RESUMO
Circulating tumor cells (CTCs) in blood are accepted as a prognostic marker for patients with metastatic colorectal cancer (CRC). However, there is limited data on the use of CTCs as a prognostic marker for non-metastatic patients. In the current study, we used a rare cell automated analysis platform, the MiSelect R System, to enumerate CTCs from blood in non-metastatic CRC patients, and corelated the number of CTCs with the clinical staging and survival. The presence of CTCs in mesenteric vein blood (MVB) samples from 101 CRC patients was significantly associated with T stage. Patients with 1 or more CTCs per 8 mL of MVB exhibited significantly worse disease-free survival (DFS) and cancer-specific survival (CSS) compared to patient without CTCs. The presence of CTCs before surgery is an independent marker for both DFS and CSS. CTC presence after surgical resection is also a prognostic marker. CTCs are a potentially useful prognostic and predictive biomarker in non-metastatic CRC patients that may further stratify patient's risk status within different stages of disease.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Células Neoplásicas Circulantes , Neoplasias Retais , Humanos , Neoplasias Colorretais/patologia , Prognóstico , Células Neoplásicas Circulantes/patologia , Biomarcadores TumoraisRESUMO
BACKGROUND: Circulating tumor cells (CTCs) have been investigated as a potential biomarker for predicting prognosis and monitoring therapeutic responses in colorectal cancer (CRC). However, the sensitivity of CTCs detection is low, thus limiting the clinical utility of CTCs. We aim to examine the clinicopathological parameters that improve prognosis prediction for CRC using CTCs as a biomarker. METHODS: We enumerated CTCs in 186 CRC patients and associated the number of CTCs with the clinicopathological features and overall survival (OS) using a univariate and multivariate Cox regression model and Kaplan-Meier survival analysis. RESULTS: The presence of CTCs from 186 CRC patients was significantly associated with stage, preoperational carcinoembryonic antigen (CEA), and CA19-9 levels. Using Kaplan-Meier survival and Cox regression analysis, patients with five or more CTCs exhibited significantly worse OS compared to patients with fewer than five CTCs. The combination of CTCs with tumor marker CEA has a better OS prediction than individual CTCs or CEA and serves as a more effective prediction model in patients with CRC. CONCLUSION: We identified that patients with more than five CTCs exhibited significantly worse OS. Additionally, patients with the normal level of CEA, but who also had more than five CTCs trended towards a worse OS.
Assuntos
Neoplasias Colorretais , Células Neoplásicas Circulantes , Humanos , Prognóstico , Antígeno Carcinoembrionário , Células Neoplásicas Circulantes/patologia , Biomarcadores TumoraisRESUMO
Our previous studies showed that colorectal tumor has high interleukin-4 receptor α (IL-4Rα) expression, whereas adjacent normal tissue has low or no IL-4Rα expression. We also observed that human atherosclerotic plaque-specific peptide-1 (AP1) can specifically target to IL-4Rα. In this study, we investigated the therapeutic efficacy and systemic toxicity of AP1-conjuagted liposomal doxorubicin. AP1 bound more strongly to and was more efficiently internalized into IL-4Rα-overexpressing CT26 cells than CT26 control cells. Selective cytotoxicity experiment revealed that AP1-conjugated liposomal doxorubicin preferentially killed IL-4Rα-overexpressing CT26 cells. AP1-conjugated liposomal doxorubicin administered intravenously into mice produced significant inhibition of tumor growth and showed decreased cardiotoxicity of doxorubicin. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Rα-overexpressing colorectal cancer cells, thus providing a model for targeted anticancer therapy.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/administração & dosagem , Peptídeos/administração & dosagem , Receptores de Interleucina-4/metabolismo , Animais , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Doxorrubicina/metabolismo , Doxorrubicina/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Peptídeos/metabolismo , Peptídeos/toxicidade , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
PURPOSE: Colorectal polyps are generally believed to be the precursors of colorectal cancers (CRC); however, the proportion and speed of progression differed widely in different subsets of polyps. Using microarray-based comparative genomic hybridization (aCGH) platform and CD133 immunostaining, we characterized colon polyps according to their association with CRC that developed in the same individual. PATIENTS AND METHODS: aCGH was performed to unveil genomic changes in 18 cancer-synchronous polyps (CSP), and 9 cancer-preceding polyps (CPP), together with their corresponding cancers and 16 cases of incidental polyps (IP), were examined for comparison. aCGH profiles were analyzed to determine the clonal relationship (CR) between the paired adenoma and carcinoma. CD133 expressions in each subset of polyps were quantified by immunohistochemistry (IHC) staining. RESULTS: Progressive genomic changes were observed from IP, CSP/CPP to CRC; they encompass an entire chromosomal region in IP and sub-chromosomal region in CSP/CPP and CRC. CR analyses demonstrated that 50 % of CSP and 67 % of CPP were clonally related to the concurrent or later developed carcinomas, respectively. The CD133 expression levels were significantly higher in CSP/CPP than those in IP (P < 0.0001) and even higher in CSP/CPP that were clonally related to their corresponding carcinomas than CSP/CPP that were unrelated (P < 0.05). CONCLUSIONS: There were more genomic changes in CSP/CPP than IP; more than half of the CSP/CPP were clonally related to the corresponding carcinomas. Genomic changes at sub-chromosomal regions and/or high CD133 expression were associated with CSP/CPP and highlighted their carcinogenic potential.
Assuntos
Antígenos CD/genética , Pólipos do Colo/genética , Glicoproteínas/genética , Peptídeos/genética , Antígeno AC133 , Adenoma/genética , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Carcinoma/genética , Pólipos do Colo/metabolismo , Hibridização Genômica Comparativa , Feminino , Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Peptídeos/metabolismo , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Tumor initiating cells are a small subset of cancer cells responsible for tumor growth and recurrence. The status of tumor initiating cells was measured using the surface markers CD133 (prominin-1) and ESA (epithelial-specific antigen). The aims of this study were to investigate the significance of CD133(+)/ESA(+) cells in mesenteric venous blood (MVB) and tumor mass (TM) for overall survival (OS) and disease-free survival (DFS) in colorectal cancer (CRC) patients undergoing curative resection. MATERIALS AND METHODS: A total of 229 CRC patients undergoing curative resection were prospectively enrolled in the study. Using CD133 and ESA as surface markers, CD133(+)/ESA(+) cells were enumerated from MVB and TM using flow cytometry. RESULTS: We analyzed the presence of CD133(+)/ESA(+) cells in TM from 158 patients and found no correlation to patient DFS, OS, or clinical stage. In 135 patients, an analysis of CD133(+)/ESA(+) cells in MVB showed an inverse correlation with both DFS and OS (P = 0.014 and P = 0.008, respectively). It exhibited an increase-then-decrease pattern with the peak in stage II patients. A multivariate Cox analysis demonstrated that the status of CD133(+)/ESA(+) cells in MVB, but not the TM, was a significant prognostic factor for DFS and OS (P = 0.003 and P = 0.011, respectively). CONCLUSIONS: The status of CD133(+)/ESA(+) cells in MVB, but not in TM, could be a useful indicator for predicting tumor recurrence and a prognostic marker for CRC patients.
Assuntos
Antígenos CD/análise , Antígenos de Neoplasias/análise , Moléculas de Adesão Celular/análise , Neoplasias Colorretais/sangue , Glicoproteínas/análise , Células-Tronco Neoplásicas , Peptídeos/análise , Antígeno AC133 , Idoso , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Taiwan/epidemiologiaRESUMO
Breast cancer resistance protein [BCRP/ATP-binding cassette subfamily G member 2 (ABCG2)] is a member of the ATP-binding cassette transporter family. The presence of ABCG2 on the plasma membrane in many kinds of human cancer cells contributes to multidrug resistance during chemotherapy, and it has been used as the side population marker for identifying cancer stem cells in lung cancers. We report here that, in addition to the membranous form, ABCG2 proteins are also found inside the nucleus, where they bind to the E-box of CDH1 (E-cadherin) promoter and regulate transcription of this gene. Increased expression of ABCG2 causes an increase of E-cadherin and attenuates cell migration, whereas knockdown of ABCG2 downregulates E-cadherin and enhances cell motility. In mice, xenografted A549 cells that have less ABCG2 are more likely to metastasize from the subcutaneous inoculation site to the internal organs. However, for the cancer cells that have already entered the blood circulation, an increased level of ABCG2, and correspondingly increased E-cadherin, may facilitate circulating cancer cells to colonize at a distant site and form a metastatic tumor. We propose a novel role for nuclear ABCG2 that functions as a transcription regulator and participates in modulation of cancer metastasis.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Caderinas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transporte Ativo do Núcleo Celular , Animais , Antígenos CD , Caderinas/metabolismo , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Xenoenxertos , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Masculino , Modelos Biológicos , Proteínas de Neoplasias/genética , Células Neoplásicas Circulantes , Interferência de RNA , Transcrição GênicaRESUMO
Circulating tumor cells (CTCs) can be detected in the blood of different types of early or advanced cancer using immunology-based assays or nucleic acid methods. The detection and quantification of CTCs has significant clinical utility in the prognosis of metastatic breast, prostate, and colorectal cancers. CTCs are a heterogeneous population of cells and often different from those of their respective primary tumor. Understanding the biology of CTCs may provide useful predictive information for the selection of the most appropriate treatment. Therefore, CTC detection and characterization could become a valuable tool to refine prognosis and serve as a "real-time biopsy" and has the potential to guide precision cancer therapies, monitor cancer treatment, and investigate the process of metastasis.
RESUMO
PURPOSE: Metastasis is the major cause of death in patients with colorectal cancer (CRC). Circulating tumor cells (CTC) are believed to cause metastasis and serve as a prognostic marker for mortality in clinical stage IV patients. However, most studies are conducted in late-stage cases when distant metastases have already occurred; thus, such results provide limited clinical use. This study focused on whether CTCs can predict the risk of metastasis after treatment of the primary tumor in early-stage patients with CRC. EXPERIMENTAL DESIGN: CTCs were quantified using EpCAM-positive/CD45-negative immunoselection and flow cytometry in patients with CRC. A mouse model was used to investigate the mechanistic roles of CTCs and interleukin (IL)-17A in metastasis. RESULTS: The number of mesenteric CTCs obtained from stage II patients was higher than that obtained from patients in stages I, III, and IV. In addition, following invasion of orthotopically implanted tumors in our mouse model, we found that CTCs exhibited an increase-then-decrease pattern, accompanied by corresponding changes in serum IL-17A levels and opposing changes in serum granulocyte macrophage colony-stimulating factor (GM-CSF) levels. Ablation of IL-17A and administration of rGM-CSF effectively suppressed the increase in CTCs and prevented metastasis in mice. Moreover, IL-17A promoted cancer cell motility, matrix digestion, and angiogenesis, whereas GM-CSF stimulated the elimination of CTCs by boosting host immunity. Notably, serum levels of IL-17A were also correlated with disease-free survival in patients with CRC. CONCLUSIONS: Our results showed that CTCs and IL-17A could serve as prognostic markers and therapeutic targets for CRC metastasis. Clin Cancer Res; 20(11); 2885-97. ©2014 AACR.