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1.
BMC Cancer ; 24(1): 939, 2024 Aug 02.
Article in English | MEDLINE | ID: mdl-39095766

ABSTRACT

BACKGROUND: The randomized, dose-optimization, open-label ReDOS study in US patients with metastatic colorectal cancer (CRC) showed that, compared with a standard dosing approach, initiating regorafenib at 80 mg/day and escalating to 160 mg/day depending on tolerability increased the proportion of patients reaching their third treatment cycle and reduced the incidence of adverse events without compromising efficacy. Subsequently, the ReDOS dose-escalation strategy was included as an alternative regorafenib dosing option in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. A retrospective analysis was conducted using a US claims database to assess whether inclusion of this dose-escalation strategy in NCCN Guidelines has influenced the use of flexible dosing in routine US clinical practice, and to describe clinical outcomes pre- and post-inclusion in NCCN Guidelines. METHODS: Patients with CRC in the Optum's de-identified Clinformatics® Data Mart database initiating regorafenib for the first time between January 2016 and June 2020 were stratified based on whether they initiated regorafenib pre- or post-inclusion of ReDOS in NCCN Guidelines, and in two groups: flexible dosing (< 160 mg/day; < 84 tablets in the first treatment cycle) and standard dosing (160 mg/day; ≥ 84 tablets in the first treatment cycle). The primary endpoints were the proportion of patients who initiated their third treatment cycle and the mean number of treatment cycles per group. RESULTS: 703 patients initiated regorafenib during the study period, of whom 310 (44%) initiated before and 393 (56%) initiated after inclusion of ReDOS in NCCN Guidelines. After inclusion in the guidelines, the proportion of patients who received flexible dosing increased from 21% (n = 66/310) to 45% (n = 178/393), the proportion who received standard dosing decreased from 79% (n = 244/310) to 55% (n = 215/393), the proportion who initiated their third treatment cycle increased from 36% (n = 113/310) to 46% (n = 179/393), and the mean (standard deviation) number of treatment cycles increased from 2.6 (2.9) to 3.2 (3.1). CONCLUSIONS: Following inclusion of ReDOS in NCCN Guidelines, real-world data suggest that US clinicians have markedly increased use of flexible dosing in clinical practice, potentially maximizing clinical benefits and safety outcomes for patients with metastatic CRC receiving regorafenib.


Subject(s)
Colorectal Neoplasms , Phenylurea Compounds , Pyridines , Humans , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Phenylurea Compounds/therapeutic use , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridines/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Female , Retrospective Studies , Male , Middle Aged , Aged , United States , Neoplasm Metastasis , Treatment Outcome , Dose-Response Relationship, Drug , Adult
2.
Cell Commun Signal ; 22(1): 388, 2024 Aug 02.
Article in English | MEDLINE | ID: mdl-39095886

ABSTRACT

Acidic microenvironments is a cancer progression driver, unclear core mechanism hinders the discovery of new diagnostic or therapeutic targets. ASIC3 is an extracellular proton sensor and acid-sensitive, but its role in acidic tumor microenvironment of colorectal cancer is not reported. Functional analysis data show that colorectal cancer cells respond to specific concentration of lactate to accelerate invasion and metastasis, and ASIC3 is the main actor in this process. Mechanism reveal de novo lipid synthesis is a regulatory process of ASIC3, down-regulated ASIC3 increases and interacts with ACC1 and SCD1, which are key enzymes in de novo lipid synthesis pathway, this interaction results in increased unsaturated fatty acids, which in turn induce EMT to promote metastasis, and overexpression of ASIC3 reduces acidic TME-enhanced colorectal cancer metastasis. Clinical samples of colorectal cancer also exhibit decreased ASIC3 expression, and low ASIC3 expression is associated with metastasis and stage of colorectal cancer. This study is the first to identify the role of the ASIC3-ACC1/SCD1 axis in acid-enhanced colorectal cancer metastasis. The expression pattern of ASIC3 in colorectal cancer differs significantly from that in other types of cancers, ASIC3 may serve as a novel and reliable marker for acidic microenvironmental in colorectal cancer, and potentially a therapeutic target.


Subject(s)
Acid Sensing Ion Channels , Colorectal Neoplasms , Epithelial-Mesenchymal Transition , Lactic Acid , Neoplasm Metastasis , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Acid Sensing Ion Channels/metabolism , Acid Sensing Ion Channels/genetics , Lactic Acid/metabolism , Cell Line, Tumor , Stearoyl-CoA Desaturase/metabolism , Stearoyl-CoA Desaturase/genetics , Tumor Microenvironment , Animals , Lipids , Gene Expression Regulation, Neoplastic
3.
PLoS One ; 19(8): e0308051, 2024.
Article in English | MEDLINE | ID: mdl-39093890

ABSTRACT

Preclinical models that replicate patient tumours as closely as possible are crucial for translational cancer research. While in vitro cancer models have many advantages in assessing tumour response therapy, in vivo systems are essential to enable evaluation of the role of the tumour cell extrinsic factors, such as the tumour microenvironment and host immune system. The requirement for a functional immune system is particularly important given the current focus on immunotherapies. Therefore, we set out to generate an immunocompetent, transplantable model of colorectal cancer suitable for in vivo assessment of immune-based therapeutic approaches. Intestinal tumours from a genetically engineered mouse model, driven by expression of a Pik3ca mutation and loss of Apc, were transplanted into wild type C57BL/6 host mice and subsequently passaged to form a novel syngeneic transplant model of colorectal cancer. Our work confirms the potential to develop a panel of mouse syngeneic grafts, akin to human PDX panels, from different genetically engineered, or carcinogen-induced, mouse models. Such panels would allow the in vivo testing of new pharmaceutical and immunotherapeutic treatment approaches across a range of tumours with a variety of genetic driver mutations.


Subject(s)
Adenocarcinoma , Class I Phosphatidylinositol 3-Kinases , Disease Models, Animal , Mice, Inbred C57BL , Animals , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Mice , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Intestinal Neoplasms/genetics , Intestinal Neoplasms/pathology , Adenomatous Polyposis Coli Protein/genetics , Phosphatidylinositol 3-Kinases/metabolism , Transplantation, Isogeneic , Mutation , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology
4.
Langenbecks Arch Surg ; 409(1): 242, 2024 Aug 06.
Article in English | MEDLINE | ID: mdl-39105876

ABSTRACT

PURPOSE: The value of upfront primary tumor resection (PTR) for asymptomatic unresectable metastatic colorectal cancer (mCRC) patients remains contentious. This meta-analysis aimed to assess the prognostic significance of upfront PTR for asymptomatic unresectable mCRC. METHODS: A systematic literature search was performed on June 21st, 2024. To minimize the bias and ensure robust evidence, only randomized controlled trials (RCTs) and case-matched studies (CMS) that compared PTR followed by chemotherapy to chemotherapy alone were included. The primary outcome was overall survival (OS), while cancer-specific survival (CSS) served as the secondary outcome. RESULTS: Eight studies (three RCTs and five CMS) involving 1221 patients were included. Compared to chemotherapy alone, upfront PTR followed by chemotherapy did not improve OS (hazard ratios [HR] 0.91, 95% confidence interval [CI] 0.79-1.04, P = 0.17), but was associated with slightly better CSS (HR 0.59, 95% CI 0.40-0.88, P = 0.009). CONCLUSIONS: The current limited evidence indicates that upfront PTR does not improve OS but may enhance CSS in asymptomatic unresectable mCRC patients. Ongoing trials are expected to provide more reliable evidence on this issue.


Subject(s)
Colorectal Neoplasms , Randomized Controlled Trials as Topic , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , Colorectal Neoplasms/surgery , Asymptomatic Diseases , Case-Control Studies , Prognosis
5.
Ned Tijdschr Geneeskd ; 1682024 07 24.
Article in Dutch | MEDLINE | ID: mdl-39087450

ABSTRACT

In case of suspicion of a T1 colorectal tumor, the tumor should not be biopsied but removed completely (so-called en-bloc resection). With more recent endoscopic techniques, T1 colorectal tumors can be more often radical resected. If at least one of the following four characteristics is present, there is a high-risk T1 colorectal tumor and it is recommended to consider surgical resection with adequate lymphadenectomy; poor differentiation, presence of (lymphatic) angioinvasion, high-grade tumor budding (grade 2-3) and a positive resection margin (where the malignant cells approach the cut edge to 0.1mm). The risk of recurrent disease after endoscopic resection of a high-risk T1 colorectal tumor without additional surgery is not well known. Scheduled surgery for bowel cancer at an early stage is associated with the same risk of a serious complication and/or death as scheduled surgery at a more advanced stage.


Subject(s)
Colorectal Neoplasms , Humans , Colorectal Neoplasms/surgery , Colorectal Neoplasms/pathology , Neoplasm Staging , Lymph Node Excision , Neoplasm Recurrence, Local
6.
Med ; 5(8): 839-841, 2024 Aug 09.
Article in English | MEDLINE | ID: mdl-39127029

ABSTRACT

dMMR tumors, which have high tumor mutational and neoantigen burdens, are highly responsive to immune checkpoint blockade. Wu et al.1 showed that combining COX inhibitors with PD-1 blockade could be a safe and effective treatment option for dMMR metastatic colorectal cancer. The study highlights the potential of this combination therapy in achieving deep and long-lasting responses in dMMR colorectal cancers.


Subject(s)
Colorectal Neoplasms , Immune Checkpoint Inhibitors , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Cyclooxygenase Inhibitors/therapeutic use , Cyclooxygenase Inhibitors/pharmacology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Antigen Presentation/drug effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology
7.
Turk J Gastroenterol ; 35(6): 465-474, 2024 Jun.
Article in English | MEDLINE | ID: mdl-39128081

ABSTRACT

BACKGROUND/AIMS:  Incidence of colorectal cancer is rapidly increasing worldwide. Extracellular superoxide dismutase (EcSOD; SOD3) is an antioxidant enzyme. However, SOD3 roles in colorectal cancer progression remain uncertain. MATERIALS AND METHODS:  Superoxide dismutase 3 expression was evaluated, and we analyzed clinical relevance of SOD3 expression in colorectal cancer. Subsequently, SOD3 roles in colorectal cancer progression were detected by gain of function experiments. Changes in subcutaneous tumor and liver nodule size after SOD3 overexpression were examined in nude mice. The expression of proliferation marker Ki67 was assessed by immunohistochemical staining. RESULTS:  Supperoxide dismutase 3 was downregulated in colorectal cancer (P <.01). Downregulation of SOD3 was correlated with unfavorable outcomes (P < .05). Superoxide dismutase 3 upregulation limited the proliferative (P <.05), migrative (P <.01) and invasive actions of colorectal cancer cells (P <.01) by suppressing epithelial-mesenchymal transition. Moreover, SOD3 overexpression reduced Ki67 expression (P <.01) and blocked tumor growth (P <01) and liver metastasis (P <.001) in mouse tumor model. CONCLUSION:  Superoxide dismutase 3 upregulation attenuates tumor growth and liver metastasis in colorectal cancer, suggesting that SOD3 has potential diagnostic and prognostic values regarding colorectal cancer treatment.


Subject(s)
Cell Movement , Cell Proliferation , Colorectal Neoplasms , Epithelial-Mesenchymal Transition , Mice, Nude , Superoxide Dismutase , Superoxide Dismutase/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Humans , Animals , Mice , Male , Female , Up-Regulation , Down-Regulation , Liver Neoplasms/pathology , Ki-67 Antigen/metabolism , Cell Line, Tumor , Disease Progression , Middle Aged , Mice, Inbred BALB C
8.
Turk J Gastroenterol ; 35(4): 288-298, 2024 Apr.
Article in English | MEDLINE | ID: mdl-39128094

ABSTRACT

BACKGROUND/AIMS:  Anti-programmed cell death protein 1 (PD-1) treatment has exhibited clinical benefits in colorectal cancer (CRC). However, the low response rate of CRC to immunotherapy is an urgent problem that needs to be solved. MATERIALS AND METHODS:  MC-38 tumor cells was challenged subcutaneously in the flank of 7-week-old male C57BL/6 mice. The mice were randomly divided into 3 groups, and 200µg/mouse anti-PD-1 antibody and 100 mg/kg RAS-Seletive Lethal 3 (RSL) or phosphate buffer saline (PBS) were intraperitoneally injected every 2 days. The expression of oxidative stress and ferroptosis-related genes was measured by Western blotting, real-time reverse transcription-polymerase chain reaction, Prussian blue staining, and enzyme-linked immunosorbent assay. RESULTS:  Anti-PD-1 treatment-unresponsive tumors showed stronger immunosuppression than responsive tumors. Notably, the responsive tumors showed higher levels of H2O2 and reactive oxygen species, both of which could impair the antitumor effect of cytotoxic CD8+ T cells. The anti-PD-1 treatment-responsive tumors showed a higher expression of pro-ferroptosis genes and Fe2+ accumulation than those of anti-PD-1 nonresponsive tumors, indicating the potential role of ferroptosis in the efficacy of anti-PD-1 treatment. In MC-38 syngeneic tumor model, (1S, 3R)-RSL3 (RSL), a glutathione peroxidase 4 inhibitor, effectively promoted the antitumor effect of anti-PD-1 treatment in vivo. However, anti-PD-1 treatment did not affect the levels of ferroptosis-related genes in tumor model. Mechanistically, RSL treatment significantly upregulated the frequency of proliferating (ki67+) and cytotoxic (GZMB+) CD8+ T cells. Furthermore, the frequency of tumor neoantigen-specific interferon (IFN)-γ CD8+ T cells showed a significant increase after RSL plus anti-PD-1 treatment. CONCLUSION:  RSL may be a promising drug for potentiating the antitumor efficiency of anti-PD-1 treatment in CRC.


Subject(s)
Colorectal Neoplasms , Ferroptosis , Mice, Inbred C57BL , Programmed Cell Death 1 Receptor , Animals , Ferroptosis/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Male , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Cell Line, Tumor , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Oxidative Stress/drug effects , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Reactive Oxygen Species/metabolism , Disease Models, Animal , Immunotherapy/methods , Carbolines
9.
Cancer Cell ; 42(8): 1370-1385.e9, 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39137726

ABSTRACT

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS- tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS- tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.


Subject(s)
Chemokine CCL19 , Colorectal Neoplasms , Immunoglobulin G , Liver Neoplasms , Tertiary Lymphoid Structures , Colorectal Neoplasms/pathology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/metabolism , Animals , Tertiary Lymphoid Structures/immunology , Tertiary Lymphoid Structures/pathology , Humans , Liver Neoplasms/immunology , Liver Neoplasms/secondary , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Mice , Immunoglobulin G/immunology , Chemokine CCL19/metabolism , Chemokine CCL19/genetics , Fibroblasts/metabolism , Fibroblasts/immunology , Antibodies, Monoclonal/pharmacology , Plasma Cells/immunology , Plasma Cells/metabolism , Female , Cell Line, Tumor
10.
Cancer Cell ; 42(8): 1386-1400.e8, 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39137727

ABSTRACT

Changes in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848-0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC.


Subject(s)
Adenoma , Biomarkers, Tumor , Colorectal Neoplasms , Disease Progression , Feces , Metabolomics , Humans , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/blood , Colorectal Neoplasms/pathology , Feces/chemistry , Adenoma/metabolism , Adenoma/diagnosis , Adenoma/pathology , Adenoma/blood , Metabolomics/methods , Animals , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/blood , Mice , Male , Female , Early Detection of Cancer/methods , Metabolome , Middle Aged , Oleic Acid/metabolism , Oleic Acid/blood , Aged
11.
Cell Biol Toxicol ; 40(1): 64, 2024 Aug 03.
Article in English | MEDLINE | ID: mdl-39096436

ABSTRACT

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) is a widespread malignancy with a complex and not entirely elucidated pathogenesis. This study aims to explore the role of Bifidobacterium in the urea cycle (UC) and its influence on the progression of CRC, a topic not extensively studied previously. EXPERIMENTAL APPROACH: Utilizing both bioinformatics and experimental methodologies, this research involved analyzing bacterial abundance in CRC patients in comparison to healthy individuals. The study particularly focused on the abundance of BA. Additionally, transcriptomic data analysis and cellular experiments were conducted to investigate the impact of Bifidobacterium on ammonia metabolism and mitochondrial function, specifically examining its regulation of the key UC gene, ALB. KEY RESULTS: The analysis revealed a significant decrease in Bifidobacterium abundance in CRC patients. Furthermore, Bifidobacterium was found to suppress ammonia metabolism and induce mitochondrial dysfunction through the regulation of the ALB gene, which is essential in the context of UC. These impacts contributed to the suppression of CRC cell proliferation, a finding corroborated by animal experimental results. CONCLUSIONS AND IMPLICATIONS: This study elucidates the molecular mechanism by which Bifidobacterium impacts CRC progression, highlighting its role in regulating key metabolic pathways. These findings provide potential targets for novel therapeutic strategies in CRC treatment, emphasizing the importance of microbiota in cancer progression.


Subject(s)
Bifidobacterium , Colorectal Neoplasms , Urea , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/microbiology , Colorectal Neoplasms/pathology , Bifidobacterium/metabolism , Humans , Urea/metabolism , Animals , Cell Proliferation , Ammonia/metabolism , Mice , Mitochondria/metabolism , Cell Line, Tumor , Male , Gastrointestinal Microbiome/physiology , Female
12.
Turk J Gastroenterol ; 35(7): 532-538, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39128096

ABSTRACT

BACKGROUND/AIMS:  Colorectal cancer (CRC) is a prevalent gastrointestinal cancer with high incidence and mortality rate. lncRNAs could regulate the expression of miRNAs and further affect cancer development. Previous research has suggested that FAM30A is involved in various cancer. We aimed to investigate the function of FAM30A in the prognosis of CRC and its underlying molecular mechanisms. MATERIALS AND METHODS:  Matched tissues were collected from 107 CRC patients. FAM30A was measured by quantitative real-time transcription polymerase chain reaction and its clinical significance was evaluated by its correlation with patients' prognosis and clinicopathological features. Furthermore, the dual luciferase reporter assays were employed to assess the interactions between FAM30A and miR-21-3p and to evaluate the role of miR-21-3p in regulating the tumor suppressor effects of FAM30A. Cell proliferation and metastasis were evaluated by the Transwell assay and cell counting kit-8 assay. RESULTS:  FAM30A level was markedly decreased in CRC tissues (P <.001). A prominent association was observed in FAM30A with tumor- node-metastasis stage (P = .022), carcinoembryonic antigen (P = .027), and differentiation (P = .043) of CRC patients. The lower the FAM30A level was associated with the lower the survival rate of the CRC patients (log rank P = .034). FAM30A could negatively modulate miR-21-3p (P <.001), and the overexpression of FAM30A significantly suppressed CRC cell proliferation and metastasis (P <.001). The suppressive function of FAM30A overexpression was mediated by miR-21-3p. CONCLUSION:  FAM30A can be considered a poor prognostic indicator in CRC. Decreased FAM30A can promote the proliferation and metastasis of CRC cells by negatively regulating miR-21-3p.


Subject(s)
Cell Proliferation , Colorectal Neoplasms , Gene Expression Regulation, Neoplastic , MicroRNAs , RNA, Long Noncoding , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Male , Female , Prognosis , Middle Aged , Cell Proliferation/genetics , Cell Line, Tumor , Aged , Down-Regulation
13.
J Biochem Mol Toxicol ; 38(8): e23799, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39132768

ABSTRACT

It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17ß-estradiol (E2) signaling is also known to modulate glycolysis markers in cancer cells. However, whether the inhibition of PKM2 combined with E2 treatment could adversely affect glucose metabolism in CRC cells remains to be investigated. First, we confirmed the metabolic plasticity of CRC cells under varying environmental conditions. Next, we identified glycolysis markers that were upregulated in CRC patients and assessed in vitro mRNA levels following E2 treatment. We found that PKM2 expression, which is highly upregulated in CRC clinical samples, is not altered by E2 treatment in CRC cells. In this study, glucose uptake, generation of reactive oxygen species (ROS), lactate production, cell viability, and apoptosis were evaluated in CRC cells following E2 treatment, PKM2 silencing, or a combination of both. Compared to individual treatments, combination therapy resulted in a significant reduction in cell viability and enhanced apoptosis. Glucose uptake and ROS production were markedly reduced in PKM2-silenced E2-treated cells. The data presented here suggest that E2 signaling combined with PKM2 inhibition cumulatively targets glucose metabolism in a manner that negatively impacts CRC cell growth. These findings hold promise for novel therapeutic strategies targeting altered metabolic pathways in CRC.


Subject(s)
Colorectal Neoplasms , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Thyroid Hormones/metabolism , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Estrogens/pharmacology , Thyroid Hormone-Binding Proteins , Estradiol/pharmacology , Apoptosis/drug effects , Glucose/metabolism , Carrier Proteins/metabolism , Pyruvate Kinase/metabolism , Pyruvate Kinase/antagonists & inhibitors , Pyruvate Kinase/genetics , Glycolysis/drug effects , Membrane Proteins/metabolism , Membrane Proteins/genetics , Female
14.
BMJ Open Gastroenterol ; 11(1)2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39106985

ABSTRACT

BACKGROUND: Faecal immunochemical test (FIT)-based screening is effective in reducing colorectal cancer (CRC) incidence, but its sensitivity for proximal lesions remains low. OBJECTIVES: We compared age-adjusted CRC surgical resection rates across anatomic sites (proximal colon, distal colon, rectum), age groups and sex over 20 years in a large Italian population. We particularly focused on changes in trends following FIT-screening implementation in the target population (50-69 years). DESIGN: This retrospective study analysed data from the Veneto Region's administrative Hospital Discharge Dataset, involving over 54 000 patients aged 40-89 (43.4% female) who underwent CRC surgery between 2002 and 2021. RESULTS: Overall, surgery rates increased until 2007 (annual percentage changes: 2.5% in males, 2.9% in females) and then declined (-4.2% in males, -3.4% in females). This decline was steeper for distal and rectal cancers compared with proximal cancer, suggesting a shift towards more right-sided CRC surgery.In males, the prescreening increase in proximal surgery was reversed after screening implementation (slope change: -6%) while the prescreening decline accelerated for distal (-4%) and rectal (-3%) surgeries. In females, stable prescreening trends shifted downward for all sites (-5% for proximal, -8% for distal and -7% for rectal surgery). However, the change in trends between prescreening and postscreening periods was not different across anatomic sites for either sex (all slope change differences in pairwise comparisons were not statistically significant). CONCLUSION: The shift towards proximal surgery may not be entirely due to the FIT's low sensitivity but may reflect an underlying upward trend in proximal cancers independent of screening.


Subject(s)
Colorectal Neoplasms , Early Detection of Cancer , Humans , Male , Italy/epidemiology , Female , Retrospective Studies , Middle Aged , Aged , Early Detection of Cancer/methods , Early Detection of Cancer/trends , Early Detection of Cancer/statistics & numerical data , Colorectal Neoplasms/surgery , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/pathology , Adult , Aged, 80 and over , Occult Blood , Mass Screening/methods , Mass Screening/trends , Mass Screening/statistics & numerical data , Incidence
15.
Cancer Control ; 31: 10732748241270582, 2024.
Article in English | MEDLINE | ID: mdl-39109953

ABSTRACT

SIGNIFICANCE: This study on the relationship between early life high BMI and the development of CRC reveals the role of high BMI during childhood and adolescence in the occurrence and progression of CRC. It suggests the importance of restoring normal weight or reducing weight in individuals with high BMI early in life for the prevention of colorectal cancer.


Subject(s)
Body Mass Index , Colorectal Neoplasms , Humans , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms/pathology , Female , Male , Adolescent , Adult , Child , Risk Factors , Middle Aged , Young Adult
16.
J Cancer Res Clin Oncol ; 150(8): 386, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39110225

ABSTRACT

Colorectal cancer (CRC) remains a highly prevalent gastrointestinal neoplasm, presenting significant prevalence and lethality rate. DEAD/H box RNA helicase 10 (DDX10) has been proposed as a potential oncogene in CRC, the specific action mechanism by which DDX10 modulates the aggressive biological cellular events in CRC remains implicitly elucidated, however. During this study, DDX10 expression was detected via RT-qPCR and Western blotting. Cell proliferation was estimated via EDU staining. TUNEL staining and Western blotting appraised cell apoptosis. Cell stemness was evaluated by sphere formation assay, RT-qPCR, Western blotting as well as immunofluorescence staining. Relevant assay kit examined aldehyde dehydrogenase (ALDH) activity. Western blotting and immunofluorescence staining also detected autophagy. DDX10 was hyper-expressed in CRC cells. Down-regulation of DDX10 hampered cell proliferation, aggravated the apoptosis while eliminated the ability to form spheroid cells in CRC. In addition, DDX10 deletion improved ATG10 expression and therefore activated autophagy in CRC cells. Consequently, ATG10 depletion or treatment with autophagy inhibitor 3-Methyladenine (3-MA) partially compensated the influences of DDX10 silencing on the proliferation, apoptosis and stemness of CRC cells. Accordingly, DDX10 deficiency may aggravate autophagy mediated by ATG10 to impede cell proliferation, stemness and facilitate cell apoptosis, hence blocking the progression of CRC.


Subject(s)
Apoptosis , Autophagy-Related Proteins , Autophagy , Cell Proliferation , Colorectal Neoplasms , DEAD-box RNA Helicases , Neoplastic Stem Cells , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Autophagy/physiology , DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , Autophagy-Related Proteins/metabolism , Autophagy-Related Proteins/genetics , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/metabolism , Cell Line, Tumor , Ubiquitin-Conjugating Enzymes/metabolism , Ubiquitin-Conjugating Enzymes/genetics , Mice , Animals , Vesicular Transport Proteins
17.
Cell Biol Toxicol ; 40(1): 66, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39110260

ABSTRACT

OBJECTIVE: Colorectal cancer progression involves complex cellular mechanisms. This study examines the effects of Lactobacillus plantarum-derived extracellular vesicles (LEVs) on the SIRT5/p53 axis, focusing on glycolytic metabolic reprogramming and abnormal proliferation in intestinal epithelial cells. METHODS: LEVs were isolated from Lactobacillus plantarum and incubated with Caco-2 cells. Differential gene expression was analyzed through RNA sequencing and compared with TCGA-COAD data. Key target genes and pathways were identified using PPI network and pathway enrichment analysis. Various assays, including RT-qPCR, EdU staining, colony formation, flow cytometry, and Western blotting, were used to assess gene expression, cell proliferation, and metabolic changes. Co-immunoprecipitation confirmed the interaction between SIRT5 and p53, and animal models were employed to validate in vivo effects. RESULTS: Bioinformatics analysis indicated the SIRT5/p53 axis as a critical pathway in LEVs' modulation of colorectal cancer. LEVs were found to inhibit colorectal cancer cell proliferation and glycolytic metabolism by downregulating SIRT5, influencing p53 desuccinylation. In vivo, LEVs regulated this axis, reducing tumor formation in mice. Clinical sample analysis showed that SIRT5 and p53 succinylation levels correlated with patient prognosis. CONCLUSION: Lactobacillus-derived extracellular vesicles play a pivotal role in suppressing colonic tumor formation by modulating the SIRT5/p53 axis. This results in decreased glycolytic metabolic reprogramming and reduced proliferation in intestinal epithelial cells.


Subject(s)
Cell Proliferation , Colorectal Neoplasms , Extracellular Vesicles , Glycolysis , Sirtuins , Tumor Suppressor Protein p53 , Sirtuins/metabolism , Sirtuins/genetics , Tumor Suppressor Protein p53/metabolism , Humans , Extracellular Vesicles/metabolism , Animals , Caco-2 Cells , Mice , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Epithelial Cells/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Lactobacillus plantarum/metabolism , Mice, Nude , Mice, Inbred BALB C
18.
Technol Cancer Res Treat ; 23: 15330338241271906, 2024.
Article in English | MEDLINE | ID: mdl-39110418

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) remains a global health concern with persistently high incidence and mortality rates. However, the specific pathogenesis of CRC remains poorly understood. This study aims to investigate the role and pathogenesis of serine and arginine rich splicing factor 10 (SRSF10) in colorectal cancer. METHODS: Bioinformatics analysis was employed to predict SRSF10 gene expression in CRC patients. Functional experiments involving SRSF10 knockdown and overexpression were conducted using CCK8, transwell, scratch assay, and flow cytometry. Additionally, the PRIdictor website was utilized to predict the SRSF10 interaction site with RFC5. The identification of different transcripts of SRSF10-acting RFC5 pre-mRNA was achieved through agarose gel electrophoresis. RESULT: The knockdown of SRSF10 inhibited the proliferation and migration ability of CRC cells, while promoting apoptosis and altering the DNA replication of CRC cells. Conversely, when SRSF10 was highly expressed, it enhanced the proliferation and migration ability of CRC cells and caused changes in the cell cycle of colorectal cancer cells. This study revealed a change in the replicating factor C subunit 5 (RFC5) gene in colorectal cancer cells following SRSF10 knockdown. Furthermore, it was confirmed that SRSF10 increased RFC5 exon2-AS1(S) transcription variants, thereby promoting the development of colorectal cancer through AS1 exclusion to exon 2 of RFC5. CONCLUSION: In summary, this study demonstrates that SRSF10 promotes the progression of colorectal cancer by generating an aberrantly spliced exclusion isoform of AS1 within RFC5 exon 2. These findings suggest that SRSF10 could serve as a crucial target for the clinical diagnosis and treatment of CRC.


Subject(s)
Alternative Splicing , Apoptosis , Cell Movement , Cell Proliferation , Colorectal Neoplasms , Disease Progression , Gene Expression Regulation, Neoplastic , Replication Protein C , Serine-Arginine Splicing Factors , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Serine-Arginine Splicing Factors/genetics , Serine-Arginine Splicing Factors/metabolism , Cell Proliferation/genetics , Cell Movement/genetics , Apoptosis/genetics , Cell Line, Tumor , Replication Protein C/genetics , Replication Protein C/metabolism , Gene Knockdown Techniques , Repressor Proteins , Cell Cycle Proteins
19.
Cell Death Dis ; 15(8): 570, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39112459

ABSTRACT

Bromodomain Adjacent to Zinc Finger Domain 1A (BAZ1A) is a critical regulator of chromatin remodeling. We sought to clarify the roles of BAZ1A in the etiology of colorectal cancer, including the mechanisms of its alternatively spliced variants. Public databases were examined and revealed high BAZ1A expression in the majority of colorectal cancer patients, which was corroborated in a panel of human colon cancer cell lines. BAZ1A silencing reduced cell viability and increased markers of DNA damage, apoptosis, and senescence, along with the downregulation of Wnt/ß-catenin signaling. The corresponding molecular changes resulted in tumor growth inhibition when BAZ1A-knockout cells were implanted into nude mice. In rescue experiments, a short isoform of BAZ1A that was associated with alternative splicing by the DBIRD complex failed to restore DNA repair activity in colon cancer cells and maintained chemosensitivity to phleomycin treatment, unlike the full-length BAZ1A. A working model proposes that a buried domain in the N-terminus of the BAZ1A short isoform lacks the ability to access linker DNA, thereby disrupting the activity of the associated chromatin remodeling complexes. Given the current interest in RNA splicing deregulation and cancer etiology, additional mechanistic studies are warranted with new lead compounds targeting BAZ1A, and other members of the BAZ family, with a view to improved therapeutic interventions.


Subject(s)
Alternative Splicing , Colorectal Neoplasms , DNA Damage , Mice, Nude , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Alternative Splicing/genetics , Alternative Splicing/drug effects , Animals , Mice , Cell Line, Tumor , Apoptosis/drug effects , Apoptosis/genetics , Gene Expression Regulation, Neoplastic/drug effects , Wnt Signaling Pathway/drug effects , DNA Repair/drug effects , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Transcription Factors/metabolism , Transcription Factors/genetics , HCT116 Cells
20.
J Cancer Res Clin Oncol ; 150(8): 388, 2024 Aug 09.
Article in English | MEDLINE | ID: mdl-39120743

ABSTRACT

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a crucial role in the progression of colorectal cancer (CRC). However, the impact of CAF subpopulation trajectory differentiation on CRC remains unclear. METHODS: In this study, we first explored the trajectory differences of CAFs subpopulations using bulk and integrated single-cell sequencing data, and then performed consensus clustering of CRC samples based on the trajectory differential genes of CAFs subpopulations. Subsequently, we analyzed the heterogeneity of CRC subtypes using bioinformatics. Finally, we constructed relevant prognostic signature using machine learning and validated them using spatial transcriptomic data. RESULTS: Based on the differential genes of CAFs subpopulation trajectory differentiation, we identified two CRC subtypes (C1 and C2) in this study. Compared to C1, C2 exhibited worse prognosis, higher immune evasion microenvironment and high CAF characteristics. C1 was primarily associated with metabolism, while C2 was primarily associated with cell metastasis and immune regulation. By combining 101 combinations of 10 machine learning algorithms, we developed a High-CAF risk signatures (HCAFRS) based on the C2 characteristic gene. HCAFRS was an independent prognostic factor for CRC and, when combined with clinical parameters, significantly predicted the overall survival of CRC patients. HCAFRS was closely associated with epithelial-mesenchymal transition, angiogenesis, and hypoxia. Furthermore, the risk score of HCAFRS was mainly derived from CAFs and was validated in the spatial transcriptomic data. CONCLUSION: In conclusion, HCAFRS has the potential to serve as a promising prognostic indicator for CRC, improving the quality of life for CRC patients.


Subject(s)
Cancer-Associated Fibroblasts , Colorectal Neoplasms , Tumor Microenvironment , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Humans , Cancer-Associated Fibroblasts/pathology , Cancer-Associated Fibroblasts/metabolism , Prognosis , Tumor Microenvironment/genetics , Cluster Analysis , Machine Learning , Biomarkers, Tumor/genetics , Transcriptome , Gene Expression Regulation, Neoplastic , Gene Expression Profiling/methods , Female , Male
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