RESUMEN
PIWI proteins, traditionally associated with germline development, have recently gained attention for their expression in various cancers, including colorectal cancer. However, the molecular mechanisms underlying their reactivation and impact on cancer initiation and progression remain elusive. Here, we found that PIWIL1 is expressed at relatively high levels in CRC-derived samples and cell lines, where it undergoes a dynamic relocalization to the centrosome during mitosis. Knockdown of PIWIL1 induces G2/M arrest associated with disruption of the mitotic spindle and aberrant metaphase events, highlighting its role in cell cycle progression. We also found that the expression of PIWIL1 is lost during the differentiation of Caco-2 cells into enterocytes and that PIWIL1 is expressed in cells at the base of the intestinal crypts in normal human colon tissue, where intestinal stem cells are known to reside. Thus, it is possible that the presence of PIWIL1 in cancer cells reflects a physiological role of this protein in stem cell maintenance, which would argue in favor of the proposed stem cell origin of CRC. Supporting this view, dedifferentiation of human fibroblasts into induced pluripotent stem cells (iPSCs) involves the reactivation of PIWIL2 expression, another member of the PIWI protein family. Overall, our findings suggest a role of PIWIL1 in mediating cell cycle dynamics, both in colorectal cancer cells and possibly also in intestinal stem cells. In a broader aspect, we provide evidence supporting an involvement of PIWI proteins in somatic stem cell maintenance, thus expanding the known non-gonadal functions of this protein family.
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Proteínas Argonautas , Centrosoma , Neoplasias Colorrectales , Mitosis , Humanos , Proteínas Argonautas/metabolismo , Proteínas Argonautas/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Centrosoma/metabolismo , Células CACO-2 , Ciclo Celular , Diferenciación Celular , Línea Celular TumoralRESUMEN
LAH, an acetogenin from the Annonaceae family, has demonstrated antitumor activity in several cancer cell lines and in vivo models, where it reduced the tumor size and induced programmed cell death. We focused on the effects of LAH on mitochondrial dynamics, mTOR signaling, autophagy, and apoptosis in colorectal cancer (CRC) cells to explore its anticancer potential. METHODS: CRC cells were treated with LAH, and its effects on mitochondrial respiration and glycolysis were measured using Seahorse XF technology. The changes in mitochondrial dynamics were observed through fluorescent imaging, while Western blot analysis was used to examine key autophagy and apoptosis markers. RESULTS: LAH significantly inhibited mitochondrial complex I activity, inducing ATP depletion and a compensatory increase in glycolysis. This disruption caused mitochondrial fragmentation, a trigger for autophagy, as shown by increased LC3-II expression and mTOR suppression. Apoptosis was also confirmed through the cleavage of caspase-3, contributing to reduced cancer cell viability. CONCLUSIONS: LAH's anticancer effects in CRC cells are driven by its disruption of mitochondrial function, triggering both autophagy and apoptosis. These findings highlight its potential as a therapeutic compound for further exploration in cancer treatment.
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Apoptosis , Autofagia , Proliferación Celular , Neoplasias Colorrectales , Mitocondrias , Humanos , Autofagia/efectos de los fármacos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Acetogeninas/farmacología , Transducción de Señal/efectos de los fármacos , Glucólisis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
Metastases in the oral and maxillofacial region, particularly in soft tissues, are exceedingly rare. Such metastases can present as swelling in older individuals, especially in the tongue and gingiva. Furthermore, colorectal metastases at this site are commonly found in the mandible and gingiva and usually share the same morphology as the primary tumor. Herein, we report the case of a 61-year-old woman with a metastatic nodule in the tongue covered by normal mucosa. The clinical, histopathological, and immunohistochemical findings were essential for the final diagnosis of colorectal metastasis, consistent with adenocarcinoma with mucinous differentiation and intestinal phenotype. Metastases of colorectal adenocarcinoma to the tongue are rare but should be included in the differential diagnosis of nodular lesions at this site. The diagnosis can therefore be made based on meticulous clinical and histopathological examination complemented by immunohistochemistry.
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Adenocarcinoma Mucinoso , Neoplasias Colorrectales , Neoplasias de la Lengua , Humanos , Femenino , Persona de Mediana Edad , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/secundario , Neoplasias Colorrectales/patología , Neoplasias de la Lengua/patología , Biomarcadores de Tumor/análisisRESUMEN
Colorectal cancer (CRC) is the third most common type of cancer worldwide. Its treatment options have had a limited impact on cancer remission prognosis. Therefore, there is an ongoing need to discover novel anti-cancer agents. Medicinal plants have gained recognition as a source of anti-cancer bioactive compounds. Recently, ethanolic extract of L. virginicum stems ameliorated dinitrobenzene sulfonic acid (DNBS)-induced colitis by modulating the intestinal immune response. However, no scientific study has demonstrated this potential cytotoxic impact on colon cancer cells. The objective of this study was to evaluate the cytotoxic effect of the methanolic extract of L. virginicum (ELv) on a human colorectal adenocarcinoma cell line (Caco-2) and to identify and quantify the phenolic compounds present in ELv extracts by liquid chromatography-mass spectrometry analysis. The cytotoxic activity was assessed using cell viability assays by reduction in the compound 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH). MTT and LDH assays revealed that the ELv decreases cell viability in the Caco-2 cell line in a concentration-dependent manner. Cell death was a result of DNA fragmentation and p53-mediated apoptosis. Eight phenolic acids and five flavonoids were identified and quantified in the stems. In conclusion, our findings demonstrate that the extract of L. virginicum possesses cytotoxic properties on Caco-2 cell line, suggesting that it could be a potential source of new drugs against CRC.
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Apoptosis , Supervivencia Celular , Lepidium , Metanol , Extractos Vegetales , Proteína p53 Supresora de Tumor , Humanos , Células CACO-2 , Extractos Vegetales/farmacología , Extractos Vegetales/química , Apoptosis/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Supervivencia Celular/efectos de los fármacos , Metanol/química , Lepidium/química , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Fenoles/farmacología , Fenoles/químicaRESUMEN
BACKGROUND: The key endpoints for the assessment of the effect of maintenance therapy for metastatic colorectal cancer (mCRC) are survival and quality-of-life outcomes. We aimed to compare dermatology-related quality of life (DRQOL) in patients with RAS wild-type (wt) mCRC treated with fluorouracil and folinic acid (FU/FA) + panitumumab (Pmab) versus FU/FA alone as maintenance therapy after folinic acid, fluorouracil and oxaliplatin + Pmab induction. PATIENTS AND METHODS: The phase II randomized PanaMa (AIO KRK 0212; NCT01991873) trial included 387 patients at 70 community/academic sites in Germany. For this prespecified secondary analysis, DRQOL outcomes were assessed using the Functional Assessment of Cancer Therapy-epidermal growth factor receptor inhibitor (FACT-EGFRI), Dermatology Life Quality Index (DLQI), and Skindex-16 questionnaires at every second cycle of therapy until disease progression/death. RESULTS: At least one DRQOL questionnaire was completed by a total of 310/377 (82%) patients who received induction therapy, and by 216/248 (87%) patients who were randomized and received maintenance therapy. Patients who experienced skin toxicity according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) during induction therapy had significantly worse DRQOL according to all three measures, compared to those who did not [i.e. Skindex-16, mean difference at cycle 2 -12.87; 95% confidence interval (CI) -20.01 to -5.73; P < 0.001]. During maintenance therapy, significantly improved recovery was observed in all DRQOL measures for patients receiving FU/FA, compared to those receiving additional Pmab (i.e. Skindex-16, mean difference at cycle 6 -16.53; 95% CI -22.68 to -10.38; P < 0.001). CONCLUSIONS: In this secondary analysis of a phase II randomized clinical trial, patient-reported DRQOL outcomes correlated with skin toxicity according to NCI-CTCAE during induction therapy. Maintenance therapy with FU/FA + Pmab was associated with deteriorated DRQOL versus FU/FA alone in patients with RAS wt mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Fluorouracilo , Leucovorina , Panitumumab , Calidad de Vida , Humanos , Fluorouracilo/uso terapéutico , Fluorouracilo/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Masculino , Femenino , Leucovorina/uso terapéutico , Leucovorina/farmacología , Leucovorina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Panitumumab/uso terapéutico , Panitumumab/farmacología , Persona de Mediana Edad , Anciano , Adulto , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/farmacologíaRESUMEN
INTRODUCTION AND OBJECTIVES: Although unlimited sessions of conventional transarterial chemoembolization (cTACE) may be performed for liver metastases, there is no data indicating when treatment becomes ineffective. This study aimed to determine the optimal number of repeat cTACE sessions for nonresponding patients before abandoning cTACE in patients with liver metastases. MATERIALS AND METHODS: In this retrospective, single-institutional analysis, patients with liver metastases from neuroendocrine tumors (NET), colorectal carcinoma (CRC), and lung cancer who underwent consecutive cTACE sessions from 2001 to 2015 were studied. Quantitative European Association for Study of the Liver (qEASL) criteria were utilized for response assessment. The association between the number of cTACE and 2-year, 5-year, and overall survival was evaluated to estimate the optimal number of cTACE for each survival outcome. RESULTS: Eighty-five patients underwent a total of 186 cTACE sessions for 117 liver metastases, of which 30.7 % responded to the first cTACE. For the target lesions that did not respond to the first, second, and third cTACE sessions, response rates after the second, third, and fourth cTACE sessions were 33.3 %, 23 %, and 25 %, respectively. The fourth cTACE session was the optimal number for 2-year survival (HR 0.40; 95 %CI: 0.16-0.97; p = 0.04), 5-year survival (HR 0.31; 95 %CI: 0.11-0.87; p = 0.02), and overall survival (HR 0.35; 95 %CI: 0.13-0.89; p = 0.02). CONCLUSIONS: Repeat cTACE in the management of liver metastases from NET, CRC, and lung cancer was associated with improved patient survival. We recommend at least four cTACE sessions before switching to another treatment for nonresponding metastatic liver lesions.
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Quimioembolización Terapéutica , Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidad , Quimioembolización Terapéutica/métodos , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/mortalidad , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Resultado del Tratamiento , Adulto , Tumores Neuroendocrinos/secundario , Tumores Neuroendocrinos/terapia , Tumores Neuroendocrinos/mortalidad , Anciano de 80 o más Años , Factores de Tiempo , RetratamientoRESUMEN
Tumor hypoxia may compromise the results of chemotherapy for treating colorectal cancer because it stimulates angiogenesis and the release of tumor growth factors. Hyperbaric oxygen (HBO) supplementation may potentiate the effects of chemotherapy in such cases. This study aimed to assess the effect of HBO therapy combined with chemotherapy on the treatment of colorectal cancer in mice. C57BL6 mice were submitted to the intrarectal instillation of N-methyl-N-nitrosoguanidine (MNNG) and treated with 5-fluorouracil (5FU) and/or HBO therapy. The MNNG group presented the highest dysplastic crypt rate. The 5FU + HBO group presented the highest rate of apoptotic cells per dysplastic crypt. The 5FU group presented the highest expression of hypoxia-inducible factor-1 alpha and CD44. HBO therapy increased the effect of 5FU on the treatment of the experimental colorectal neoplasia in mice.
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Neoplasias Colorrectales , Fluorouracilo , Oxigenoterapia Hiperbárica , Ratones Endogámicos C57BL , Animales , Fluorouracilo/farmacología , Ratones , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Masculino , Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Receptores de Hialuranos/metabolismo , Terapia Combinada , Metilnitronitrosoguanidina/farmacologíaRESUMEN
This study aimed to evaluate the prognostic value of thigh muscle assessed by CT images to predict overall mortality in patients with colorectal cancer (CRC). This was a multicenter cohort study including adults (≥ 18 years old) newly diagnosed with CRC, who performed a diagnostic computed tomography (CT) exam including thigh regions. CT images were analyzed to evaluate skeletal muscle (SM in cm2), skeletal muscle index (SMI in cm2/m2), and skeletal muscle density (SMD in HU). Muscle abnormalities (low SM, SMI, and SMD) were defined as the values below the median by sex. Kaplan-Meyer curves and hazard ratios (HRs) for low SM, SMI and SMD were evaluated for overall mortality, stratified by sex. A total of 257 patients were included in the final analysis. Patients' mean age was 62.6 ± 12.1 years, and 50.2% (n = 129) were females. In males, low thigh SMI was associated with shorter survival (log-rank P = .02). Furthermore, this low thigh SMI (cm2/m2) was independently associated with higher mortality rates (HR adjusted 2.08, 95% CI 1.03-4.18). Our additional findings demonstrated that low SMD was independently associated with overall mortality among early-stage patients (I-III) (HR adjusted 2.78, 95% CI 1.26-6.15).
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Neoplasias Colorrectales , Músculo Esquelético , Muslo , Tomografía Computarizada por Rayos X , Humanos , Masculino , Femenino , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/patología , Persona de Mediana Edad , Tomografía Computarizada por Rayos X/métodos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Muslo/diagnóstico por imagen , Anciano , Pronóstico , Estimación de Kaplan-MeierRESUMEN
OBJECTIVE: To examine the relationship between the age-adjusted Charlson comorbidity index (A-CCI) with body composition and overall survival in patients newly diagnosed with colorectal cancer (CRC). RESEARCH METHODS AND PROCEDURES: In this cohort study, patients (≥ 18 years old) with CRC were followed for 36 months. Computed tomography images of the third lumbar were analyzed to determine body composition, including skeletal muscle area (SMA), skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Phenotypes based on comorbidity burden assessed by A-CCI and body composition parameters were established. RESULTS: A total of 436 participants were included, 50% male, with a mean age of 61 ± 13.2 years. Approximately half of the patients (50.4%) had no comorbidity, and the A-CCI median score was 4 (interquartile range: 3-6). A higher A-CCI score was a risk factor for 36-month mortality (HR = 3.59, 95% CI = 2.17-5.95). Low SMA and low SMD were associated with a higher A-CCI. All abnormal phenotypes (high A-CCI and low SMA; high A-CCI and low SMD; high A-CCI and high VAT) were independently associated with higher 36-month mortality hazard (adjusted HR 5.12, 95% CI 2.73-9.57; adjusted HR 4.58, 95% CI 2.37-8.85; and adjusted HR 2.36, 95% CI 1.07-5.22, respectively). CONCLUSION: The coexistence of comorbidity burden and abnormal body composition phenotypes, such as alterations in muscle or fat compartments, may pose an additional risk of mortality in patients newly diagnosed with CRC. Early assessment and management of these phenotypes could be crucial in optimizing outcomes in such patients.
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Composición Corporal , Neoplasias Colorrectales , Comorbilidad , Humanos , Masculino , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Persona de Mediana Edad , Femenino , Anciano , Estudios de Cohortes , Factores de Riesgo , Tomografía Computarizada por Rayos X/métodos , Factores de EdadRESUMEN
INTRODUCTION AND AIMS: Colorectal cancer is the most frequent malignant tumor of the digestive system. Its pathogeny is complex and involves the APC/ß-catenin sequence. Lymph node metastases are a significant indicator for determining treatment and are a prognostic factor. SOX9 overexpression is related to oncogenic qualities and the capacity for metastasis. Our aim was to analyze SOX9 immunoexpression in primary colorectal cancer and lymph node metastasis status. MATERIAL AND METHODS: Seventy-nine available cases were divided into the group with lymph node metastasis (n=38) and the group without lymph node metastasis (n=41), evaluating their SOX9 expression. The IBM SPSS version 27 program in Spanish was utilized to carry out the statistical analysis, obtaining measures of central tendency, the kappa index, standard deviation, Wilcoxon Mann-Whitney nonparametric measurements, Spearman's correlation coefficient, and chi-square test and Student's t test values. SOX9 immunoexpression was evaluated through the mean-based H-score, with high immunoexpression as a score ≥145 and low immunoexpression as a score ≤144. RESULTS: A p=0.73 was obtained that was not statistically significant, regarding the relation of SOX9 expression in primary colorectal cancer to lymph node metastasis. CONCLUSIONS: The absence or presence of lymph node metastasis was independent from SOX9 immunoexpression in primary colorectal cancer. However, due to the limited size of the population analyzed, further research is needed.
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Neoplasias Colorrectales , Metástasis Linfática , Factor de Transcripción SOX9 , Humanos , Neoplasias Colorrectales/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , AdultoRESUMEN
Introduction: schwannomas are benign and common soft tissue tumors. They are usually asymptomatic and are discovered for other reasons. Materials: we present the case of an 82-year-old male patient with a recent diagnosis of moderately differentiated adenocarcinoma of the colon and a hypermetabolic periaortic nodule as an incidental finding. Results: percutaneous biopsy of the periaortic nodule confirmed the diagnosis of schwannoma. At one year of follow-up, growth of the schwannoma has been demonstrated. There are no signs of progression of his oncological disease. Conclusions: schwannomas are benign tumors, rarely found in the retroperitoneum and can be sources of false-positive positron emission tomography results.
Introducción: los schwannomas son tumores benignos y frecuentes de las partes blandas. Habitualmente son asintomáticos y son descubiertos por otros motivos. Materiales y métodos: presentamos el caso de un paciente masculino de 82 años con diagnóstico reciente de adenocarcinoma de colon moderadamente diferenciado y con un nódulo periaórtico hipermetabólico como hallazgo incidental. Resultados: la biopsia percutánea del nódulo periaórtico confirmó el diagnóstico de schwannoma. Al año de seguimiento, se ha demostrado crecimiento del schwannoma. No hay signos de progresión de su enfermedad oncológica. Conclusión: los schwannomas son tumores benignos, infrecuentes en el retroperitoneo y pueden ser fuentes de resultados falsos positivos en tomografía por emisión de positrones.
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Adenocarcinoma , Neurilemoma , Neoplasias Retroperitoneales , Humanos , Masculino , Neoplasias Retroperitoneales/diagnóstico por imagen , Neoplasias Retroperitoneales/patología , Neurilemoma/patología , Neurilemoma/diagnóstico por imagen , Anciano de 80 o más Años , Reacciones Falso Positivas , Diagnóstico Diferencial , Adenocarcinoma/secundario , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico por imagen , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/diagnóstico por imagen , Tomografía de Emisión de PositronesRESUMEN
Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Combinación de Medicamentos , Pirrolidinas , Timina , Trifluridina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Trifluridina/uso terapéutico , Trifluridina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pirrolidinas/uso terapéutico , Pirrolidinas/administración & dosificación , Metástasis de la Neoplasia , Supervivencia sin Progresión , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/administración & dosificación , Resistencia a AntineoplásicosRESUMEN
Colorectal cancer is one of the most common malignant cancers. Pseudogenes have been identified as oncogenes or tumor suppressor genes in the development of various cancers. However, the function of pseudogene CSPG4P12 in colorectal cancer remains unclear. Therefore, the aim of this study was to investigate the potential role of CSPG4P12 in colorectal cancer and explore the possible underlying mechanism. The difference of CSPG4P12 expression between colorectal cancer tissues and adjacent normal tissues was analyzed using the online Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. Cell viability and colony formation assays were conducted to evaluate cell viability. Transwell and wound healing assays were performed to assess cell migration and invasion capacities. Western blot was used to measure the expression levels of epithelial-mesenchymal transition-related proteins. Colorectal cancer tissues had lower CSPG4P12 expression than adjacent normal tissues. The overexpression of CSPG4P12 inhibited cell proliferation, invasion, and migration in colorectal cancer cells. Overexpressed CSPG4P12 promoted the expression of E-cadherin, whereas it inhibited the expression of vimentin, N-cadherin, and MMP9. These findings suggested that CSPG4P12 inhibits colorectal cancer development and may serve as a new potential target for colorectal cancer.
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Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Seudogenes , Humanos , Transición Epitelial-Mesenquimal/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Seudogenes/genética , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Western Blotting , Cadherinas/genética , Cadherinas/metabolismo , Supervivencia Celular/genética , Invasividad Neoplásica/genéticaRESUMEN
Patients with colorectal cancer (CRC) often exhibit changes in body composition (BC) which are associated with poorer clinical outcomes. Many studies group colon and rectal cancers together, irrespective of staging, potentially affecting assessment and treatment strategies. Our study aimed to compare BC in patients with CRC focusing on tumor location and metastasis presence. A total of 635 individuals were evaluated, with a mean age of 61.8 ± 12.4 years and 50.2% female. The majority had rectal cancer as the primary cancer site (51.0%), and 23.6% had metastatic disease. The first regression model showed tumor site and metastasis as independent factors influencing skeletal muscle (SM), skeletal muscle index (SMI), and visceral adipose tissue variability (all p values < 0.05). The second model, adjusted for BMI, indicated tumor site as the primary factor affecting SMI variations (adjusted R2 = 0.50 p < 0.001), with colon tumors inversely associated with SM (standardized ß - 2.15(- 3.3; - 0.9) p < 0.001). A third model, considering all the confounders from the directed acyclic graphs, was constructed and the found association remained independent. Our findings highlight significant BC variations in patients with CRC, influenced by tumor location and metastases presence, underscoring the need for location-specific assessment in CRC management.
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Composición Corporal , Neoplasias Colorrectales , Estadificación de Neoplasias , Humanos , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Colorrectales/patología , Anciano , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Grasa Intraabdominal , Índice de Masa CorporalRESUMEN
BACKGROUND: Colorectal carcinoma (CRC) is one of the common carcinomas with a rising incidence of metastasis due to its advanced stage of presentation. The existing biomarkers such as CEA (Carcinoembryonic antigen) etc., for prognosis, have low sensitivity and specificity. Hence a need for a newer definitive biomarker. Obesity is the leading cause of CRC. Leptin and adiponectin secreted by adipose tissue have been studied as potential biomarkers in the field of CRC. The present study helps to understand the association of leptin and adiponectin receptors with clinicopathological parameters. OBJECTIVE: To correlate the various clinicopathological parameters with the tissue expression of leptin and adiponectin receptors in CRC. METHODS: It is a cross-sectional prospective study conducted at a tertiary care hospital. Formalin fixed paraffin blocks of all radical resection CRC cases were collected and immunohistochemistry (IHC)was carried out on tumor tissue for leptin and adiponectin receptor. Tumor characteristics and clinical parameters were collected from the hospital medical records. Pearson's correlation coefficient test was used. RESULTS: Immunohistochemistry was performed on 60 cases of CRC. Significant positive correlation of leptin was observed with size, lymph node metastasis, advanced stage, and grade of tumor (P<0.05). A significant correlation between adiponectin receptor and CRC was observed concerning age, stage, lymph node metastasis, distant metastasis and grade of tumor. CONCLUSION: Positive expression of leptin and negative expression of adiponectin receptors in CRC helps to predict the risk of metastasis.
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Biomarcadores de Tumor , Neoplasias Colorrectales , Inmunohistoquímica , Leptina , Estadificación de Neoplasias , Receptores de Adiponectina , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Estudios Transversales , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Leptina/metabolismo , Leptina/análisis , Receptores de Adiponectina/análisis , Receptores de Adiponectina/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Adulto , Receptores de Leptina/metabolismo , Receptores de Leptina/análisis , Clasificación del Tumor , Metástasis LinfáticaRESUMEN
PURPOSE: The advent of circulating tumor DNA (ctDNA) technology has provided a convenient and noninvasive means to continuously monitor cancer genomic data, facilitating personalized cancer treatment. This study aimed to evaluate the supplementary benefits of plasma ctDNA alongside traditional tissue-based next-generation sequencing (NGS) in identifying targetable mutations and tumor mutational burden (TMB) in colorectal cancers (CRC). METHODS: Our study involved 76 CRC patients, collecting both tissue and plasma samples for NGS. We assessed the concordance of gene mutational status between ctDNA and tissue, focusing on actionable genes such as KRAS, NRAS, PIK3CA, BRAF, and ERBB2. Logistic regression analysis was used to explore variables associated with discordance and positive mutation rates. RESULTS: In total, 26 cancer-related genes were identified. The most common variants in tumor tissues and plasma samples were in APC (57.9% vs 19.7%), TP53 (55.3% vs 22.4%) and KRAS (47.4% vs 43.4%). Tissue and ctDNA showed an overall concordance of 73.53% in detecting actionable gene mutations. Notably, plasma ctDNA improved detection for certain genes and gene pools. Variables significantly associated with discordance included gender and peritoneal metastases. TMB analysis revealed a higher detection rate in tissues compared to plasma, but combining both increased detection. CONCLUSIONS: Our study highlights the importance of analyzing both tissue and plasma for detecting actionable mutations in CRC, with plasma ctDNA offering added value. Discordance is associated with gender and peritoneal metastases, and TMB analysis can benefit from a combination of tissue and plasma data. This approach provides valuable insights for personalized CRC treatment.
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ADN Tumoral Circulante , Neoplasias Colorrectales , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Masculino , Femenino , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Persona de Mediana Edad , Anciano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Proteínas Proto-Oncogénicas B-raf/genética , GTP Fosfohidrolasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Adulto , Anciano de 80 o más Años , Proteína p53 Supresora de Tumor/genética , Receptor ErbB-2/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/sangreRESUMEN
PURPOSE: RAS (KRAS/NRAS) mutational status on a tumor biopsy is mandatory to guide the best treatment in metastatic colorectal cancer (mCRC). Determining the RAS mutational status by tumor-tissue biopsy is essential in guiding the optimal treatment decision for mCRC. RAS mutations are negative predictive factors for the use of EGFR monoclonal antibodies. Cell-free DNA (cfDNA) analysis enables minimally invasive monitoring of tumor evolution. METHODS/PATIENTS: PERSEIDA was an observational, prospective study assessing cfDNA RAS, BRAF and EGFR mutations (using Idylla™) in first-line mCRC, RAS wild-type (baseline tumor-tissue biopsy) patients (cohort 2). Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. RESULTS: 117 patients were included (103 received panitumumab + chemotherapy as first-line treatment). At baseline, 7 (6.8%) patients had RAS mutations, 4 (3.9%) BRAF mutations and no EGFR mutations were detected (cfDNA, panitumumab + chemotherapy subpopulation [panitumumab + Ch]). The baseline RAS mutational status concordance between tissue and liquid biopsies was 94.0% (93.2%, panitumumab + Ch). At 20 weeks, only one patient in the study (included in the panitumumab + Ch) had an emerging cfDNA RAS mutation. No emerging BRAF or EGFR mutations were reported. At disease progression, 6 patients had emergent mutations not present at baseline (RAS conversion rate: 13.3% [6/45]; 15.0% [6/40], panitumumab + Ch). CONCLUSIONS: The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.
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Ácidos Nucleicos Libres de Células , Neoplasias Colorrectales , Mutación , Panitumumab , Proteínas Proto-Oncogénicas B-raf , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/sangre , Femenino , Masculino , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Proteínas Proto-Oncogénicas B-raf/genética , Panitumumab/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores ErbB/genética , Adulto , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , GTP Fosfohidrolasas/genética , Progresión de la Enfermedad , Proteínas de la Membrana/genéticaRESUMEN
The advanced stage at diagnosis of colorectal cancer (CRC) may be related to individual factors, socioeconomic conditions, and healthcare service availability. The objective of the study was to analyze the prevalence of advanced stage CRC at the time of diagnosis and its association with individual, contextual, socioeconomic, and healthcare service indicators. An observational, cross-sectional study was conducted, analyzing cases of malignant neoplasms of the colon and rectum in individuals of both sexes, aged between 18 and 99 years, diagnosed between 2010 and 2019 in Brazil (n = 69,047). Data were collected from the Hospital Cancer Registry (HCR), Atlas of Human Development in Brazil, and from the National Registry of Health Institutions (NRHI). A Multilevel Poisson Regression model with random intercept was used. The prevalence of advanced stage CRC at diagnosis was 65.6%. Advanced stage was associated with older age groups prevalence ratio (PR) 4.40 and younger age groups (PR 1.84), low Human Development Index (HDI) (PR 1.22), and low density of family health strategy teams (PR 1.10). The study highlights the unequal distribution of social determinants of health in the diagnosis CRC in Brazil, revealing the need to evaluate and redirect public policies aimed at improving early detection and prevention of CRC in the country.
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Neoplasias Colorrectales , Análisis Multinivel , Estadificación de Neoplasias , Determinantes Sociales de la Salud , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Anciano , Adulto , Brasil/epidemiología , Anciano de 80 o más Años , Estudios Transversales , Adolescente , Adulto Joven , Factores Socioeconómicos , Prevalencia , Sistema de RegistrosRESUMEN
PURPOSE: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event with poor prognosis. Apart from (K)RAS status and lung and bone metastasis no biomarkers exist to identify patients at risk. This study aimed to identify a gene expression signature associated with colorectal BM. METHODS: Three patient groups were formed: 1. CRC with brain metastasis (BRA), 2. exclusive liver metastasis (HEP) and, 3. non-metastatic disease (M0). RNA was extracted from primary tumors and mRNA expression was measured using a NanoString Panel (770 genes). Expression was confirmed by qPCR in a validation cohort. Statistical analyses including multivariate logistic regression followed by receiver operating characteristic (ROC) analysis were performed. RESULTS: EMILIN3, MTA1, SV2B, TMPRSS6, ACVR1C, NFAT5 and SMC3 were differentially expressed in BRA and HEP/M0 groups. In the validation cohort, differential NFAT5, ACVR1C and SMC3 expressions were confirmed. BRA patients showed highest NFAT5 levels compared to HEP/M0 groups (global p = 0.02). High ACVR1C expression was observed more frequently in the BRA group (42.9%) than in HEP (0%) and M0 (7.1%) groups (global p = 0.01). High SMC3 expressions were only detectable in the BRA group (global p = 0.003). Only patients with BM showed a combined high expression of NFAT5, ACVR1C or SMC3 as well as of all three genes. ROC analysis revealed a good prediction of brain metastasis by the three genes (area under the curve (AUC) = 0.78). CONCLUSIONS: The NFAT5, ACVR1C and SMC3 gene expression signature is associated with colorectal BM. Future studies should further investigate the importance of this biomarker signature.
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Biomarcadores de Tumor , Neoplasias Encefálicas , Neoplasias Colorrectales , Humanos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Anciano , Transcriptoma , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Pronóstico , Perfilación de la Expresión Génica , Curva ROC , Adulto , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT01733628.