangiogenic, antioxidant and chemopreventive potentials and bioactive composition of the active extracts were characterized. Cold ethanolic extracts from the leaves and seeds of two interspecific Cucurbita genera (CLU01002 and COK01001) exhibited potent antiproliferative, specific and non-hepatotoxic activity against CRC cell lines, with a slight synergistic effect in combination with oxaliplatin. This antitumor activity was related to G2/M cell cycle arrest, the extrinsic apoptosis pathway, cytokinesis inhibition and autophagy. The extracts also inhibited tumor clonogenicity and angiogenesis, and modulated cancer stem cell (CSC) gene expression, as well as expressing antioxidant and chemopreventive cellular capabilities. Finally, phenolic and cucurbitane-type triterpenoid compounds (pengxianencins and cucurbitacins) were tentatively identified in the active extracts by UPLC-MS analysis and bioguided fractionation. Extracts from leaves the and seeds of two interspecific Cucurbita genera (CLU01002 and COK01001) may contribute to the improvement of prevention and treatment strategies for CRC patients.

Extracellular nicotinamide phosphoribosyltransferase visfatin activates JAK2-STAT3 pathway in cancer-associated fibroblasts to promote colorectal cancer metastasis.

Metastasis is one of the major challenges in the treatment of colorectal cancer (CRC), during which cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critically involved. In this study, we aim to explore the regulatory role of extracellular nicotinamide phosphoribosyltransferase Visfatin and its impact on CRC metastasis. To examine the effect of visfatin on CAFs, human CRC tissue-derived CAFs were exposed to visfatin, and the expression of inflammatory factors, activation of JAK-STAT pathway and production of ROS in CAFs were assessed. To examine the effect of visfatin-treated CAFs on CRC metastasis, human CRC cell line SW480 or SW620 were cultured with the conditioned medium derived from visfatin-treated CAFs, and the invasion and migration ability of SW480 or SW620 cells were evaluated by transwell migration and matrigel invasion assays. Our previous study found that visfatin, a secreted form of nicotinamide phosphoribosyltransferase that governs the rate-limiting step of NAD synthesis, promoted CRC metastasis. However, little is known about the effect of visfatin on CAFs. The conditioned medium derived from visfatin- treated CAFs promotes the migratory and invasive capability of CRC cells, and enhance lung metastasis in mouse model. Visfatin treatment stimulated the expression of a couple of inflammatory factors in CAFs, which was mediated by visfatin-induced activation of JAK- STAT pathway and accumulation of ROS. Inhibition of JAK-STAT pathway or neutralization of cellular ROS attenuated visfatin-mediated migration and invasion of CRC cells. The present work highlights a critical role of visfatin in the crosstalk between CRC cells and CAFs, which moonlight as a non-metabolic extracellular signal molecule to hijacks JAK-STAT pathway in CAFs to promote CRC metastasis.

Global research progress of nanomedicine and colorectal cancer: a bibliometrics and visualization analysis.

Surgery and chemoradiotherapy are the main clinical treatment methods for colorectal cancer (CRC), but the prognosis is poor. The emergence of nanomedicine brings bright light to the treatment of CRC. However, there has not been a comprehensive and systematic analysis of CRC and nanomedicine by bibliometrics. We searched the Web of Science Core Collection database (WOSCC) for relevant literature published from 2011 to 2024. We used VOSviewer and Citespace to analyze countries, institutions, authors, keywords, highly cited references, and co-cited references. 3105 pieces of literatures were included in the research analysis, and PEOPLES R CHINA and the USA took the leading position in the number of papers published and had academic influence. The Chinese Academy of Sciences posted the most papers. The most prolific scholar was Abnous Khalil. The level of economic development is inversely proportional to the number of cases and deaths of colorectal cancer. Nanoparticles (NPs), the nanomedical drug delivery system (NDDS) is a hot topic in the field. Photodynamic therapy (PDT), immunogenic cell death (ICD), tumor microenvironment (TEM), folic acid, and pH are the cutting edge of the field. This paper introduces the research hotspot, emphasis, and frontier of CRC and nanomedicine, and points out the direction for this field.

LINC01614 Accelerates CRC Progression via STAT1/LINC01614/miR-4443/PFKFB3-Mediated Aerobic Glycolysis.

Colorectal cancer (CRC) is an aggressive malignancy among malignant tumours, with a high incidence globally. LINC01614, a long non-coding RNA, has been identified as an essential regulator in multiple cancer types. However, its biological functions and underlying molecular mechanisms in CRC remain largely unknown. In this study, we employed RT-qPCR to assess the expression levels of LINC01614 in CRC samples. In vitro, glucose metabolism experiments were conducted to evaluate glucose metabolism in cells. The binding relationship between miR-4443, PFKFB3, and LINC01614 was confirmed through fluorescence reporter gene detection. The subcellular localization of LINC01614 in CRC cells was determined using FISH and subcellular fractionation experiments. Additionally, a mouse subcutaneous tumor model was established for in vivo experiments. Our findings reveal that LINC01614 is upregulated in CRC tissues. Silencing of LINC01614 suppresses the malignant behaviors of CRC cells, including cell proliferation, invasion, migration, and aerobic glycolysis. Furthermore, we discovered that LINC01614 promotes the expression of PFKFB3. Additional experiments demonstrated that LINC01614 binds to miR-4443, leading to the upregulation of PFKFB3 expression. Further experiments confirmed that the LINC01614/miR-4443/PFKFB3 axis promotes CRC cell malignancy by enhancing aerobic glycolysis. Additionally, we found that STAT1 promotes the transcription of LINC01614. These findings uncover a novel regulatory pathway wherein STAT1-induced LINC01614 enhances PFKFB3 expression by sponging miR-4443, thereby accelerating CRC development. This understanding may lead to novel therapeutic strategies for CRC treatment.

Molecular characteristics, clinical significance and cancer‑immune interactions of pyroptosis‑related genes in colorectal cancer.

Colorectal cancer (CRC) is a malignant tumor with poor prognosis. Pyroptosis is a newly discovered type of programmed cell death that is typically accompanied by a strong inflammatory response. Accumulating evidence suggests that pyroptosis-related genes (PRGs) may have important roles in the development of malignant tumors. However, the association between PRG expression and clinical outcomes in CRC remain unclear. In the present study, the genetic variations and transcriptional patterns of 52 PRGs were comprehensively analyzed using cohorts from The Cancer Genome Atlas and Gene Expression Omnibus and the mRNA expression levels of 7 PRGs in collected CRC samples were validated using reverse transcription-quantitative PCR. Using LASSO-Cox analysis, a PRG score was then generated and the relationship between the PRG score and prognosis, immune cell infiltration and drug sensitivity in CRC was uncovered. In the present study, the mutation and expression patterns of PRGs were analyzed and it was found that these genes were differentially expressed in CRC tissues compared with normal tissues. Based on the expression patterns of the PRGs, patients with CRC were divided into two subtypes (cluster A and B), of which cluster B had an improved prognosis and a higher abundance of immune cells. Next, differentially expressed genes between clusters A and B were identified and a PRG risk score closely related to the prognosis of CRC was constructed. Then, a nomogram for evaluating the overall survival of patients was constructed. Furthermore, a low PRG risk score was characterized by immune activation and closely related to the microsatellite instability-high pattern. Additionally, the PRG risk score was notably correlated with drug sensitivity. In conclusion, the mutation and expression characteristics of PRGs in CRC were comprehensively analyzed and a prognostic PRG signature was constructed in the present study. This signature may predict immune cell infiltration and therapeutic response in CRC, providing new insights into the prognosis and treatment of CRC.

The Role of LncRNA ROR in Colorectal Cancer Diagnosis and Treatment

Context: Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, particularly in developed countries. Despite advances in detection and treatment, CRC remains difficult to diagnose in its early stages, complicating patient outcomes. Recently, long non-coding RNAs (lncRNAs) have emerged as significant regulators in cancer biology, offering new opportunities for cancer diagnostics. Evidence Acquisition: This review highlights the molecular mechanisms through which LncRNA ROR influences CRC development, its diagnostic potential as a biomarker, and the future challenges of integrating LncRNA ROR into clinical practice. Results: Future research must focus on large-scale validation studies and explore the therapeutic implications of targeting LncRNA ROR. Conclusions: Overall, this review positions LncRNA ROR as a promising biomarker with potential applications in both CRC diagnosis and treatment.

Clinical Characteristics, Management and Outcomes of Colitis-associated Colorectal Cancer and the Comparison to Sporadic Colorectal Cancer in Taiwan.

We explored the clinical characteristics, treatment, and outcomes of colitis-associated colorectal cancer and compared with sporadic colorectal cancer in Taiwan. In this retrospective study spanning 1987-2022, colitis-associated colorectal cancers diagnosed according to endoscopic and pathological reports from 14 tertiary centers were reported to our cohort. Clinical demographics, endoscopic findings, histological results, treatment modalities, and outcomes were analyzed. Sporadic colorectal cancer data were retrieved from the Cancer Registry Annual Report, Ministry of Health and Welfare, Taiwan. We enrolled 65 colitis-associated colorectal cancer patients (median age: 56 years; male: 66.2%). Distal colon was the most common tumor location (41.5%). Of ulcerative colitis patients, 77.2% had extensive colitis and 76.5% had Mayo endoscopic subscores of ≥2. Moreover, 50% of lesions were nonpolypoid with indistinct borders in 66.7%. Signet-ring cell subtype consisted 12.3%. Surveillance colonoscopy adherence was 78.4%, yet 51.3% interval cancers occurred. Disease stage 0-4 distribution was 15%, 20%, 13.3%, 20%, and 31.7%, respectively. Endoscopic resection was feasible for 14%, while 67.7% required surgery. During follow-up (median: 21.5 months), we recorded 23.2% recurrence and 34.5% mortality. Lesions with indistinct borders were associated with adverse outcomes (adjusted odds ratio = 11.5 [1.35-98.16]). Colitis-associated rectal cancers, diagnosed later (p < 0.001), had worse outcomes than sporadic rectal cancers. This is the largest Asian colitis-associated colorectal cancer cohort study, emphasizing the need for stringent disease control, improving detection and reducing interval cancers. Signet-ring cell subtype was prevalent. Rectal colitis-associated cancers were diagnosed later with poorer outcomes then sporadic rectal cancers.

4′-Demethylpodophyllotoxin functions as a mechanism-driven therapy by targeting the PI3K-AKT pathway in Colorectal cancer

The treatment of colorectal cancer (CRC) poses significant challenges in terms of drug resistance and poor prognosis, necessitating the exploration of effective therapeutic strategies. In this study, high-throughput drug screening was utilized to identify Chinese herbal medicines with notable therapeutic effects on CRC. Among the compounds identified, 4′-demethylpodophyllotoxin (DOP), a derivative of podophyllotoxin, emerged as a potent anti-cancer compound. DOP exhibited time- and dose-dependent growth inhibition on CRC cell lines and tumor organoids derived from patients. RNA-seq revealed that DOP activated the PI3K-AKT pathway, leading to tumor cell apoptosis and cell cycle arrest at the G2/M phase. Additionally, DOP induced DNA damage in CRC cells. To further validate its therapeutic efficacy in CRC, the DLD1-derived xenograft model demonstrated that DOP effectively suppressed CRC growth in vivo. In conclusion, these findings highlight the significant therapeutic potential of DOP as an anti-tumor drug for treating CRC, thereby opening new avenues for investigating Podophyllotoxin derivatives in this specific field.

Survival Outcomes with Regorafenib and/or Trifluridine/Tipiracil Sequencing to Rechallenge with Third-Line Regimens in Metastatic Colorectal Cancer: A Multicenter Retrospective Real-World Subgroup Comparison from the ReTrITA Study.

There is ongoing discussion around the optimal course of treatment for metastatic colorectal cancer (mCRC) following the second line. Trifluridine/tipiracil (T) and regorafenib (R) have been the mainstay of therapy in this situation, as they both increased overall survival (OS) in comparison to a placebo. Despite the paucity of evidence, therapy rechallenge is also recognized as an option for practical use. In the third-line scenario of mCRC, we planned to investigate the survival outcomes using (T) and (R), both with and without prior rechallenge treatment. Between 2012 and 2023, we examined the medical records of 1156 patients with refractory mCRC who were enrolled in the multicenter retrospective ReTrITA study. We then separated the patients into two cohorts based on the rechallenge therapy that was given before regorafenib and/or trifluridine/tipiracil at 17 Italian centres. A total of 981 patients underwent T and/or R therapy, while 175 patients had therapy rechallenge before T and/or R. The median overall survival (mOS) for patients treated with T/R and R/T sequences in the rechallenge therapy cohort was 14.5 months and 17.6 months, respectively (p = 0.1955). A statistically significant survival benefit was observed in patients who received monotheraphy with R (mOS: 6 months) compared to the T group (mOS: 4.2 months) (p = 0.0332). In the same cohort, a median progression-free survival (mPFS) benefit was demonstrated in favour of the R/T group (11.3 months) vs. 9 months of the reverse sequence (p = 0.4004). In the no-rechallenge cohort, the mOS was statistically longer in the R/T sequence than in the T/R sequence (16.2 months vs. 12.3 months, respectively; p = 0.0014). In terms of the mPFS, we saw the same significant result for the adoption of R/T treatment (11.5 months vs. 8.4 months, respectively; p < 0.0001). The two monotherapy groups did not reveal any significant differences. This study suggests that rechallenge therapy may improve survival rates in the third-line treatment of mCRC, particularly if it is administered before sequential R/T treatment. This could allow for the extension of mCRC treatment choices until prospective studies are finished or randomised trials are performed.

Risk Factors for Perforation in Endoscopic Treatment for Early Colorectal Cancer: A Nationwide ENTER-K Study.

Early colorectal cancer (ECC) is commonly resected endoscopically. Perforation is a devastating complication of endoscopic resection. We aimed to identify the characteristics and predictive risk factors for perforation related to endoscopic resection of ECC. This nationwide retrospective multicenter study included patients with ECC who underwent endoscopic resection. We investigated the demographics, endoscopic findings at the time of treatment, and histopathological characteristics of the resected specimens. Logistic regression analysis was used to investigate the clinical factors associated with procedure-related perforations. Survival analysis was conducted to assess the impact of perforation on the overall survival of patients with ECC. This study included 965 participants with a mean age of 63.4 years. The most common endoscopic treatment was conventional endoscopic mucosal resection (n=573, 59.4%), followed by conventional endoscopic submucosal dissection (n=259, 26.8%). Thirty-three patients (3.4%) experienced perforations, most of which were managed endoscopically (n=23/33, 69.7%). Patients who undergo endoscopic submucosal dissection-hybrid and precut endoscopic mucosal resection have a higher risk of perforation than those who undergo conventional endoscopic mucosal resection (odds ratio, 78.65 and 39.72, p<0.05). Procedure-related perforations were not associated with patient survival. Perforation after endoscopic resection had no significant impact on the prognosis of ECC. The type of endoscopic resection was a crucial predictor of perforation. Large-scale prospective studies are needed to further investigate endoscopic resection of ECC.

ORG-317 Repurposing as a Potential Agonist Targeting TMEM236 in Colorectal Cancer Treatment: Insights from Molecular Dynamics Simulation, Principal Component Analysis, and Free Energy Landscape Study.

<p> Background and objective: Colorectal Cancer (CRC) affects the colon and rectum part of the digestive system and is a significant global health concern, with approximately 1.1 million new cases annually. It ranks second in cancer-related deaths. Studies have shown future projections of CRC cases to enhance at a worrisome rate, estimating 3.2 million new cases and 1.6 million deaths worldwide by 2040. Studies have shown the downregulation of TMEM236 in CRC, and this study aimed to find the agonist to restore the function of TMEM236 via the drug repurposing method. </p><p> Methods: The different molecular and structural level analyses were performed to understand how the TMEM236 expression can be restored. To obtain the molecular level data, the following analyses were employed to understand the binding affinity and agonistic behaviour of the screened drugs: molecular docking, oral toxicity prediction, Molecular Dynamics (MD) simulation, Free Energy Landscape (FEL) analysis, and g_mmpbsa. </p><p> Results: The molecular docking, oral toxicity, and molecular interaction analyses have identified db06435, db05423, and db15197 drugs from the DrugBank database to either belong to an approved or investigational class of drugs as a potential agonist for TMEM236. The MD simulation and PCA analysis had shown db05423 (ORG-317) to exhibit stable interaction with TMEM236 protein. Similar results were obtained through FEL analysis. </p><p> Conclusion: The downregulation of TMEM236 expression and its constant binding affinity with db05423 during MD simulation suggest that this drug may restore the diminished function and expression of TMEM236. Additionally, it could function as an agonist and can be used for CRC treatment.</p>.

Targeting cuproptosis with nano material: new way to enhancing the efficacy of immunotherapy in colorectal cancer.

Colorectal cancer has emerged as one of the predominant malignant tumors globally. Immunotherapy, as a novel therapeutic methodology, has opened up new possibilities for colorectal cancer patients. However, its actual clinical efficacy requires further enhancement. Copper, as an exceptionally crucial trace element, can influence various signaling pathways, gene expression, and biological metabolic processes in cells, thus playing a critical role in the pathogenesis of colorectal cancer. Recent studies have revealed that cuproptosis, a novel mode of cell death, holds promise to become a potential target to overcome resistance to colorectal cancer immunotherapy. This shows substantial potential in the combination treatment of colorectal cancer. Conveying copper into tumor cells via a nano-drug delivery system to induce cuproptosis of colorectal cancer cells could offer a potential strategy for eliminating drug-resistant colorectal cancer cells and vastly improving the efficacy of immunotherapy while ultimately destroy colorectal tumors. Moreover, combining the cuproptosis induction strategy with other anti-tumor approaches such as photothermal therapy, photodynamic therapy, and chemodynamic therapy could further enhance its therapeutic effect. This review aims to illuminate the practical significance of cuproptosis and cuproptosis-inducing nano-drugs in colorectal cancer immunotherapy, and scrutinize the current challenges and limitations of this methodology, thereby providing innovative thoughts and references for the advancement of cuproptosis-based colorectal cancer immunotherapy strategies.

HM13 is a predictive biomarker of metastasis and neutrophil infiltration in colorectal cancer.

High levels of histocompatibility minor 13 (HM13) have been related to the progression of several cancers. Here, we investigated the function of HM13 in colorectal cancer (CRC). HM13 expression, clinicopathology analysis, and its influence on survival were analyzed in multiple public databases (TCGA, TIMER2.0, and GEPIA). HM13 mRNA and protein levels in CRC cells were examined by qRT-PCR and western blot, respectively. CCK-8, Transwell, wound-healing, and adhesion assays were used to measure cell proliferation, migration, invasion, and adhesion in HM13-overexpressed and -silenced cells. The relationship between HM13 expression and neutrophil infiltration was also analyzed. CRC xenograft mouse models were used for in vivo verification of HM13 function. In this study, TCGA dataset analysis revealed that elevated HM13 levels correlated with malignant progression and worse survival outcomes in CRC. Cell migration, proliferation, invasion, and adhesion were suppressed through the knockdown of sh-HM13 and enhanced through HM13 overexpression. Additionally, HM13 expression significantly correlated with the infiltration level of neutrophils in CRC in TCGA and TIMER analyses. HM13 levels were also positively correlated with myeloperoxidase (MPO) levels. In addition, in vivo studies further confirmed that MPO overexpression partially abolished the inhibition of tumor growth by sh-HM13 in CRC. The results suggested that high HM13 expression in CRC could promote tumor growth and metastasis by reducing neutrophil infiltration and may serve as a useful target in the treatment of metastatic CRC.