RESUMO
Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-κB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTα and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and lymphotoxin ß receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.
Assuntos
Proliferação de Células , Endotélio Linfático/metabolismo , Linfangiogênese , Vasos Linfáticos/metabolismo , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Linfático/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/patologia , Linfotoxina-alfa/metabolismo , Regulação para CimaRESUMO
Head and neck squamous cell carcinoma (HNSCC) represents the most frequent malignancy in the head and neck region, and the survival rate has not been improved significantly over the past three decades. It has been reported the infiltrated macrophages contribute to the malignant progression of HNSCC. However, the crosstalk between macrophages and cancer cells remains poorly understood. In the present study, we explored interactions between monocytes/macrophages and HNSCC cells by establishing the direct co-culture system, and found that the crosstalk promoted the migration and invasion of cancer cells by enhancing the invadopodia formation through a CCL2/EGF positive feedback loop. Our results demonstrated HNSCC cells educated monocytes into M2-like macrophages by releasing C-C motif chemokine ligand 2 (CCL2, or MCP-1). And the M2-like macrophages secreted epithelial growth factor (EGF), which increased the motility of HNSCC cells by enhancing the invadopodia formation. These subcellular pseudopodia degraded extracellular matrix (ECM), facilitating tumor local invasion and distant metastasis. Moreover, EGF up-regulated CCL2 expression in HNSCC cells, which recruited monocytes and turned them into M2-like macrophages, thus forming a positive feedback paracrine loop. Finally, we reported that curcumin, a powerful natural drug, suppressed the production of EGF and CCL2 in macrophages and cancer cells, respectively, blocking the feedback loop and suppressing the migration and invasion of HNSCC cells. These results shed light on the possibilities and approaches based on targeting the crosstalk between cancer cells and monocytes/macrophages in HNSCC for potential cancer therapy.
Assuntos
Carcinoma de Células Escamosas/patologia , Comunicação Celular , Quimiocina CCL2/fisiologia , Fator de Crescimento Epidérmico/fisiologia , Neoplasias de Cabeça e Pescoço/patologia , Macrófagos/fisiologia , Carcinoma de Células Escamosas/tratamento farmacológico , Diferenciação Celular , Movimento Celular , Polaridade Celular , Curcumina/farmacologia , Retroalimentação Fisiológica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Monócitos/fisiologia , Invasividade Neoplásica , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Tumor-associated macrophages (TAMs) play an important role in the progression and prognostication of numerous cancers. However, the role and clinical significance of TAM markers in oral squamous cell carcinoma (OSCC) has not been elucidated. The present study was designed to investigate the correlation between the expression of TAM markers and pathological features in OSCC by tissue microarray. Tissue microarrays containing 16 normal oral mucosa, 6 oral epithelial dysplasia, and 43 OSCC specimens were studied by immunohistochemistry. We observed that the protein expression of the TAM markers CD68 and CD163 as well as the cancer stem cell (CSC) markers ALDH1, CD44, and SOX2 increased successively from the normal oral mucosa to OSCC. The expressions of CD68 and CD163 were significantly associated with lymph node status, and SOX2 was significantly correlated with pathological grade and lymph node status, whereas ALDH1 was correlated with tumor stage. Furthermore, CD68 was significantly correlated with CD163, SOX2, and ALDH1 (P < 0.05). Kaplan-Meier analysis revealed that OSCC patients overexpressing CD163 had significantly worse overall survival (P < 0.05). TAM markers are associated with cancer stem cell marker and OSCC overall survival, suggesting their potential prognostic value in OSCC.
Assuntos
Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Carcinoma de Células Escamosas/terapia , Neoplasias Bucais/terapia , Receptores de Superfície Celular/biossíntese , Família Aldeído Desidrogenase 1 , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/biossíntese , Isoenzimas/biossíntese , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Células-Tronco Neoplásicas/patologia , Prognóstico , Retinal Desidrogenase/biossíntese , Fatores de Transcrição SOXB1/biossínteseRESUMO
Adenoid cystic carcinoma (ACC) is one of the most common malignancies of the major and minor salivary glands. However, the molecular mechanism underlying the aggressive growth of human salivary ACC remains unclear. In the present study, we showed that survivin, which belongs to the family of inhibitors of apoptosis, is closely related to the high expression of CDK4 and cyclin D1 in human ACC specimens. By employing the small-molecule drug YM155, we found that the inhibition of survivin in ACC cells caused significant cell death and induced autophagy. Chloroquine, an autophagy inhibitor, prevented cell death induced by YM155, suggesting YM155-induced autophagy contributed to the cell death effects in ACC cells. More importantly, evidence obtained from a xenograft model using ACC-2 cells proved the occurrence of YM155-induced autophagy and cell death in vivo was correlated with the suppression of Erk1/2 and S6 activation as well as increased TFEB nuclear translocation. Taken together, our results indicate YM155 is a novel inducer of autophagy-dependent cell death and possesses therapeutic potential in ACC.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Adenoide Cístico/patologia , Imidazóis/farmacologia , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Bucais/patologia , Naftoquinonas/farmacologia , Glândulas Salivares/metabolismo , Animais , Carcinoma Adenoide Cístico/tratamento farmacológico , Carcinoma Adenoide Cístico/metabolismo , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Transplante de Neoplasias , Fosforilação , Glândulas Salivares/patologia , Transdução de Sinais , SurvivinaRESUMO
Oxidative stress has been reported to play an important role in progression and prognostication in various kinds of cancers. However, the role and clinical significance of oxidative stress markers Keap1 and Nrf2 in oral squamous cell carcinoma (OSCC) has not been elucidated. This study aimed to investigate the correlation of oxidative stress markers Keap1 and Nrf2 expression and pathological features in OSCC by using tissue microarray. Tissue microarrays containing 17 normal oral mucosa, 7 oral epithelial dysplasia and 43 OSCC specimens were studied by immunohistochemistry. The association among these proteins and pathological features were analyzed. Expression of oxidative stress markers Keap1, Nrf2, and antioxidants PPIA, Prdx6, as well as CD147 was found to increase consecutively from normal oral mucosa to OSCC, and the Keap1, Nrf2, PPIA, Prdx6, CD147 expression in OSCC were significantly higher when compared to normal oral mucosa. Expression of Keap1, Nrf2 in tumors was not found to be significantly associated with T category, lymph node metastases, and pathological grade. Furthermore, we checked the relationship among these oxidative stress markers and found that Keap1 was significantly correlated with Nrf2, Prdx6 and CD147. Significant relationship between Nrf2 and Prdx6 was also detected. Finally, we found patients with overexpression of Keap1 and Nrf2 had not significantly worse overall survival by Kaplan-Meier analysis. These findings suggest that ROS markers are associated with carcinogenesis and progression of OSCC, which may have prognostic value and could be regarded as potential therapeutic targets in OSCC.