RESUMO
Colorectal cancer (CRC) is the most commonly diagnosed cancer worldwide, and over 50% of patients will develop hepatic metastasis during the course of their disease. CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α)/chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we have shown that lipopolysaccharides (LPS) promoted the migratory capacity of colon cancer cells in vivo and in vitro, which correlated with the activation of SDF-1α/CXCR4 axis and epithelial-mesenchymal transition (EMT) occurrence. Additionally, we found that LPS-induced CXCR4 expression and EMT through NF-κB signaling pathway activation. And inhibition of NF-κB pathway, which recovered the epithelial phenotype and attenuated CXCR4 expression, inhibited cell migratory capacity. Clinically, high levels of CXCR4 always correlated with metastasis and poor prognosis of CRC patients. In conclusion, LPS participate in the whole process of hepatic metastasis of CRC, not only causing liver damage resulting in the production of SDF-1α, but also enhancing the invasive potential of CRC cells by promoting CXCR4 expression and EMT occurrence, which would contribute to the enhancement of cell migration and invasion.
Assuntos
Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Lipopolissacarídeos/farmacologia , Mesoderma/patologia , Receptores CXCR4/metabolismo , Animais , Linhagem Celular Tumoral , Quimiocina CXCL12/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Fenótipo , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
The biological behaviors of hepatocellular carcinoma (HCC) are complex mainly due to heterogeneity of progressive genetic and epigenetic mutations as well as tumor environment. Hepatocyte growth factor (HGF)/c-Met signaling pathway is regarded to be a prototypical example for stromal-epithelial interactions during developmental morphogenesis, wound healing, organ regeneration and cancer progression. And p53 plays as an important regulator of Met-dependent cell motility and invasion. Present study showed that 2 HCC cell lines, Hep3B and HepG2, displayed different invasive capacity when treated with HGF which was secreted by hepatic stellate cells (HSCs). We found that HGF promoted Hep3B cells invasion and migration as well as epithelial-mesenchymal transition (EMT) occurrence because Hep3B was p53 deficient, which leaded to the c-Met over-expression. Then we found that HGF/c-Met promoted Hep3B cells invasion and migration by upregulating Snail expression. In conclusion, HGF/c-Met signaling is enhanced by loss of p53 expression, resulting in increased ability of invasion and migration by upregulating the expression of Snail.
Assuntos
Carcinoma Hepatocelular/metabolismo , Células Estreladas do Fígado/fisiologia , Fator de Crescimento de Hepatócito/fisiologia , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Células Hep G2 , Células Estreladas do Fígado/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-met/fisiologia , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismoRESUMO
Cancer stem cells (CSCs) or tumor-initiating cells (TICs), a small subset of tumor cells, are involved in tumor initiation, progression, recurrence and metastasis. In human hepatocellular carcinoma (HCC), TICs are enriched with cell surface markers and play a key role in chemotherapy resistance, tumor invasion and migration. Toll like receptor 4 (TLR4), acting as a receptor for lipopolysaccharide (LPS), has been reported to be responsible for carcinogenesis, invasion, metastasis and cancer progression. In our study, two HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasive ability of TLR4 positive HCC cells in vitro and in vivo. Stem-like features were also detected in TLR4 positive HCC cells. A total of 88 clinical samples from HCC patients were used to evaluate the association of TLR4 and stem-cell marker expression, and the relationship between TLR4 expression and clinicopathological characteristics was analyzed. The in vitro and in vivo experiments indicated that TLR4 positive HCC cells displayed significantly enhanced invasion and migration, and stem-like properties were also detected in TLR4 positive HCC cells. Clinically, TLR4 expression levels were found to be significantly higher in HCC tissues with microvascular invasion. Additionally, high expression of TLR4 in HCC tissues was strongly associated with both early recurrence and poor survivals in patients. Our results indicated that there was a relationship between TLR4 expression and CSC's features, TLR4 may act as a CSC marker, prompting tumor invasion and migration, which contributes to the poor prognosis of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Animais , Biomarcadores/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptor 4 Toll-Like/genética , Carga TumoralRESUMO
Hepatitis B virus (HBV) infection is a risk factor for hepatocarcinogenesis and recurrence. Here, we sought to characterize intratumoral and peritumoral expression of HBsAg and its specific receptors in HBsAg-positive hepatocellular carcinoma (HCC) patients and further examined their correlation with the recurrence-free survival (RFS). HCC tissue and adjacent normal tissue specimens were acquired from HBsAg-positive patients. The presence of HBsAg and receptors, as well as hepatic progenitor cells (HPCs) were detected by tissue microassay and immunohistochemistry. Necroinflammatory activity was evaluated by HE staining. The mean IOD of HBsAg and HBV DNA in the intratumoral tissues was markedly lower than that in the peritumoral tissues (P < 0.001). Pearson correlation analysis further showed a significant correlation between the expression of HBsAg and NTCP (r = 0.461, P < 0.001) or ASGPR (r = 0.506, P < 0.001) in peritumoral tissues. And the peritumoral HBsAg and receptors presented a positive association with necroinflammatory activity (P < 0.05). Inflammation induced by HBV infection presented a positive association with HPCs activation (P < 0.05). Additionally, due to lack of HBV receptors, HPCs was not preferentially infected with HBV, but activated HPCs had a significant correlation with HBsAg expression in peritumoral tissues, and the peritumoral HPCs activation was associated with RFS of HCC patients, therefore, the overexpression of HBsAg and receptors in peritumor were also with higher recurrence risk (P < 0.05). In conclusion, lack of HBV receptors resulted in scant HBV infection in tumor cells, and overexpression of HBsAg and receptors in peritumor was strongly associated with higher recurrence risk in HCC patients.
Assuntos
Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Hepatite B/complicações , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Recidiva Local de Neoplasia/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptor de Asialoglicoproteína/análise , Receptor de Asialoglicoproteína/biossíntese , Carcinoma Hepatocelular/mortalidade , Criança , DNA Viral/análise , Intervalo Livre de Doença , Feminino , Antígenos de Superfície da Hepatite B/análise , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Inflamação/patologia , Inflamação/virologia , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/análise , Transportadores de Ânions Orgânicos Dependentes de Sódio/biossíntese , Simportadores/análise , Simportadores/biossíntese , Análise Serial de Tecidos , Adulto JovemRESUMO
Tumor-associated macrophages (TAMs), a crucial component of immune cells infiltrated in tumor microenvironment, have been found to be associated with progression and metastasis of hepatocellular carcinoma (HCC). In this study, we aimed to clarify the mechanism underlying the crosstalk between TAMs and cancer stem cells (CSCs) in HCC. Mouse macrophage cell line RAW264.7 cells were used to investigate the effects of TAMs on mouse hepatoma cell line Hepa1-6 cells in vivo and vitro. A total of 90 clinical samples had pathology-proven HCC were used to evaluate the distribution of TAMs and CSCs and analyze their value in predicting the prognosis. In the study, we have found that the number of TAMs has a positive correlation with the density of CSCs in the marginal of human HCC. Our results show that, cocultured with TAM-conditioned medium (CM) promoted CSC-like properties in Hepa1-6 cells, which underwent EMT and gained higher invasive capability. TAMs secreted more transforming growth factor- beta1 (TGF-beta1) than other phenotypes of macrophage. Furthermore, depletion of TGF-beta1 blocked acquisition of CSC-like properties by inhibition of TGF-beta1-induced EMT. High expression of CD68 in the EpCAM positive expression HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients. Our results indicate that the TAMs promote CSC-like properties via TGF-beta1-induced EMT and they may contribute to investigate the prognosis of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Idoso , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Técnicas de Cocultura , Intervalo Livre de Doença , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Comunicação Parácrina , Fenótipo , Transdução de Sinais , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Ductular reactions (DRs) are well documented in many acute and chronic liver disease.The DRs are thought to be the transit amplifying cells deriving from activation of the stem/progenitor cell compartments of the liver. The aim of this study was to examine the presence of proliferative index of DR (PI-DR) and HPC markers' expression in HCCs after curative hepatectomy, as well as their relationship with clinicopathological features and prognosis. RESULTS: Tissue microarray with peritumoral and intratumoral tissue samples of 120 HCCs after hepatectomy was analysed for peritumoral expression of proliferating cell nuclear antigen for PI-DR. Peritumoral and intratumoral expression status of HPC markers including EpCAM, OV6, CD133 and c-kit were also examined by immunohistochemistry. TMA analysis of HCCs revealed that peritumoral PI-DR strongly correlated with the degree of inflammation and fibrosis. The peritumoral PI-DR positively correlated with peritumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Moreover, there were highly significant correlations between peritumoral PI-DR and intratumoral HPC markers EpCAM, OV6, CD133 and c-kit expression. Further, multivariate analysis showed that peritumoral PI-DR was the independent prognostic factor for overall survival (HR; 3.316, P < 0.001), and peritumoral PI-DR had a better power to predict disease-free survival (HR; 2.618, P < 0.001). CONCLUSIONS: Peritumoral PI-DR, as a valid surrogate for peritumoral and intratumoral expression of HPC markers, could be served as a potential prognostic marker for recurrence and survival in HCC after hepatectomy.