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1.
Crit Rev Oncol Hematol ; 143: 153-163, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31678702

RESUMO

Despite significant progress in management of metastatic colorectal cancer (mCRC) pertaining to better screening procedures and amelioration of the therapeutic armamentarium with targeted therapies, prognosis remains poor. Targeting epidermal growth factor receptor (EGFR) has been of particular interest owing to favourable efficacy benefits demonstrated by monoclonal antibodies (cetuximab and panitumumab) in various clinical settings and development of predictive biomarkers informing treatment decisions respectively. In spite of optimal patient selection based on RAS mutation status, primary and secondary resistance to monoclonal antibodies is higher than desired. Further research into predictive biomarkers is therefore essential, but has, to date, been conducted with considerable limitations. Whilst molecular heterogeneity has been demonstrated by several studies in mCRC, for incomprehensible reasons, multiple resistant genetic alterations that emerge under the selective pressure of EGFR-targeted therapies are somehow able to influence the biological and clinical behaviour of cancer cells, despite being detectable at extremely low frequencies. Intriguingly, these subclonal events largely seem to converge on RAS/RAF/MAPK pathway in patients treated with EGFR-targeted monoclonal antibodies. This review describes the clinical and biological evolution and development of EGFR targeted therapies in mCRC, the challenges in the presence of molecular complexities, the role of cell free (cf)-DNA and future strategies that could lead to further optimal discovery of clinically meaningful biomarkers and application of precision medicine.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Heterogeneidade Genética , Humanos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
2.
Gene ; 721: 144097, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493507

RESUMO

BACKGROUND: Polo-like kinase 1 (PLK1) is a potential prognostic marker in colorectal cancer (CRC). Nevertheless, the clinicopathological and prognostic roles of PLK1 in CRC are still undefined. Therefore, we performed a meta-analysis to investigate the clinicopathological and prognostic relevance of PLK1 expression in CRC patients. METHODS: Studies published between 2003 and 2016 were selected for the meta-analysis based on an electronic literature search (PubMed, EMBASE and Chinese databases). Studies that investigated the clinicopathological and prognostic impacts of PLK1 expression in CRC patients were included for this analysis. RESULTS: Eleven studies that enrolled 1147 CRC patients were included in our meta-analysis. The effect of PLK1 level on overall survival (OS) was reported in five studies, which included 702 patients. Ten studies investigated the clinicopathological role of PLK1 expression in CRC patients. Consequently, PLK1 overexpression was associated with poorer OS in CRC patients. Furthermore, the results revealed that higher PLK1 levels were also observed in CRC tissues compared with that of normal colorectal tissues. In addition, this meta-analysis also revealed positive correlations between PLK1 upregulation and lymph node metastasis or invasion. PLK1 overexpression was significantly correlated with advanced TNM stages and higher Dukes stages. CONCLUSION: This meta-analysis strongly supports the hypothesis that PLK1 might serve as an important factor in evaluating the biological behavior and prognosis of CRC.


Assuntos
Biomarcadores Tumorais/biossíntese , Proteínas de Ciclo Celular/biossíntese , Neoplasias Colorretais , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Taxa de Sobrevida
3.
Int J Biol Macromol ; 138: 125-134, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279884

RESUMO

Carboxypeptidase A4 (CPA4) is a novel cancer-related gene that is aberrantly expressed in various malignant tumors. However, the roles and mechanisms of CPA4 have not been explored in colorectal cancer (CRC). In this study, we investigated the functions and mechanisms by which CPA4 promotes CRC progression. Quantitative real-time PCR (qRT-PCR) and western blot showed that CPA4 mRNA and CPA4 protein levels were up-regulated in CRC compared to levels in adjacent normal tissue. Immunohistochemistry (IHC) results indicating high CPA4 levels were positively associated with poor prognoses. In addition, Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and transwell assays demonstrated that CPA4 overexpression facilitated the growth of CRC cells, whereas CPA4 knockdown resulted in decreased proliferation, G1/S phase transition arrest, and apoptosis. Subcutaneous tumorigenesis was performed in nude mice to confirm the tumor-promoting effects of CPA4 in vivo. Western blot revealed that activation of the STAT3 and ERK pathways is one of the oncogenic functions of CPA4 in CRC. Accordingly, CPA4 promotes CRC cell growth via activating the STAT3 and ERK pathways and may be a prognostic factor or therapeutic target for CRC.


Assuntos
Carboxipeptidases A/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Sistema de Sinalização das MAP Quinases , Fator de Transcrição STAT3/metabolismo , Idoso , Animais , Apoptose , Carboxipeptidases A/deficiência , Carboxipeptidases A/genética , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Neoplasias Colorretais/enzimologia , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
5.
Asian Pac J Cancer Prev ; 20(6): 1675-1681, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31244287

RESUMO

Background: Colorectal carcinoma (CRC) is the most common neoplasm of the gastrointestinal tract. COX-2 plays an important role in CRC development and is a key target for the regression of colorectal tumorigenesis by nonsteroidal anti-inflammatory drugs. The present study was conducted to examine the relationship of the levels of COX-2 in CRC patients with the clinico-pathological parameters and also to assess its usefulness as a potential biomarker for diagnosis of CRC. Methods: Prior to surgery, 30 CRC patients were enrolled and the samples from colon tumors and surrounding tissues were taken after they underwent surgical intervention at PGIMER, Chandigarh. mRNA expression levels of COX-2 were examined in 30 CRC and adjacent normal colonic mucosa by quantitative polymerase chain reaction (qPCR). The expression of COX-2 was assessed by immunohistochemical method using rabbit polyclonal antibodies against human COX-2 protein. Results: The quantitative relative expression of COX-2 mRNA was observed to be significantly higher (p<0.05) in colorectal cancer tissues as compared to adjacent normal colon tissues. Also, female CRC patients showed significantly higher (p<0.009) expression of COX-2 mRNA vis-a-vis male colorectal cancer patients. This is the first study which has reported a direct relationship between COX-2 mRNA expressions in male colorectal cancer patients versus females. Further, immunohistochemistry of COX-2 confirmed the quantitative real time-PCR findings. Conclusion: Our study shows that COX-2 over expression in colorectal carcinoma patients is closely associated with clinico-pathological parameters and is more pronounced in males versus females. Further, COX-2 mRNA expression can serve as a potential biomarker for the diagnosis of CRC.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Ciclo-Oxigenase 2/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores Sexuais , Adulto Jovem
6.
Acta Oncol ; 58(9): 1205-1211, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31109224

RESUMO

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzyme defect worldwide. There is a growing scientific evidence for a protective role of G6PD deficiency against carcinogenesis. In this retrospective analysis, we tested the hypothesis that G6PD deficiency may reduce the risk of developing cancer in a tissue-specific manner. Material and methods: The study was conducted using data from 11,708 subjects undergoing gastrointestinal endoscopic procedures between 2002 and 2018 and tested for G6PD status in a teaching hospital of Northern Sardinia, Italy. Results: A 40% reduction of risk for cancer of endodermal origin was observed among G6PD-deficient patients compared with subjects with normal enzyme activity (relative risk (RR) 0.61, 95% confidence interval (CI) 0.47-0.80) in both genders, confirmed by multivariable generalized linear regression after adjusting for age, sex, smoking habits, body mass index, diabetes and socio-economic status. The 'protective' effect of G6PD deficiency was larger for gastric cancer (RR 0.41, 95% CI 0.18-0.99), hepatocellular carcinoma (RR 0.48, 95% CI 0.26-0.92) and colorectal cancer (RR 0.72, 95% CI 0.53-0.98), while a non-significant risk was observed for breast, prostate, lung, hematopoietic and metastases (primary site unknown). Conclusions: Our results suggest a reduced susceptibility to develop cancers, mostly of endodermal origin (stomach, colon and liver), but not of ectodermal/mesodermal origin, in carriers of G6PD deficiency. The effects of G6PD deficiency on carcinogenesis need further studies to better understand how cancer cells originating from different germ layers use pentose phosphate pathway to proliferate.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Glucosefosfato Desidrogenase/sangue , Neoplasias/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/enzimologia , Neoplasias da Mama/enzimologia , Carcinoma Hepatocelular/enzimologia , Estudos de Casos e Controles , Neoplasias Colorretais/enzimologia , Intervalos de Confiança , Suscetibilidade a Doenças , Feminino , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Humanos , Modelos Lineares , Neoplasias Hepáticas/enzimologia , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Neoplasias da Próstata/enzimologia , Estudos Retrospectivos , Neoplasias Gástricas/enzimologia
7.
Pathol Res Pract ; 215(6): 152383, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30890279

RESUMO

AIM: Arginase-1 (Arg-1) metabolizes l-arginine to l-ornithine and urea. It has been documented to have a role in various malignancies. However, the relationship between Arg-1 expression and clinicopathological characteristics of colorectal cancer (CRC) patients remains to be elucidated. The present study aimed to analyze the expression and prognostic value of Arg-1 in patients with CRC. MATERIAL AND METHODS: The mRNA and protein expressions of Arg-1 in fresh colorectal cancer tissue specimens and the corresponding noncancerous tissue specimens were examined by RT-qPCR (n = 24) and western blot analysis (n = 17). Arg-1 expression levels were determined in paraffin-embedded CRC tissue specimens (n = 236) by immunohistochemistry. The associations of Arg-1 expression and clinicopathological features and clinical prognosis in 236 CRC patients were analyzed. RESULTS: The expression levels of Arg-1 were significantly higher in the CRC tissues compared with the matched noncancerous tissues, and elevated Arg-1 expression was remarkably associated with stage III-IV tumors (P = 0.007), lymph node metastasis (P = 0.019) and a plasma albumin concentration <35 g/l (P = 0.022). Kaplan-Meier analysis indicated that Arg-1 overexpression was associated with adverse prognoses for overall survival (OS) (P < 0.001) and disease-free survival (DFS) (P < 0.001) in all cases. Further analysis revealed that the patients with high Arg-1 expression had significantly shorter OS and DFS at the advanced stages (III + IV) (P = 0.032 for OS, and P = 0.012 for DFS) but not at the early stages (I + II) (P = 0.194 for OS, and P = 0.065 for DFS). Multivariate analysis revealed that Arg-1 overexpression was an independent prognostic factor for OS (P = 0.002) and DFS (P < 0.001) in patients with CRC. CONCLUSION: The data indicated that Arg-1 overexpression in CRC may be a marker that can discriminate subgroups of patients with a poor prognosis.


Assuntos
Arginase/biossíntese , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Adulto , Idoso , Arginase/análise , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Regulação para Cima
8.
Biol Cell ; 111(5): 121-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30834544

RESUMO

BACKGROUND: The mammalian gut epithelium displays among the highest rates of self-renewal, with a turnover time of less than 5 days. Renewal involves concerted proliferation at the bottom of the crypt, migration and differentiation along the crypt-villus axis and anoïkis/shedding in the luminal epithelium. Renewal is controlled by interplay between signalling pathways, among which canonical and non-canonical Wnt signals play prominent roles. Overall 92% of colon tumours show increased canonical Wnt signalling resulting from mutations, established as major driver steps towards carcinogenesis. RESULTS: Here, we examined the physiological role of RhoU/Wrch1 in gut homeostasis. RhoU is an atypical Rho GTPase related to Cdc42/Rac1 and identified as a transcriptional target of non-canonical Wnt signalling. We found that RHOU expression is reduced in human colorectal tumour samples. We show that RhoU is mainly expressed in the differentiated compartment of the gut epithelium. Rhou specific invalidation in the mouse gut elicits cell hyperplasia and is associated in the colon with a highly disorganized luminal epithelium. Hyperplasia affects all cell types in the small intestine and colon and has a higher impact on goblet cells. Hyperplasia is associated with a reduction of apoptosis and an increased proliferation. RhoU knockdown in human DLD-1 colon cancer cells also elicits a higher growth index and reduces cell apoptosis. Last, loss of RhoU function in the mouse gut epithelium or in DLD-1 cells increases RhoA activity and the level of phosphorylated Myosin Light Chain-2, which may functionally link RhoU activity to apoptosis. CONCLUSION: RhoU is mostly expressed in the differentiated compartment of the gut. It plays a role in homeostasis as its specific invalidation elicits hyperplasia of all cell types. This mainly results from a reduction of apoptosis, through actomyosin-dependent mechanisms. SIGNIFICANCE: RhoU negatively controls cell growth in the intestinal epithelium. Since its expression is sensitive to non-canonical Wnt signals and is reduced in colorectal tumours, downregulating RhoU may thus have an instrumental role in tumour progression.


Assuntos
Apoptose , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/patologia , Via de Sinalização Wnt , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Células Caliciformes/enzimologia , Células Caliciformes/patologia , Humanos , Hiperplasia , Camundongos Endogâmicos C57BL , Proteínas rho de Ligação ao GTP/genética
9.
J Clin Pathol ; 72(6): 443-447, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30723092

RESUMO

Colorectal cancer (CRC) is common with 3% of cases associated with germline mutations in the mismatch repair pathway characteristic of Lynch syndrome (LS). The UK National Institute for Health and Care Excellence recommends screening for LS in all patients newly diagnosed with CRC, irrespective of age. The Yorkshire Cancer Research Bowel Cancer Improvement Programme includes a regional LS screening service for all new diagnoses of CRC. In the first 829 cases screened, 80 cases showed deficient mismatch repair (dMMR) including four cases showing areas with loss of expression of all four mismatch repair proteins by immunohistochemistry. The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/-MSH6 rather than underlying LS. Recognition and accurate interpretation of this unusual phenotype is important to prevent unnecessary referrals to clinical genetics and associated patient anxiety.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Metilação de DNA , Proteínas de Ligação a DNA/análise , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/análise , Regiões Promotoras Genéticas , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Detecção Precoce de Câncer/métodos , Inglaterra , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Fenótipo , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética
10.
PLoS One ; 14(1): e0211108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30677088

RESUMO

Although small bowel cancer (SBC) is extremely rare, its prognosis is poor, and molecular mechanism of the SBC development remains unclear. The aim of our study is to elucidate whether DNA methylation of the promoter region of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in SBC. The study group comprised patients with 53 patients with SBC, 107 colorectal cancer (CRC), and other rare tumors of the small intestine such as 4 malignant lymphomas, 2 leiomyosarcomas, and 9 gastrointestinal stromal tumors. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. Significantly higher CDO1 methylation was observed in cancer tissues compared with non-cancerous mucosa of the small intestine (ROC = 0.96). Among the various clinicopathological factors, positive correlation of CDO1 methylation with tumor diameter was observed (R = 0.31, p = 0.03), and the CDO1 methylation level was a possible prognostic factor for relapse-free survival (p = 0.09). Compared with CRC, SBC had a significantly poorer prognosis (p = 0.007) and displayed a significantly higher CDO1 methylation level (p < 0.0001). Intriguingly, especially in pStage I/II, there were robust prognostic difference between SBC and CRC (p = 0.08 / p < 0.0001), which may reflect CDO1 methylation status (p = 0.02 / p = 0.001). Among small bowel tumors, CDO1 methylation in SBC was higher in order of malignant lymphoma, cancer, and leiomyosarcoma/GIST (p = 0.002) by ANOVA. The CDO1 gene shows extremely cancer-specific hypermethylation, and it can be a prognostic marker in SBC.


Assuntos
Neoplasias Colorretais , Cisteína Dioxigenase , Metilação de DNA , DNA de Neoplasias , Leiomiossarcoma , Linfoma , Proteínas de Neoplasias , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Cisteína Dioxigenase/genética , Cisteína Dioxigenase/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Intervalo Livre de Doença , Feminino , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Leiomiossarcoma/enzimologia , Leiomiossarcoma/genética , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Linfoma/enzimologia , Linfoma/genética , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
11.
Mol Cancer Res ; 17(4): 882-894, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30655319

RESUMO

Serine threonine kinase 17A (STK17A) is a ubiquitously expressed kinase originally identified as a regulator of apoptosis; however, whether it functionally contributes to colorectal cancer has not been established. Here, we have analyzed STK17A in colorectal cancer and demonstrated decreased expression of STK17A in primary tumors, which is further reduced in metastatic lesions, indicating a potential role in regulating the metastatic cascade. Interestingly, changes in STK17A expression did not modify proliferation, apoptosis, or sensitivity of colorectal cancer cell lines to treatment with the chemotherapeutic 5-fluorouracil. Instead, STK17A knockdown induced a robust mesenchymal phenotype consistent with the epithelial-mesenchymal transition, including spindle-like cell morphology, decreased expression of adherens junction proteins, and increased migration and invasion. Additionally, overexpression of STK17A decreased cell size and induced widespread membrane blebbing, a phenotype often associated with activation of cell contractility. Indeed, STK17A-overexpressing cells displayed heightened phosphorylation of myosin light chain in a manner dependent on STK17A catalytic activity. Finally, patient-derived tumor organoid cultures were used to more accurately determine STK17A's effect in primary human tumor cells. Loss of STK17A induced morphologic changes, decreased E-cadherin, increased invasion, and augmented organoid attachment on 2D substrates, all together suggesting a more metastatic phenotype. Collectively, these data indicate a novel role for STK17A in the regulation of epithelial phenotypes and indicate its functional contribution to colorectal cancer invasion and metastasis. IMPLICATIONS: Loss of serine threonine kinase 17A occurs in colorectal cancer metastasis, induces mesenchymal morphologies, and contributes to tumor cell invasion and migration in colorectal cancer.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Neoplasias Colorretais/tratamento farmacológico , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Fluoruracila/farmacologia , Células HCT116 , Humanos , Metástase Neoplásica
12.
Cancer Treat Rev ; 73: 41-53, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30616224

RESUMO

BACKGROUND: Despite advances in precision oncology and immunotherapy of tumors, little progress has been made in metastatic colorectal cancer (mCRC) in recent years. Therefore, making the most of available therapies is a necessity. Several studies, based on the pulsatile behavior of RAS clones under EGFR blockade, investigated whether readministration of EGFR-targeted agents is effective beyond second line. METHODS: A systematic review of studies of retreatment with anti-EGFR monoclonal antibodies has been performed from January 2005 to December 2018 according to PRISMA criteria from PubMed, ESMO and ASCO meetings libraries and Clinicaltrial.gov. Efficacy has been evaluated as objective response rate and survival in available publications. In addition, type and incidence of side effects occurring during on anti-EGFR retreatment have been considered. RESULTS: 26 publications have been retrieved, of which 20 full-text articles and 6 abstracts and categorized as for the retreatment strategy into five groups: rechallenge (n = 10), reintroduction (n = 4), sequence (n = 5), dose escalation (n = 1) and mixed (n = 6). Data of efficacy displayed high heterogeneity across different strategies (objective response rate, ORR = 0.0-53.8%; disease control rate, DCR = 24.0-89.7%), with best results in the setting of rechallenge (ORR = 2.9-53.8%; DCR = 40.0-89.7%). CONCLUSIONS: Rechallenge with anti-EGFR provides clinical benefit in molecularly selected mCRC patients beyond second line. Further ctDNA-guided studies comparing this option of treatment with current approved advanced line treatments are warranted.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/imunologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Humanos
13.
Biochem Biophys Res Commun ; 508(3): 825-831, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528730

RESUMO

Identification of new therapeutic targets may improve the survival rate of patients with colorectal cancer (CRC). Recent studies have suggested that the level of phosphodiesterase 4B (PDE4B) is elevated in fatal/refractory diffuse large B-cell lymphoma (DLBCL), and therapeutic efficacy of a PDE4 inhibitor in B-cell lymphoma has been successfully tested in clinical settings. Here, we show that PDE4B is a potential therapeutic target in CRC. Treatment with forskolin, an activator of adenylyl cyclase (AC), increased intracellular cyclic AMP (cAMP) levels in PDE4B-low, but not PDE4B-high cells, indicating that PDE4B was a major regulator of cAMP levels in CRC cells. Furthermore, cAMP modulated the activities of AKT and AMPK in a PDE4B-dependent manner, which was associated with a marked decrease in mTOR-Myc signals and oncogenic properties of CRC cells such as anchorage-independent growth and colony formation. We found that the Myc proto-oncogene was a crucial downstream target of the AKT/mTOR and AMPK/mTOR signals that mediated cAMP-induced anti-tumor effect. A natural polyphenol resveratrol that was reported to have PDE4 inhibitory effects also showed tumor suppressive effects by inhibiting the mTOR-Myc axis. Intriguingly, we identified Myc as a transcriptional activator of PDE4B in CRC cells, which maintains the intracellular cAMP levels low and promotes cell survival. These data suggest that cAMP/PDE4B signals play a significant role in regulating the malignant phenotype of CRC cells and targeting of PDE4B should be actively pursued.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Azepinas/farmacologia , Carcinogênese , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Resveratrol/farmacologia , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Triazóis/farmacologia
14.
Neoplasma ; 66(3): 357-366, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30569725

RESUMO

Signal Transducers (STATs) 1 and 3 and Activator Protein 1 (AP-1) are transcription factors involved in the development of malignancy in colorectal carcinoma (CRC). Matrix Metalloproteinase 1 (MMP-1) is a protease frequently dysregulated in de-differentiated and invasive cancer cells. Its expression is influenced by STAT and AP-1 transcription factors. We studied their contributions to transcriptional regulation of MMP-1 in colorectal carcinoma (CRC) cells. Both STAT3 and AP-1 contribute individual expression-inducing and additive effects and interact with the MMP-1 promoter. DNA binding of AP-1 protein c-Jun is stimulation-independent but modulated by STAT3 and a STAT recognition DNA element. Activated STAT3 showed a suppressive effect on AP-1-mediated MMP-1 mRNA upregulation as shown by STAT3 knockdown. Surprisingly, activated STAT1 overcame STAT3-dependent repression of AP-1-driven MMP-1 expression. Moreover, combined STAT3, STAT1 and AP-1 activities evoked maximal MMP-1 mRNA levels in a synergistic manner. Our results suggest a dominant role of AP-1 in transcriptional upregulation of MMP-1 in CRC cells which is modulated by joint functions of STAT3 and STAT1. The individual and combinatorial activity of these factors is of diagnostic and prognostic interest.


Assuntos
Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 1 da Matriz , Regiões Promotoras Genéticas , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Fator de Transcrição AP-1 , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Regiões Promotoras Genéticas/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição AP-1/metabolismo
15.
Biotech Histochem ; 94(1): 60-64, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30317880

RESUMO

Although angiogenesis plays a crucial role in cancer growth and progression, no reliable method for assessing angiogenesis in tumor tissue sections currently is available. Using biomarkers with high specificity for proliferating endothelial cells could help quantify angiogenic activity. Thymidine kinase-1 (TK1) is an enzyme involved in the salvage pathway of DNA synthesis and its activity is correlated with cell proliferation. We investigated the use of double immunostaining for TK1 and CD31 for identifying activated tumor vessels. Differences in TK1/CD31 positive vessel rates (PVRs) between tumor and adjacent normal tissues were evaluated in 39 colorectal carcinoma (CRC) samples and compared with those of Ki67/CD31 double stained tissues. Mean TK1/CD31 PVR (23.6%) in CRCs was 13.9 fold greater than in adjacent normal tissues (1.7%)). By comparison, mean Ki67/CD31 PVR in CRCs was 20.0%, i.e. only 4.8 fold greater than in normal tissues (4.2%). Also, mean TK1/CD31 PVR in normal tissues was significantly less than mean Ki67/CD31 PVR. Our findings indicate that double immunostaining for TK1/CD31 can detect activated tumor vessels more accurately than staining for Ki67/CD31 and potentially could identify tumors that will respond to anti-angiogenic therapy.


Assuntos
Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Timidina Quinase/metabolismo , Biomarcadores Tumorais , Proliferação de Células , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Timidina Quinase/genética
16.
Mol Biol Rep ; 46(1): 657-667, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30484108

RESUMO

Colorectal cancer (CRC) is among the leading causes of cancer-related mortality worldwide. Compelling evidence suggests that long non-coding RNA (lncRNAs) can control carcinogenesis by regulating various aspects of cell biology. However, limited number of CRC-related lncRNAs has been well characterized. This study was undertaken to investigate the expression pattern of the novel lncRNA-CCHE1 in CRC patients and to examine its correlation with clinicopathological features, ERK/COX-2 pathway and some cell proliferation markers in order to gain biological insights on its role in CRC pathogenesis. Colon cancer specimens with their adjacent non-cancerous tissues were taken from 60 patients with primary CRC. LncRNA-CCHE1 relative expression was assessed using quantitative real-time RT-PCR. P-ERK ½ and cyclin D1 levels were estimated by ELISA. COX-2 and proliferating cell nuclear antigen (PCNA) expression were assessed immunohistochemically. lncRNA-CCHE1 expression was upregulated in CRC tissues compared to adjacent non-cancerous tissues, and was significantly associated with larger tumor size, less differentiated histology, advanced dukes' stage, positive lymph node involvement and vascular invasion. It also showed a significant positive correlation with the expression of p-ERK1/2, COX-2 as well as cyclin D1and PCNA (as markers for cell proliferation). These findings signify that lncRNA-CCHE1 is a key oncogene possibly involved in CRC development and progression by modulating ERK/COX-2 pathway and cell proliferation activity. Our study also provides a rationale for potential use of lncRNA-CCHE1 as a novel prognostic marker, and opens the door for the development of lncRNA-CCHE1-directed therapeutic approaches for CRC patients.


Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Ciclo-Oxigenase 2/metabolismo , Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Colo/patologia , Neoplasias Colorretais/patologia , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Longo não Codificante/metabolismo
17.
Cancer Lett ; 442: 383-395, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30472186

RESUMO

Pseudopodium enriched atypical kinase 1 (PEAK1), a novel non-receptor tyrosine kinase, was recently implicated in cancer pathogenesis. However, its functional role in colorectal cancer (CRC) is not well known. Herein, we demonstrated that PEAK1 was frequently downregulated in CRC and significantly associated with tumor size, differentiation status, metastasis, and clinical stage. PEAK1 overexpression suppressed CRC cell growth, invasion, and metastasis in vitro and in vivo, whereas knockout had the opposite effects. Further evaluation revealed that PEAK1 expression was positively correlated with protein phosphatase 1 regulatory subunit 12B (PPP1R12B) in CRC cell lines and clinical tissues, and this protein was found to suppress activation of the Grb2/PI3K/Akt pathway. Moreover, PPP1R12B knockdown markedly abrogated PEAK1-mediated tumor suppressive effects, whereas its upregulation recapitulated the effects of PEAK1 knockout on cell behaviours and the activation of signalling. Mechanistically, PI3K and Akt inhibitors reversed impaired the effect of PEAK1 function on cell proliferation, migration, and invasion. Our results provide compelling evidence that the PEAK1-PPP1R12B axis inhibits colorectal tumorigenesis and metastasis through deactivation of the Grb2/PI3K/Akt pathway, which might provide a novel therapeutic strategy for CRC treatment.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais/enzimologia , Proteína Adaptadora GRB2/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteína Fosfatase 1/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células CACO-2 , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Proteína Fosfatase 1/genética , Proteínas Tirosina Quinases/genética , Transdução de Sinais , Carga Tumoral
18.
Biochem Biophys Res Commun ; 508(2): 380-386, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30502090

RESUMO

Little is known about an oncogenic signal transducer ß-1,4-galactosyltransferase-V (ß-1,4-GalT-V), in human colorectal cancer. Using quantitative RT-PCR, immunohistochemical staining and ELISA assays, we determined that ß-1,4-GalT-V gene/protein expression is specifically increased in human colorectal cancer (CRC) tumors, compared to visibly normal tissue. Furthermore, we observed a marked increase in its enzymatic activity, and its product lactosylceramide. Moreover, we found increased dihydrosphingolipid metabolites, in particular dihydrosphingomyelin in cancer tissue compared to normal. Further, inhibition of glycosphingolipid synthesis by the synthetic ceramide analog, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), concurrently inhibited colorectal cancer cell (HCT-116) proliferation, as well as ß-1,4-GalT-V mass and several glycosphingolipid levels. We conclude that ß-1,4-GalT-V may serve as a diagnostic and therapeutic biomarker for the progression of human colorectal cancer, and consequently, inhibition of GSL synthesis may be a novel approach for the treatment of this life-threatening disease.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/enzimologia , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Biomarcadores Tumorais/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Galactosiltransferases/antagonistas & inibidores , Células HCT116 , Humanos , Imuno-Histoquímica , Lactosilceramidas/biossíntese , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Esfingolipídeos/biossíntese , Regulação para Cima
19.
Appl Radiat Isot ; 143: 87-97, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30391716

RESUMO

Human carbonic anhydrase IX is a membrane enzyme that is significantly expressed in some types of cancer cells, while copper radioisotopes offer wide range of diagnostic, therapeutic and theranostic properties. The work was focused on a new approach to the labelling of antibody IgG M75 for epitope human carbonic anhydrase IX with copper radioisotopes 61Cu and 64Cu and its in vivo testing in mice with inoculated colorectal cancer. Monoclonal antibody IgG M75 for epitope human carbonic anhydrase IX was successfully conjugated with copper-specific chelator "phosphinate" and labelled with 61Cu and 64Cu The obtained molecule has considerable potential as a radioimmuno pharmaceutical suitable for imaging of tumours expressing carbonic anhydrase IX by positron emission tomography (PET).


Assuntos
Anticorpos Monoclonais/química , Antígenos de Neoplasias/imunologia , Anidrase Carbônica IX/imunologia , Radioisótopos de Cobre/química , Animais , Anticorpos Monoclonais/farmacocinética , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/enzimologia , Radioisótopos de Cobre/farmacocinética , Células HT29 , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoglobulina G/química , Masculino , Camundongos , Camundongos Nus , Tomografia por Emissão de Pósitrons , Radioimunodetecção , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
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