Saikosaponin D Inhibits Lung Metastasis of Colorectal Cancer Cells by Inducing Autophagy and Apoptosis.

Saikosaponin D (SSD), derived from Bupleurum falcatum L., has various pharmacological properties, including immunoregulatory, anti-inflammatory, and anti-allergic effects. Several studies have investigated the anti-tumor effects of SSD on cancer in multiple organs. However, its role in colorectal cancer (CRC) remains unclear. Therefore, this study aimed to elucidate the suppressive effects of SSD on CRC cell survival and metastasis. SSD reduced the survival and colony formation ability of CRC cells. SSD-induced autophagy and apoptosis in CRC cells were measured using flow cytometry. SSD treatment increased LC3B and p62 autophagic factor levels in CRC cells. Moreover, SSD-induced apoptosis occurred through the cleavage of caspase-9, caspase-3, and PARP, along with the downregulation of the Bcl-2 family. In the in vivo experiment, a reduction in the number of metastatic tumor nodules in the lungs was observed after the oral administration of SSD. Based on these results, SSD inhibits the metastasis of CRC cells to the lungs by inducing autophagy and apoptosis. In conclusion, SSD suppressed the proliferation and metastasis of CRC cells, suggesting its potential as a novel substance for the metastatic CRC treatment.

Serum small RNAs in metastatic colorectal cancer predict response to chemotherapy and characterize high-risk patients.

Metastatic colorectal cancer (mCRC) presents significant challenges in clinical management due to its heterogeneity and variable response to treatment. In this study, we conducted comprehensive small RNA (sRNA) sequencing analyses to identify sRNA biomarkers associated with survival and treatment response in mCRC patients. We measured serum sRNAs before and after chemotherapy treatment in a discovery cohort of 189 mCRC patients. Our analysis revealed 25 microRNAs (miRNA) as significantly associated with overall survival at baseline. We found that 11 of the 25 significant miRNAs were also significant in an independent validation cohort of 20 mCRC patients, including the top five miRNAs from the discovery cohort. Importantly, all but four of the 25 significant miRNAs from the discovery cohort had hazard ratios in the same direction in the validation cohort. Among the 25 significant miRNAs, we identified the miR-320 family of miRNAs as the strongest independent prognostic marker, with high baseline levels correlating with poor survival outcomes. Furthermore, post-treatment levels of the same miRNAs were even more predictive of overall survival, emphasizing the prognostic value of serum changes in miRNA levels before and after treatment. Moreover, we observed significant changes in serum miRNAs and other sRNAs when comparing samples before and after chemotherapy, with distinct expression patterns between responders and non-responders. Leveraging these differential expression patterns, we established a serum sRNA signature that accurately predicts response to chemotherapy with an area under the curve (AUC) of 0.8. In summary, our study highlights the prognostic and predictive potential of sRNA biomarkers in mCRC, offering valuable insights into patient stratification and personalized treatment approaches.

Antibiotic use during radical surgery in stage I-III colorectal cancer: correlation with outcomes?

AIMS: Accumulating evidence indicates that the use of antibiotics (ATBs) in cancer patients is potentially correlated with patient prognosis. Interestingly, the use of these agents is not uncommon in colorectal cancer (CRC) patients during surgery; however, their prognostic value in the clinic has never been addressed. MATERIALS AND METHODS: Data on ATB use during surgery, including the cumulative defined daily dose (cDDD) and the number of categories, were collected. Differences in the clinical data between the low and high cDDD subgroups and between subgroups with ≤ 4 and >4 categories. Additionally, the disease-free survival (DFS) and overall survival (OS) among these subgroups and the specific categories were compared. Finally, a Cox proportional hazard model was used to validate the risk factors for the outcome. RESULTS: The number of categories, rather than the cDDD, was a significant predictor of both DFS (P = 0.043) and OS (P = 0.039). Patients with obstruction are more likely to have a high cDDD, whereas older patients are more likely to have multiple categories. There were no significant differences in the DFS (log rank = 1.36, P = 0.244) or OS (log rank = 0.40, P = 0.528) between patients in the low- and high-cDDD subgroups, whereas patients with ≤ 4 categories had superior DFS (log rank = 9.92, P = 0.002) and OS (log rank = 8.30, P = 0.004) compared with those with >4 categories. Specifically, the use of quinolones was harmful to survival (DFS: log rank = 3.67, P = 0.055; OS: log rank = 5.10, P = 0.024), whereas the use of macrolides was beneficial to survival (DFS: log rank = 12.26, P < 0.001; OS: log rank = 9.77, P = 0.002). Finally, the number of categories was identified as an independent risk factor for both DFS (HR = 2.05, 95% CI: 1.35-3.11, P = 0.001) and OS (HR = 1.82, 95% CI: 1.14-2.90, P = 0.012). CONCLUSIONS: The cDDD of ATBs during surgery in stage I-III CRC patients did not correlate with outcome; however, patients in multiple categories or a specific category are likely to have inferior survival. These results suggest that particular caution should be taken when selecting ATBs for these patients in the clinic.

APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

Neoadjuvant camrelizumab plus apatinib for locally advanced microsatellite instability-high or mismatch repair-deficient colorectal cancer (NEOCAP): a single-arm, open-label, phase 2 study.

BACKGROUND: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. METHODS: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. FINDINGS: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. INTERPRETATION: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Comparison of genomic profiling of patient-matched primary colorectal and surgical resected distant metastatic (stage IV) colorectal carcinoma for drug actionability.

It is often difficult to obtain adequate tissue for genomic study from distant metastases for assessment of targeted therapy in colorectal carcinomas. The study aims to explore the genomic differences between matched distant metastatic colorectal carcinomas (mCRC) and primary carcinoma using surgical specimens of both with adequate tissue. Thirty-four paired primary and distant metastatic colorectal carcinoma samples (liver, ovary, and lung) were obtained from surgical excisions (not small biopsies) and are microsatellite stable. They were subjected to DNA sequencing using comprehensive next-generation sequencing. This included mutation concordance analysis and mutational signature analysis. The mutation concordance analysis showed 49.6% shared mutations between primary and metastatic tumours, with 23.0% mutations exclusive to primary tumours and 27.4% mutations exclusive to distant metastases. While many patients with KRAS/BRAF mutations had shared mutations, two cases had unique KRAS mutations in the primary tumours only. Additionally, TMB (tumour mutational burden) analysis revealed that half of the TMB-high (≥7.5 mutations/Mb) metastatic colorectal carcinomas had a low TMB (<7.5 mutations/Mb) in the primary tumours. The mutational signature analysis identified de novo signatures consistent with known single base substitution patterns such as SBS11 (alkylation agents) and SBS30 (base excision repair deficiency) post-chemotherapy. To conclude, this study demonstrates significant genomic variations in resected distant metastasis when compared to primary colorectal carcinomas when adequate tissue is available. This finding underscores the importance of considering these differences and selecting tissue for mutation analysis in planning targeted and effective treatment strategies for mCRC.

Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer.

Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.

PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.

BACKGROUND: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.

Immune checkpoint inhibitors in colorectal cancer: limitation and challenges.

Colorectal cancer exhibits a notable prevalence and propensity for metastasis, but the current therapeutic interventions for metastatic colorectal cancer have yielded suboptimal results. ICIs can decrease tumor development by preventing the tumor's immune evasion, presenting cancer patients with a new treatment alternative. The increased use of immune checkpoint inhibitors (ICIs) in CRC has brought several issues. In particular, ICIs have demonstrated significant clinical effectiveness in patients with MSI-H CRC, whereas their efficacy is limited in MSS. Acquired resistance can still occur in patients with a positive response to ICIs. This paper describes the efficacy of ICIs currently in the clinical treatment of CRC, discusses the mechanisms by which acquired resistance occurs, primarily related to loss and impaired presentation of tumor antigens, reduced response of IFN-λ and cytokine or metabolic dysregulation, and summarizes the incidence of adverse effects. We posit that the future of ICIs hinges upon the advancement of precise prediction biomarkers and the implementation of combination therapies. This study aims to elucidate the constraints associated with ICIs in CRC and foster targeted problem-solving approaches, thereby enhancing the potential benefits for more patients.

4-O-Methylascochlorin Synergistically Enhances 5-Fluorouracil-Induced Apoptosis by Inhibiting the Wnt/ß-Catenin Signaling Pathway in Colorectal Cancer Cells.

4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus Ascochyta viciae, shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/ß-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other ß-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells.

ß-hydroxybutyrate resensitizes colorectal cancer cells to oxaliplatin by suppressing H3K79 methylation in vitro and in vivo.

BACKGROUND: Ketone ß-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof. METHODS: CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro. RESULTS: Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function. CONCLUSIONS: ß-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.

An SNP Marker Predicts Colorectal Cancer Outcomes with 5-Fluorouracil-Based Adjuvant Chemotherapy Post-Resection.

Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan-Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the "A/G" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 "A/G" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms.

Influence of Biomarkers on Mortality among Patients with Hepatic Metastasis of Colorectal Cancer Treated with FOLFOX/CAPOX and FOLFIRI/CAPIRI, Including Anti-EGFR and Anti-VEGF Therapies.

Background and objectives: Colorectal cancer is a major global health concern, with a significant increase in morbidity and mortality rates associated with metastatic stages. This study investigates the prognostic significance of various clinical and laboratory parameters in patients with metastatic CRC. Materials and Methods: A retrospective cohort of 188 CRC patients with hepatic metastasis from the OncoHelp Association in Timisoara was analyzed from January 2016 to March 2023. Data on demographics, clinical characteristics, and biomarkers, such as lymphocyte counts, as well as various inflammation indices, were examined. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier survival analysis, and ROC curve assessments. Results: Our findings indicate significant associations between survival outcomes and several biomarkers. Higher BMI and lymphocyte counts were linked with better survival rates, while higher values of Neutrophil-Hemoglobin-Lymphocyte (NHL) score, Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), and Systemic Immune-Inflammation Index (SII) were predictors of poorer outcomes. Notably, the presence of hepatic metastasis at diagnosis was a critical factor, significantly reducing overall survival. Conclusions: The study has expanded the current understanding of prognostic factors in CRC, advocating for a multi-dimensional approach to prognostic evaluations. This approach should consider not only the traditional metrics such as tumor stage and histological grading but also incorporate a broader spectrum of biomarkers. Future studies should aim to validate these findings and explore the integration of these biomarkers into routine clinical practice, enhancing the precision of prognostic assessments and ultimately guiding more personalized treatment strategies for CRC patients.

Risks and Outcomes of Early Dose Reduction in Adjuvant CAPOX Therapy for Colorectal Cancer.

BACKGROUND/AIM: Adjuvant capecitabine and oxaliplatin (CAPOX) therapy is standard strategy for colorectal cancer with risk of recurrence. Early dose reduction (EDR) of CAPOX therapy is commonly used in real-world practice. However, there is limited evidence regarding the effectiveness of CAPOX for patients who had EDR. Therefore, this study aimed to clarify the risks of EDR and its effect on long-term outcomes and body composition factors. PATIENTS AND METHODS: Patients who received CAPOX therapy after radical surgery for colorectal cancer between June 2013 and December 2021 were included. EDR was defined as dose reduction within four courses of CAPOX therapy. Body composition factors were measured for 1 year following surgery to determine the EDR effects. RESULTS: Eighty-four patients were included; 35 (42%) of them had EDR. The multivariate analysis revealed that underweight [odds ratio (OR)=4.95, 95% confidence interval (CI)=1.13-21.7, p=0.03] was a risk factor for EDR. Relapse-free survival (RFS) was significantly better in the non-EDR group (p=0.01). The 5-year RFS rates for the non-EDR and EDR groups were 88.7% and 65.4%, respectively. The multivariate analysis revealed that age >65 years [hazard ratio (HR)=3.97; 95% CI=1.16-13.62, p=0.03] and EDR (HR=7.62; 95% CI=1.71-33.91, p=0.005) were associated with poorer RFS. The 1-year body composition analysis revealed decreases in all factors in the EDR group. CONCLUSION: Preoperative underweight status was associated with EDR, which resulted in decreased RFS and body composition factors when compared with the non-EDR group. Therefore, avoiding EDR and early nutritional intervention after EDR may improve outcomes.

NUAK2 Inhibitors, KHKI-01128 and KHKI-01215, Exhibit Potent Anticancer Activity Against SW480 Colorectal Cancer Cells.

BACKGROUND/AIM: NUAK family kinase 2 (NUAK2) is a promising target for cancer therapeutics due to its reported role in protein phosphorylation, a critical process in cancer cell survival, proliferation, invasion, and senescence. This study aimed to identify novel inhibitors that disrupt NUAK2 activity. We have already identified two KRICT Hippo kinase inhibitor (KHKI) compounds, such as KHKI-01128 and KHKI-01215. Our aim was to evaluate the impact of KHKI-01128 and KHKI-01215 on NUAK2 activity and elucidate its mechanism in colorectal cancer cells. MATERIALS AND METHODS: To evaluate anticancer properties of these inhibitors, four in vitro assays in the SW480 cell line (time-resolved fluorescence resonance energy transfer assay, KINOMEscan kinase profiling, viability, and apoptosis assays) and two pharmacological mechanism analyses (Gene Set Enrichment Analysis and western blotting) were performed. RESULTS: KHKI-01128 and KHKI-01215 exhibited potent inhibitory activity against NUAK2 (half-maximal inhibitory concentration=0.024±0.015 µM and 0.052±0.011 µM, respectively). These inhibitors suppressed cell proliferation, with half-maximal inhibitory concentrations of 1.26±0.17 µM and 3.16±0.30 µM, respectively, and induced apoptosis of SW480 cells. Gene Set Enrichment Analysis revealed negative enrichment scores of -0.84 for KHKI-01128 (false-discovery rate=0.70) and 1.37 for KHKI-01215 (false-discovery rate=0.18), indicating that both effectively suppressed the expression of YES1-associated transcriptional regulator (YAP) target genes. CONCLUSION: These results suggest that KHKI-01128 and KHKI-01215 are potent NUAK2 inhibitors with promising potential for pharmaceutical applications.

Proteomic Analysis of Butyrate-Resistant Colorectal Cancer-Derived Exosomes Reveals Potential Resistance to Anti-Cancer Drugs.

BACKGROUND: Butyrate-resistant (BR) cells play an important role in acquiring chemoresistance in colorectal cancer (CRC). Our previous study demonstrated that BR CRC cells showed cross-resistance to chemotherapy drugs, including 5-fluorouracil and oxaliplatin, in both monolayer and spheroid cultures. The mechanisms underlying drug resistance were also elucidated. However, the link between parental (PT) and BR cells remains unclear. Extracellular vesicles (EVs) are key cell-cell communications that transport various molecules, including DNA, RNA, and proteins, between the donor and target cells. EVs contribute to drug resistance in cancers, such as melanoma and lung cancer. Recently, we focused on the correlation of proteomic profiles of EVs from different cell types. METHODS: In this study, we analyzed the proteomic profiles of EVs derived from PT and BR cells to investigate the mechanisms underlying the butyrate- and chemo-resistant phenotypes. EVs were isolated from PT and BR cells using ultracentrifugation. The characteristics of the EVs were evaluated using western blot and transmission electron microscopy. The EV proteomic data were further analyzed using liquid chromatography-mass spectrometry. RESULTS: We identified a unique protein expressed in BR cells related to the chemoresistant phenotype. Functional enrichment analysis showed that BR cells had higher protein catalytic activity, binding, and transcription activity. The STITCH database showed a greater correlation between protein-drug interactions in BR cells than in PT cells. Moreover, our findings support the hypothesis that EVs promote tumor progression and metastasis and affect the tumor microenvironment. CONCLUSIONS: Proteomic analysis of EVs from BR CRC cells reveals insights into drug resistance mechanisms, including protein-mediated carcinogenesis and reduced drug uptake, offering potential strategies to overcome resistance in clinical practice.

BRAF V600E-mutant colorectal cancer with CNS metastases treated successfully with encorafenib, binimetinib and cetuximab.

This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.

[Box: see text].

[Intraperitoneal chemotherapy for colorectal cancer peritoneal metastasis].

Peritoneal metastasis is one of the common site of colorectal cancer metastasis and associated with a poor prognosis. The core strategy for colorectal cancer peritoneal metastasis primarily revolves around a comprehensive treatment approach with cytoreductive surgery and systemic chemotherapy as the mainstay, supplemented by intraperitoneal chemotherapy. As an important supplement to treatment, intraperitoneal chemotherapy has broad application prospects. The main modalities are hyperthermic intraperitoneal chemotherapy (HIPEC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), early postoperative intraperitoneal chemotherapy (EPIC), sequential postoperative intraperitoneal chemotherapy (SPIC), normothermic intraperitoneal chemotherapy (NIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). To promote the standardized application of intraperitoneal chemotherapy, further research on the mechanisms underlying peritoneal metastasis of colorectal cancer, selection of effective intraperitoneal chemotherapy agents, determination of optimal timing and administration protocols, exploration of the feasibility of sequential intraperitoneal chemotherapy and conduction of valuable basic and clinical research are currently needed. This paper will review the development and origins of intraperitoneal chemotherapy, treatment modalities, as well as the current application status and prospects of various treatment approaches in the context of peritoneal metastasis of colorectal cancer.

Signaling pathways in colorectal cancer implications for the target therapies.

Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.