RESUMO
Purpose Metabolic reprogramming is a novel hallmark and therapeutic target of cancer. Our study aimed to establish fatty acid metabolism-associated scores based on gene signature and investigated its effects on immunotherapy in colon cancer. Methods Gene expression and clinical information were collected from Gene Expression Omnibus (GEO) database to identify a gene signature by non-negative matrix factorization (NMF) clustering and Cox regression analysis. Subsequently, we constructed the fatty acid metabolism score (FA-score) model by principal component analysis (PCA) and explored its relativity of prognosis and the response to immunotherapy in colon cancer. Finally, the Cancer Genome Atlas (TCGA) database was introduced and in vitro study was performed for verification. Results The FA-score-high group had a higher level of fatty acid metabolism and was associated with worse patient overall survival. Significantly, FA-score correlated closely with the biomarkers of immunotherapy, and the FA-score-high group had a poorer therapeutic efficacy of immune checkpoint blockade. In vitro experiments demonstrated that ACSL5 may be a critical metabolic regulatory target. Conclusions Our study provided a comprehensive analysis of the heterogeneity of fatty acid metabolism in colon cancer. We highlighted the potential clinical utility of fatty acid metabolism-related genes to be biomarkers of colon cancer prognosis and targets to improve the effect of immunotherapy (AU)
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Humanos , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Imunoterapia/métodos , Biomarcadores/sangue , Ácidos Graxos , PrognósticoRESUMO
INTRODUCTION: Debate exists concerning the impact of complete mesocolic excision (CME) on long-term oncological outcomes. The aim of this review was to condense the updated literature and assess the effect of CME on long-term survival after right colectomy for cancer. METHODS: PubMed, MEDLINE, Scopus, and Web of Science were searched through July 2023. The included studies evaluated the effect of CME on survival. The primary outcome was long-term overall survival. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures. GRADE methodology was used to summarize the certainty of evidence. RESULTS: Ten studies (3665 patients) were included. Overall, 1443 (39.4%) underwent CME. The RMSTD analysis shows that at 60-month follow-up, stage I-III CME patients lived 2.5 months (95% CI 1.1-4.1) more on average compared with noCME patients. Similarly, stage III patients that underwent CME lived longer compared to noCME patients at 55-month follow-up (6.1 months; 95% CI 3.4-8.5). The time-dependent HRs analysis for CME vs. noCME (stage I-III disease) shows a higher mortality hazard in patients with noCME at 6 months (HR 0.46, 95% CI 0.29-0.71), 12 months (HR 0.57, 95% CI 0.43-0.73), and 24 months (HR 0.73, 95% CI 0.57-0.92) up to 27 months. CONCLUSIONS: This study suggests that CME is associated with unclear OS benefit in stage I-III disease. Caution is recommended to avoid overestimation of the effect of CME in stage III disease since the marginal benefit of a more extended resection may have been influenced by tumor biology/molecular profile and multimodal adjuvant treatments.
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Neoplasias do Colo , Humanos , Resultado do Tratamento , Intervalo Livre de Doença , Taxa de Sobrevida , Neoplasias do Colo/patologia , Colectomia/métodosRESUMO
As a major public health issue, colorectal cancer causes 9.4% of total cancer-related deaths and comprises 10% of new cancer diagnoses worldwide. In the year 2023, an estimated 153,020 people are expected to receive an identification of colorectal cancer (CRC), resulting in roughly 52,550 fatalities anticipated as a result of this illness. Among those impacted, approximately 19,550 cases and 3750 deaths are projected to occur in individuals under the age of 50. Irinotecan (IRN) is a compound derived from the chemical structure of camptothecin, a compound known for its action in inhibiting DNA topoisomerase I. It is employed in the treatment strategy for CRC therapies. Comprehensive in vivo and in vitro studies have robustly substantiated the anticancer efficacy of these compounds against colon cancer cell lines. Blending irinotecan in conjunction with other therapeutic cancer agents such as oxaliplatin, imiquimod, and 5 fluorouracil enhanced cytotoxicity and improved chemotherapeutic efficacy. Nevertheless, it is linked to certain serious complications and side effects. Utilizing nano-formulated prodrugs within "all-in-one" carrier-free self-assemblies presents an effective method to modify the pharmacokinetics and safety portfolio of cytotoxic chemotherapeutics. This review focuses on elucidating the mechanism of action, exploring synergistic effects, and innovating novel delivery approaches to enhance the therapeutic efficacy of irinotecan.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Colo , Humanos , Irinotecano/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Fluoruracila/farmacologiaRESUMO
BACKGROUND: There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy. METHODS: Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher's exact test. ROC curve and surv_cutpoint function of 'survminer' package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors. RESULTS: A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy. CONCLUSIONS: Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.
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Neoplasias do Colo , Neoplasias Retais , Humanos , Estudos Retrospectivos , Estudos de Coortes , ImunoterapiaRESUMO
αPhellandrene (αPA), a natural constituent of herbs, inhibits cancer cell viability and proliferation. 5Fluorouracil (5FU) is a frequently utilized chemotherapeutic medicine for the treatment of colon cancer, which works by triggering cancer cell apoptosis. The present study examined how the combination of αPA and 5FU affects the suppression of human colon cancer cells by promoting apoptosis. The impact of this treatment on cell viability, apoptosis, and the expression levels of Bcl2 family members, caspase family members and mitochondriarelated molecules in HT29 cells was assessed by the MTT assay, immunocytochemistry, western blotting and quantitative PCR. The combination of 5FU and αPA had a synergistic inhibitory effect on cell viability, as determined by assessing the combination index value. Bax protein expression levels were higher in the 50, 100 or 250 µM αPA combined with 5FU groups compared with those in the 5FU alone group (P<0.05). By contrast, Bcl2 protein expression levels and mitochondrial membrane potential (MMP, ΔΨm) were lower in the 100 or 250 µM αPA combined with 5FU groups than those in the 5FU alone group (P<0.05). In addition, hexokinase2 (HK2) protein expression levels were lower in the 50, 100 or 250 µM αPA combined with 5FU groups than those in the 5FU alone group (P<0.05). Compared with 5FU alone, after HT29 cells were treated with 50, 100 or 250 µM αPA combined with 5FU, the mRNA expression levels of extrinsicinduced apoptotic molecules, including caspase8 and Bid, were higher (P<0.05). Treatment with 50, 100 or 250 µM αPA combined with 5FU also increased the mRNA expression levels of cytochrome c, caspase9 and caspase3, regulating intrinsic apoptosis (P<0.05). These results showed that αPA and 5FU had a synergistic effect on reducing the viability of human colon cancer HT29 cells by inducing extrinsic and intrinsic apoptosis pathways. The mechanism by which apoptosis is induced may involve the intrinsic apoptosis pathway that activates the mitochondriadependent pathway, including regulating the expression levels of Bcl2 family members, including Bax, Bcl2 and Bid, regulating MMP and HK2 expression levels, and increasing the expression of caspase cascade molecules, including caspase9 and caspase3. In addition, it may involve the extrinsic apoptosis pathway that activates caspase8 and caspase3 leading to apoptosis.
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Neoplasias do Colo , Monoterpenos Cicloexânicos , Fluoruracila , Humanos , Fluoruracila/farmacologia , Caspase 3 , Caspase 9 , Caspase 8 , Células HT29 , Apoptose , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Caspases , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA MensageiroRESUMO
Recent evidence has proved that curcumin as a natural polyphenol have a great anticancer and anti-proliferative effects in cancer cells. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. In this study, we aimed to examine the effects of curcumin in ferroptosis of human colorectal cancer cells and its underlying molecular mechanisms. SW-480 colorectal cancer cells were treated by curcumin with different concentrations. Cell viability was determined by using MTT assay. The concentrations of reactive oxygen species (ROS) and intracellular iron were measured using specific related kits. Real-time PCR and Western blot analysis were used to determine the expression of ferroptosis-related proteins including ACSL4, GPx4 and FTH1 and activation of JNK protein. Curcumin suppressed SW-480 cancer cells viability in dose-dependent manner. Cell treatment with curcumin led to accumulation of ROS and iron within cells and increase in the intracellular levels of lipid peroxidation. In addition, curcumin modulated the mRNA and protein expression levels of ferroptosis-related proteins including ACSL4, GPx4 and FTH1 and suppression of JNK signaling. Curcumin may exhibit its anticancer effect on colorectal cancer by downregulating JNK signaling to induce ferroptosis in SW-480 cells.
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Neoplasias do Colo , Curcumina , Ferroptose , Humanos , Curcumina/farmacologia , Sistema de Sinalização das MAP Quinases , Espécies Reativas de Oxigênio , FerroRESUMO
BACKGROUND: Evidence for the routine use of robotic technology and its impact on short-term outcomes in colon cancer surgery is lacking. The aim of this study was to compare the surgically induced systemic stress response and clinical and patient-reported outcomes for patients undergoing robot-assisted or laparoscopic colon cancer surgery. METHODS: In this double-blinded superiority RCT completed between August 2021 and March 2023, patients with stage 1-3 colon cancer were randomized in a 1 : 1 ratio to undergo either robot-assisted or laparoscopic colon cancer surgery. The primary outcome was changes in the systemic stress response, characterized by C-reactive protein expression in the first three postoperative days. Secondary outcomes were intraoperative and postoperative complications and patient-reported outcomes. The latter included quality of recovery-15 and pain intensity using a visual analogue scale. RESULTS: In total, 128 patients were screened for potential inclusion in this study; 50 patients (25 in the robot-assisted group and 25 in the laparoscopic group) were included in the final follow-up and analysis. The postoperative C-reactive protein response was higher on the first postoperative day in the laparoscopic group (mean difference = 19.88â mg/l, 95% c.i. 3.89-35.86; P = 0.045). No statistically significant differences were noted for C-reactive protein expression on the second and third postoperative days. CONCLUSION: Adopting robot-assisted surgery for stage 1-3 colon cancer is associated with a reduction in the surgical stress response. REGISTRATION NUMBER: NCT04687384 (http://www.clinicaltrials.gov).
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Neoplasias do Colo , Laparoscopia , Robótica , Humanos , Proteína C-Reativa , Neoplasias do Colo/cirurgia , Medição da DorRESUMO
BACKGROUND: Despite significant advancements in the treatment of patients with colorectal liver metastases (CRLMs), only a minority will experience long-term survival. This study aimed to determine the effect of chemotherapy (CT) and immunotherapy (IT) compared with that of CT alone on patient survival after surgical resection. METHODS: Patients undergoing curative-intent liver resection followed by adjuvant systemic therapy for stage IV colon cancer were identified using the National Cancer Database. Patients were stratified into type of therapy (CT alone vs CT + IT) and microsatellite status. Propensity score-weighted analysis was performed through 1:1 matching based on the nearest neighbor method. RESULTS: Of 9943 patients who underwent resection of CRLMs, 7971 (80%) received systemic adjuvant therapy. Of 7971 patients, 1432 (18%) received a combination of CT and IT. Microsatellite status was not associated with overall survival (OS). Adjuvant CT + IT was associated with increased 3-year OS compared with that of CT alone in both the unmatched cohort (55% vs 48%, respectively; P < .001) and matched cohort (52% vs 48%, respectively; P = .050). On multivariate analysis, older age, positive resection margins, and KRAS mutation were independent predictors of poor survival, whereas the administration of adjuvant CT + IT was an independent predictor of improved survival. CONCLUSION: IT combined with CT was associated with improved survival compared with that of CT alone after curative-intent resection of CRLMs, regardless of microsatellite instability status. Clinical trials to determine optimal patient selection, IT regimen, and long-term efficacy to improve outcomes of patients with CRLMs are warranted.
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Neoplasias do Colo , Neoplasias Hepáticas , Humanos , Imunoterapia , Neoplasias Hepáticas/terapia , Quimioterapia Adjuvante , Hepatectomia , Neoplasias do Colo/terapiaRESUMO
BACKGROUND: Colorectal cancer (CRC) is a malignant tumor of the gastrointestinal tract with high morbidity and mortality. There is growing evidence that GRK2 plays a key role in the development and progression of several human cancers. However, the role and potential mechanisms of GRK2 in colon cancer (COAD) are unclear. METHODS: The expression data of GRK2 was downloaded from The Cancer Genome Atlas database (TCGA). Variation in GRK2 was explored based on the cBioPortal database. The TIMER and TISCH2 databases were used to analyse the relationship between GRK2 expression and tumor immune microenvironment (TME). A log-rank test was used to compare the prognosis of high and low expression of GRK2 groups. Detecting the effect of GRK2 on cell cycle and apoptosis induced by 5-Fluorouracil (5-FU) through the flow cytometry and detection of apoptosis-related molecules by Western blot. RESULTS: We demonstrated that GRK2 has a potential oncogenic role. GRK2 expression was upregulated in COAD, which predicted poorer overall survival in COAD patients. The cellular assays showed that GRK2 plays a role in the growth and proliferation of colon cancer cells, also the expression of GRK2 have relationship with the sensitivity of 5-FU and cell cycle progression. CONCLUSIONS: Our results suggest that high GRK2 expression is closely associated with the development of tumor and affects the 5-FU sensitivity.
Assuntos
Neoplasias do Colo , Humanos , Apoptose , Fluoruracila , Microambiente TumoralRESUMO
The case is a 73-year-old woman. She visited primary care doctor for abdominal pain, vomiting, diarrhea, and melena that persisted for 2 weeks. She was referred to our department because she had an elevated inflammatory response and CT showed a mass in her left upper quadrant. Contrast-enhanced CT showed a tumorous lesion mainly in the splenic flexure of the transverse colon, involving the greater curvature of the stomach, the tail of the pancreas, and the hilus of the spleen, accompanied by abscess formation. We suspected highly advanced colon cancer with multiple organ involvement, but we opted for multiple visceral resection because it was associated with high-grade inflammatory findings due to abscess formation. After she was treated with antibiotics, she underwent laparotomy on the 6th day of illness. Intraoperative findings showed no clear nodular lesions suggesting dissemination in the abdominal cavity and intraoperative washing cytology was negative. Since the mobility of the mass that invaded the posterior wall of the greater curvature of the stomach, the tail of the pancreas, and the splenic hilum centered on the splenic flexure was confirmed, the entire left upper abdominal evisceration was resected by resecting the splenic flexure of the colon, the stomach, the tail of the pancreas, and the spleen. The postoperative course was uneventful, and she was discharged on postoperative day 9. Histopathological examination confirmed invasion of colon cancer into the pancreas, spleen, and retroperitoneum. In this report, we present a case of colon cancer with multi-organ invasion that underwent left upper abdominal evisceration.
Assuntos
Colo Transverso , Neoplasias do Colo , Gastroenteropatias , Doenças Musculoesqueléticas , Humanos , Feminino , Idoso , Colo Transverso/cirurgia , Abscesso , Neoplasias do Colo/cirurgia , PâncreasRESUMO
Since the insurance coverage of colorectal stents for bowel obstruction due to colorectal cancer in 2012, the use of colorectal stenting for palliation has rapidly spread. We report a case of ascending colon cancer in which a colorectal stent was placed for palliation, but the stent was reimplanted due to obstruction, followed by radical resection. The patient was a 92- year-old woman who was brought to the emergency room at the age of 90 years with repeated vomiting and abdominal pain, and was diagnosed as colorectal cancer ileus caused by ascending colon cancer, and a colorectal stent was inserted. She received palliative care and had been asymptomatic for 1 year and 3 months, but due to in-stent stenosis, she had bowel obstruction and sent to emergency room, and another stent was installed. The patient had a good course, but 4 months after the second stenting, she was concerned about restenosis and referred to the department of surgery, then performed a radical resection. The indication for colorectal stents for palliative purposes should be considered on a case-by- case basis, including ADL, stage of the disease, and prognosis.
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Neoplasias do Colo , Obstrução Intestinal , Feminino , Humanos , Idoso de 80 Anos ou mais , Colo Ascendente , Neoplasias do Colo/complicações , Neoplasias do Colo/cirurgia , Reimplante , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Stents , Constrição PatológicaRESUMO
Regorafenib is the first multikinase inhibitor for treating metastatic colorectal cancer (mCRC). Proteinuria is a frequently encountered adverse effect, regardless of prior administration of vascular endothelial growth factor inhibitors. Herein, we aimed to assess the impact of baseline preexisting proteinuria on regorafenib-induced problematic proteinuria during real-world mCRC therapy. Patients with mCRC receiving regorafenib (n = 100) were retrospectively assessed and divided into control and preexisting proteinuria (baseline grade of 1-2) groups. The primary endpoint was the development of grade ≥ 2 (grade ≥ 3 in case of baseline grade 2 patients) proteinuria. Propensity score-matching was performed to confirm the robustness of primary analyses. Defined proteinuria occurred in 30.7 and 57.9% of patients in the control and preexisting proteinuria groups, respectively, with significant differences in the all-patient population (P = 0.01). The preexisting proteinuria group exhibited significant defined proteinuria development within 7 days of regorafenib initiation, grade ≥ 3 symptoms, and treatment suspension owing to proteinuria. Similar results were obtained in the propensity score-matched population. According to multivariate logistic regression analysis, baseline proteinuria was a singular risk factor for defined proteinuria development (adjusted odds ratio; 3.76, 95% confidence interval; 1.45-9.75, P = 0.007). Collectively, our study revealed that patients with preexisting proteinuria develop regorafenib-induced proteinuria degradation.
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Neoplasias do Colo , Neoplasias Colorretais , Piridinas , Neoplasias Retais , Humanos , Neoplasias Colorretais/patologia , Fator A de Crescimento do Endotélio Vascular , Estudos Retrospectivos , Neoplasias do Colo/induzido quimicamente , Compostos de Fenilureia/efeitos adversosRESUMO
Accurate classification and segmentation of polyps are two important tasks in the diagnosis and treatment of colorectal cancers. Existing models perform segmentation and classification separately and do not fully make use of the correlation between the two tasks. Furthermore, polyps exhibit random regions and varying shapes and sizes, and they often share similar boundaries and backgrounds. However, existing models fail to consider these factors and thus are not robust because of their inherent limitations. To address these issues, we developed a multi-task network that performs both segmentation and classification simultaneously and can cope with the aforementioned factors effectively. Our proposed network possesses a dual-branch structure, comprising a transformer branch and a convolutional neural network (CNN) branch. This approach enhances local details within the global representation, improving both local feature awareness and global contextual understanding, thus contributing to the improved preservation of polyp-related information. Additionally, we have designed a feature interaction module (FIM) aimed at bridging the semantic gap between the two branches and facilitating the integration of diverse semantic information from both branches. This integration enables the full capture of global context information and local details related to polyps. To prevent the loss of edge detail information crucial for polyp identification, we have introduced a reverse attention boundary enhancement (RABE) module to gradually enhance edge structures and detailed information within polyp regions. Finally, we conducted extensive experiments on five publicly available datasets to evaluate the performance of our method in both polyp segmentation and classification tasks. The experimental results confirm that our proposed method outperforms other state-of-the-art methods.
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Neoplasias do Colo , Aprendizagem , Humanos , Fontes de Energia Elétrica , Redes Neurais de Computação , Semântica , Neoplasias do Colo/diagnóstico por imagem , Processamento de Imagem Assistida por ComputadorRESUMO
Colon cancer affects people of all ages. However, its frequency, as well as the related morbidity and mortality, are high among older adults. The complex physiological changes in the aging gut substantially limit the development of cancer therapies. Here, we identify a potentially unique intestinal microenvironment that is linked with an increased risk of colon cancer in older adults. Our findings show that aging markedly influenced persistent fucosylation of the apical surfaces of intestinal epithelial cells, which resulted in a favorable environment for tumor growth. Furthermore, our findings shed light on the importance of the host-commensal interaction, which facilitates the dysregulation of fucosylation and promotes tumor growth as people get older. We analyzed colonic microbial populations at the species level to find changes associated with aging that could contribute to the development of colon cancer. Analysis of single-cell RNA-sequencing data from previous publications identified distinct epithelial cell subtypes involved in dysregulated fucosylation in older adults. Overall, our study provides compelling evidence that excessive fucosylation is associated with the development of colon cancer, that age-related changes increase vulnerability to colon cancer, and that a dysbiosis in microbial diversity and metabolic changes in the homeostasis of older mice dysregulate fucosylation levels with age.
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Neoplasias do Colo , Humanos , Camundongos , Animais , Idoso , Neoplasias do Colo/metabolismo , Glicosilação , Células Epiteliais/metabolismo , Mucosa Intestinal/patologia , Microambiente TumoralRESUMO
BACKGROUND: Increased mitochondrial activities contributing to cancer cell proliferation, invasion, and metastasis have been reported in different cancers; however, studies on the therapeutic targeting of mitochondria in regulating cell proliferation and invasiveness are limited. Because mitochondria are believed to have evolved through bacterial invasion in mammalian cells, antibiotics could provide an alternative approach to target mitochondria, especially in cancers with increased mitochondrial activities. In this study, we investigated the therapeutic potential of bacteriostatic antibiotics in regulating the growth potential of colorectal cancer (CRC) cells, which differ in their metastatic potential and mitochondrial functions. METHODS: A combination of viability, cell migration, and spheroid formation assays was used to measure the effect on metastatic potential. The effect on mitochondrial mechanisms was investigated by measuring mitochondrial DNA copy number by qPCR, biogenesis (by qPCR and immunoblotting), and functions by measuring reactive oxygen species, membrane potential, and ATP using standard methods. In addition, the effect on assembly and activities of respiratory chain (RC) complexes was determined using blue native gel electrophoresis and in-gel assays, respectively). Changes in metastatic and cell death signaling were measured by immunoblotting with specific marker proteins and compared between CRC cells. RESULTS: Both tigecycline and tetracycline effectively reduced the viability, migration, and spheroid-forming capacity of highly metastatic CRC cells. This increased sensitivity was attributed to reduced mtDNA content, mitochondrial biogenesis, ATP content, membrane potential, and increased oxidative stress. Specifically, complex I assembly and activity were significantly inhibited by these antibiotics in high-metastatic cells. Significant down-regulation in the expression of mitochondrial-mediated survival pathways, such as phospho-AKT, cMYC, phospho-SRC, and phospho-FAK, and upregulation in cell death (apoptosis and autophagy) were observed, which contributed to the enhanced sensitivity of highly metastatic CRC cells toward these antibiotics. In addition, the combined treatment of the CRC chemotherapeutic agent oxaliplatin with tigecycline/tetracycline at physiological concentrations effectively sensitized these cells at early time points. CONCLUSION: Altogether, our study reports that bacterial antibiotics, such as tigecycline and tetracycline, target mitochondrial functions specifically mitochondrial complex I architecture and activity and would be useful in combination with cancer chemotherapeutics for high metastatic conditions.
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Neoplasias do Colo , Neoplasias Colorretais , Animais , Humanos , Tigeciclina/metabolismo , Tigeciclina/farmacologia , Reposicionamento de Medicamentos , Linhagem Celular Tumoral , Mitocôndrias/metabolismo , Antibacterianos/farmacologia , Neoplasias do Colo/metabolismo , Proliferação de Células , Apoptose , Trifosfato de Adenosina/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Mamíferos/metabolismoRESUMO
BACKGROUND: Colorectal cancer is one of the most frequently diagnosed forms of cancer, and it is associated with several common symptoms and signs such as rectal bleeding, altered bowel habits, abdominal pain, anemia, and unintentional weight loss. Sciatica, a debilitating condition in which the patient experiences paresthesia and pain in the dermatome of associated lumbosacral nerve roots or sciatic nerve distribution, is not considered one of these. Here we present a case of colorectal cancer manifesting symptoms of sciatica alone. CASE PRESENTATION: A 68-year-old male presented with progressive lower back pain radiating to his left thigh and calf over L5/S1 dermatome. Sciatica was suspected and initially underwent conservative treatment with analgesics. However, the symptoms progressed and MRI revealed an epidural abscess surprisingly. Surgical debridement was performed and pus culture isolated Streptococcus gallolyticus. Based on the strong association of S. gallolyticus with colorectal cancer, the presence of this pathogen prompted further tumor evaluation, even in the absence of the typical symptoms and signs. This investigation ultimately leads to the diagnosis of sigmoid adenocarcinoma. CONCLUSIONS: Although rare, sciatica caused by S. gallolyticus infection of the spinal epidural space may serve as the initial presentation of colorectal cancer. Physicians should be aware of the strong association between S. gallolyticus and colorectal cancer. Based on what we currently know about the condition; a thorough systematic assessment of occult neoplasia for patients with S. gallolyticus infection is recommended.
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Neoplasias do Colo , Abscesso Epidural , Ciática , Masculino , Humanos , Idoso , Ciática/diagnóstico , Ciática/etiologia , Abscesso Epidural/diagnóstico , Abscesso Epidural/cirurgia , Neoplasias do Colo/complicações , Neoplasias do Colo/diagnóstico , Dor Abdominal , ConscientizaçãoRESUMO
Colorectal cancer is the third leading cause of death from neoplasia worldwide. Thanks to new screening programs, we are now seeing an increase in Early Onset of ColoRectal Cancer (EOCRC) in patients below the age of 50. Herein, we report a clinical case of a woman affected by EOCRC. This case illustrates the importance of genetic predisposition testing also in tumor patients. Indeed, for our patient, we used a combined approach of multiple molecular and cellular biology technologies that revealed the presence of an interesting novel variant in the SMARCA4 gene. The latter gene is implicated in damage repair processes and related, if mutated, to the onset of various tumor types. In addition, we stabilized Patient-Derived Organoids from the tumor tissue of the same patient and the result confirmed the presence of this novel pathogenic variant that has never been found before even in early onset cancer. In conclusion, with this clinical case, we want to underscore the importance of including patients even those below the age of 50 years in appropriate screening programs which should also include genetic tests for predisposition to early onset cancers.
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Neoplasias do Colo , Neoplasias Colorretais , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Colorretais/patologia , Neoplasias do Colo/genética , Testes Genéticos , Predisposição Genética para Doença , DNA , DNA Helicases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genéticaRESUMO
The protein p32 (C1QBP) is a multifunctional and multicompartmental homotrimer that is overexpressed in many cancer types, including colon cancer. High expression levels of C1QBP are negatively correlated with the survival of patients. Previously, we demonstrated that C1QBP is an essential promoter of migration, chemoresistance, clonogenic, and tumorigenic capacity in colon cancer cells. However, the mechanisms underlying these functions and the effects of specific C1QBP protein inhibitors remain unexplored. Here, we show that the specific pharmacological inhibition of C1QBP with the small molecule M36 significantly decreased the viability rate, clonogenic capacity, and proliferation rate of different colon cancer cell lines in a dose-dependent manner. The effects of the inhibitor of C1QBP were cytostatic and non-cytotoxic, inducing a decreased activation rate of critical pro-malignant and mitogenic cellular pathways such as Akt-mTOR and MAPK in RKO colon cancer cells. Additionally, treatment with M36 significantly affected the mitochondrial integrity and dynamics of malignant cells, indicating that p32/C1QBP plays an essential role in maintaining mitochondrial homeostasis. Altogether, our results reinforce that C1QBP is an important oncogene target and that M36 may be a promising therapeutic drug for the treatment of colon cancer.
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Neoplasias do Colo , Citostáticos , Humanos , Citostáticos/farmacologia , Mitógenos/farmacologia , Transdução de Sinais , Proteínas Mitocondriais/metabolismo , Proliferação de Células , Proteínas de Transporte/metabolismoRESUMO
Marine mangrove vegetation has been traditionally employed in folk medicine to address various ailments. Notably, Rhizophora apiculata Blume has exhibited noteworthy properties, demonstrating efficacy against cancer, viruses, and bacteria. The enzyme fatty acid synthase (FAS) plays a pivotal role in de novo fatty acid synthesis, making it a promising target for combating colon cancer. Our study focused on evaluating the FAS inhibitory effects of both the crude extract and three isolated compounds from R. apiculata. The n-butanol fraction of R. apiculata extract (BFR) demonstrated a significant inhibition of FAS, with an IC50 value of 93.0 µg/mL. For inhibition via lyoniresinol-3α-O-ß-rhamnopyranoside (LR), the corresponding IC50 value was 20.1 µg/mL (35.5 µM). LR competitively inhibited the FAS reaction with acetyl-CoA, noncompetitively with malonyl-CoA, and in a mixed manner with NADPH. Our results also suggest that both BFR and LR reversibly bind to the KR domain of FAS, hindering the reduction of saturated acyl groups in fatty acid synthesis. Furthermore, BFR and LR displayed time-dependent inhibition for FAS, with kobs values of 0.0045 min-1 and 0.026 min-1, respectively. LR also exhibited time-dependent inhibition on the KR domain, with a kobs value of 0.019 min-1. In human colon cancer cells, LR demonstrated the ability to reduce viability and inhibit intracellular FAS activity. Notably, the effects of LR on human colon cancer cells could be reversed with the end product of FAS-catalyzed chemical reactions, affirming the specificity of LR on FAS. These findings underscore the potential of BFR and LR as potent FAS inhibitors, presenting novel avenues for the treatment of human colon cancer.