ABSTRACT
Pulmonary adenocarcinoma (PADC) treatment limited efficacy in preventing tumor progression, often resulting in malignant pleural effusion (MPE). MPE is filled with various mediators, especially interleukin-8 (IL-8). However, the role of IL-8 and its signaling mechanism within the fluid microenvironment (FME) implicated in tumor progression warrants further investigation. Primary cultured cells from samples of patients with MPE from PADC, along with a commonly utilized lung cancer cell line, were employed to examine the role of IL-8 and its receptor, CXCR1, through comparative analysis. Our study primarily assessed migration and invasion capabilities, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties. Additionally, IL-8 levels in MPE fluid versus serum, along with immunohistochemical expression of IL-8/CXCR1 signaling in tumor tissue and cell blocks were analyzed. IL-8/CXCR1 overexpression enhanced EMT and CSC properties. Furthermore, the immunocytochemical examination of 17 cell blocks from patients with PADC and MPE corroborated the significant correlation between upregulated IL-8 and CXCR1 expression and the co-expression of IL-8 and CXCR1 in MPE with distant metastasis. In summary, the IL-8/ CXCR1 axis in FME is pivotal to tumor promotion via paracrine and autocrine signaling. Our study provides a therapeutic avenue for improving the prognosis of PADC patients with MPE.
Subject(s)
Adenocarcinoma of Lung , Epithelial-Mesenchymal Transition , Interleukin-8 , Lung Neoplasms , Pleural Effusion, Malignant , Receptors, Interleukin-8A , Signal Transduction , Aged , Female , Humans , Male , Middle Aged , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/metabolism , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/complications , Cell Line, Tumor , Cell Movement , Disease Progression , Interleukin-8/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/genetics , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Pleural Effusion, Malignant/pathology , Pleural Effusion, Malignant/metabolism , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8A/genetics , Tumor MicroenvironmentABSTRACT
The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular mechanism, remain largely unknown. In the present study, we isolated patient-derived CAFs and normal fibroblasts (NFs). Using microarray analysis, we detected chemokine ligand 11 (CCL11) overexpression in CAFs compared to NFs. CCL11 administration promoted the migration and invasion of head and neck cancer (HNC) cells with enhanced cancer stem cell-like properties and induction of epithelial-to-mesenchymal transition. Furthermore, neutralization of CCL11 activity reversed the aggressive phenotype of CAF-induced cancer cells. Confocal microscopy showed colocalization of CCL11 and CC chemokine receptor 3 (CCR3) on HNC cells. Moreover, immunohistochemical analysis of clinical samples from 104 patients with HNC showed that expression of CCL11 and CCR3 were significantly correlated with poor overall survival (p = 0.003 and 0.044, respectively). Collectively, CCL11 expressed on CAFs promotes HNC invasiveness, and neutralization of CCL11 reverses this effect. We propose that the CCL11/CCR3 signaling circuit is a potential target for optimizing therapeutic strategies against HNC.
ABSTRACT
Despite recent advances, treatment for head and neck squamous cell carcinoma (HNSCC) has limited efficacy in preventing tumor progression. We confirmed previously that carcinoma-associated fibroblasts (CAF)-induced interleukin-33 (IL-33) contributed to cancer progression. However, the molecular mechanisms underlying the complex communication network of the tumor microenvironment merited further evaluation. To simulate the IL-33-induced autocrine signaling, stable clones of IL-33-overexpressing HNSCC cells were established. Besides well-established IL-33/ST2 and SDF1/CXCR4 (stromal-derived factor 1/C-X-C motif chemokine receptor 4) signaling, the CAF-induced IL-33 upregulated CXCR4 via cancer cell induction of IL-33 self-production. The IL-33-enhanced-CXCR4 regulatory circuit involves SDF1/CXCR4 signaling activation and modulates tumor behavior. An in vivo study confirmed the functional role of IL-33/CXCR4 in tumor initiation and metastasis. The CXCR4 and/or IL-33 blockade reduced HNSCC cell aggressiveness, with attenuated invasions and metastases. Immunohistochemistry confirmed that IL-33 and CXCR4 expression correlated significantly with disease-free survival and IL-33-CXCR4 co-expression predicted a poor outcome. Besides paracrine signaling, the CAF-induced IL-33 reciprocally enhanced the autocrine cancer-cell self-production of IL-33 and the corresponding CXCR4 upregulation, leading to the activation of SDF1/CXCR4 signaling subsequent to cancer progression. Thus, targeting the IL-33-enhanced-CXCR4 regulatory circuit attenuates tumor aggressiveness and provides a potential therapeutic option for improving the prognosis in HNSCC patients.
ABSTRACT
Long-term nicotine-derived nitrosamine ketone (NNK) and arecoline exposure promotes carcinogenesis and head and neck squamous cell carcinoma (HNSCC) progression, although most associated data on the two were analyzed individually. The molecular mechanisms underlying tumor progression associated with the synergistic effects of NNK and arecoline remain unclear. We treated SCC-25 and FaDu cells with NNK and arecoline (separately or in combination) for 3 months. Comparative analysis was performed to investigate the mechanism underlying the acquisition of properties related to tumor promotion, including stemness, anti-apoptosis, and resistance to HNSCC therapeutics. Long-term exposure to NNK and arecoline resulted in an increase in cancer stem cell properties, anti-apoptosis, and the resistance to cisplatin in HNSCC. We detected abundant epidermal growth factor receptor (EGFR) expression in HNSCC cells after combined treatment with NNK and arecoline. EGFR was pivotal in inducing tumor promotion and anti-apoptosis in cancer cells by inducing pAKT and NFκB. Combined treatment with NNK and arecoline synergistically facilitated tumor aggressiveness via EGFR-AKT signaling. Targeting EGFR-AKT signaling may be a feasible strategy for treating HNSCC.
Subject(s)
Arecoline/pharmacology , Carcinoma, Squamous Cell/metabolism , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Head and Neck Neoplasms/metabolism , Nicotine/chemistry , Nitrosamines/pharmacology , Signal Transduction/drug effects , Arecoline/agonists , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , ErbB Receptors/biosynthesis , Head and Neck Neoplasms/pathology , Humans , Nitrosamines/agonists , Nitrosamines/chemistry , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
RATIONALE: Orbital apex syndrome is a complex clinical disorder featuring a collection of cranial nerve deficits characterized by impairment of the extraocular muscles, the ophthalmic branch of the trigeminal nerve, and even the optic nerve. Sino-orbital aspergillosis is rare but aggressive infection. Surgical resection accompanied by antifungal medication is advised currently. PATIENT CONCERNS: We report a 61-year-old woman diagnosed as aspergilloma presenting with the characteristic manifestations and imaging features of orbital apex syndrome. DIAGNOSES: Paranasal sinus tumor was misdiagnosed initially according to magnetic resonance imaging of the orbit. Finally aspergilloma was diagnosed by pathologic report. INTERVENTIONS: The anti-fungal medication, voriconazole, was administered immediately. Surgical excision was also done due to the poor response to medical treatment. OUTCOMES: Postoperative follow-up showed no recurrence of aspergillosis but the vision was lost permanently. LESSONS: Invasive sino-orbital aspergillosis as an aggressive disease with highly invasive patterns and it may be misdiagnosed as tumors. To achieve better prognosis and survival, clinicians should be aware of this distinct manifestation.
Subject(s)
Aspergillosis/diagnosis , Cranial Nerve Diseases/microbiology , Eye Infections, Fungal/diagnosis , Orbital Diseases/microbiology , Paranasal Sinus Neoplasms/diagnosis , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Aspergillosis/surgery , Cranial Nerve Diseases/diagnosis , Diagnostic Errors , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/surgery , Female , Humans , Magnetic Resonance Imaging , Middle Aged , Ophthalmoplegia/microbiology , Orbital Diseases/diagnosis , Paranasal Sinus Neoplasms/diagnostic imaging , Syndrome , Treatment Outcome , Vision Disorders/microbiology , Voriconazole/therapeutic useABSTRACT
Patients with atypical meningiomas have a higher recurrence rate and poorer prognosis than patients with benign meningeal tumors. However, differentiating atypical from benign meningiomas based on fragmented specimens from brain tumor biopsy is complicated. We tested the association of DDX3X cytoplasmic expression and World Health Organization grading system in various subtypes of meningiomas. In our study, DDX3X expression was evaluated immunohistochemically in 10 non-neoplastic brain tissues and 71 meningiomas. The immunostaining scores were calculated as the product of cytoplasmic DDX3X intensity and the percentage of positively stained cells. Our results revealed most of the non-neoplastic brain tissues were immunonegative for DDX3X. The average DDX3X immunostaining score was significantly higher in meningiomas than non-neoplastic brain tissues and significantly higher in atypical meningiomas than in various subtypes of benign meningiomas. In conclusion, DDX3X immunohistochemistry combined with hematoxylin and eosin staining may help differentiate atypical meningiomas from benign meningeal tumors.
Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/diagnosis , DEAD-box RNA Helicases/metabolism , Meningioma/diagnosis , Brain Neoplasms/mortality , Diagnosis, Differential , Follow-Up Studies , Humans , Immunohistochemistry , Meningioma/mortality , Neoplasm Recurrence, Local , Prognosis , Survival Analysis , Tissue Array AnalysisABSTRACT
PURPOSE: To present a case of salivary gland malignancy initially mimicking Bell's palsy. CASE REPORT: A 75-year-old woman with hypertension visited our neurological outpatient department,complaining of persistent right facial paralysis for more than a year after oral glucocorticoid therapy with recent development of vertigo and unsteady gait. She was previously diagnosed as having Bell's palsy and was prescribed oral glucocorticoid. However, her right facial muscles were still completely paralyzed, with no signs of improvement. The patient visited the outpatient department of neurology for 3 weeks, seeking treatment for the recent onset of vertigo and ataxia. Brain contrast magnetic resonance imaging (MRI) revealed the right mastoid air cells to be filled with high T2 signal intensity and low T1 signal, with destruction of the bony structure of mastoid, extending to the right jugular bulb. Results obtained from excisional biopsy and pathological analyses were used to diagnose the patient with adenoid cystic carcinoma of the salivary gland. The patient then received a thorough cancer workup and chemoradiotherapy, with the malignancy being under control. However, after a 1-year follow-up, the patient still had permanent right facial palsy. CONCLUSION: Salivary gland malignancy should be considered in patients with acute and subacute facial nerve paralysis, in addition to Bell's palsy. Brain imaging with contrast agents should be performed for differential diagnosis.
Subject(s)
Facial Paralysis/etiology , Salivary Gland Neoplasms/complications , Aged , Female , Humans , Magnetic Resonance Imaging , Salivary Gland Neoplasms/diagnostic imaging , Salivary Gland Neoplasms/pathologyABSTRACT
The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.
Subject(s)
Breast Neoplasms/enzymology , MicroRNAs/metabolism , Nucleotidyltransferases/metabolism , Tumor Escape , Adaptive Immunity , Animals , Breast Neoplasms/genetics , Breast Neoplasms/immunology , Breast Neoplasms/pathology , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Disease Progression , Epigenesis, Genetic , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Mice , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/genetics , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Nuclear Receptor Coactivator 3/genetics , Nuclear Receptor Coactivator 3/metabolism , Nucleotidyltransferases/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , RNA Interference , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , Signal Transduction , Time Factors , Transfection , Tumor Hypoxia , Tumor MicroenvironmentABSTRACT
PURPOSE: Diabetes mellitus (DM) is a global pandemic metabolic disorder. In recent years, the amount of medical resources required for the treatment of diabetes has increased as diabetes rates have gradually risen. The combined effects of individual and neighbourhood socio-economic status (SES) on DM survival rates are still not clear, especially in patients of working age. In this paper, we aim to analyze the combined effects of neighbourhood and individual SES on DM survival rates in patients of working age in Taiwan. METHODS: The study of 23,781 people who were diagnosed with DM by using population-based study between 2002 and 2006. Each sample was followed up for 4 years or as a sensor case. We defined Individual SES and neighbourhood SES by each patient's job category and household income which characterized as advantaged or disadvantaged. Then we compared the survival rates by SES group used Cox proportional hazards model for adjust risk factors. RESULTS: The 4-year overall survival rates of diabetic patients were worst for those with low individual SES who living in advantaged neighbourhoods. After adjustment for patient characteristics, DM patients with high individual SES living in disadvantaged neighbourhoods had the same risk of mortality as those patients with high individual SES living in advantaged neighbourhoods (hazard ratio: 1.11; 95% confidence interval [CI]: 0.81-1.51). The study found that DM patients with low individual SES who live in disadvantaged areas had a greater risk of mortality than those with high SES (odds ratio: 2.57; 95% CI: 2.04-3.24). There were significant differences in survival rates between patients with high individual SES and patients with low individual SES. In contrast, the results did not statistically significant differences in survival rates between advantaged and disadvantaged neighbourhood SES groups. CONCLUSION: DM patients with low individual SES had the worst survival rate, regardless of whether they were living in a high or low SES neighbourhood area. The competitive cause of death, i.e., the fact that complications, rather than DM itself, are often the cause of death, may be the reason for the inverse relationship found between the effects of individual SES and neighbourhood SES on DM survival. We conclude that the socio-economic gradient in survival among DM patients may be the result of differences in access to medical treatment and attributes related to individual SES.
Subject(s)
Diabetes Mellitus/mortality , Age Factors , Aged , Diabetes Mellitus/therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Proportional Hazards Models , Socioeconomic Factors , Survival Rate , Taiwan/epidemiologyABSTRACT
AIMS: Although ARID4B is known to promote tumour metastasis in breast cancer and inhibit transformation and progression in leukaemia, the possible effect of ARID4B on primary brain tumours (PBTs) is not well characterised. We tested the hypothesis that expression of ARID4B correlates with WHO grade and survival in patients with PBTs. METHODS: Western blot analysis was performed on protein lysates prepared from normal brain tissue and glioma cell lines (U87MG, LN229, GBM8401 and U118MG). Subsequently, immunohistochemical analysis of ARID4B was performed on 2 tissue microarrays, including 12 normal brain tissues, 63 meningiomas with different subtypes, 232 gliomas of various grades and degrees of differentiation, 8 central neurocytomas and 4 chordomas. The ARID4B immunostaining score was calculated by multiplying the intensity score by the percentage of tumour cells expressing ARID4B. RESULTS: In vitro, ARID4B protein expression was increased in some glioma cell lines. In addition, the average ARID4B immunostaining score was 38.03, 79.09, 129.76 and 119.32, respectively, in gliomas of WHO grade I, II, III and IV. Higher ARID4B immunostaining score was significantly correlated with more advanced WHO grade of gliomas (p=7.4×10-6) and meningiomas. Finally, higher ARID4B expression tended to the shorter survival rates, but did not reach statistical significance. CONCLUSIONS: ARID4B overexpression presented in most of PBTs, rather than non-neoplastic brain tissue, and correlated with WHO grades in meningiomas and gliomas. Therefore, ARID4B is a satisfactory biomarker to highlight tumour component and predict tumour behaviour in primary brain neoplasms.
Subject(s)
Antigens, Neoplasm/metabolism , Biomarkers, Tumor/metabolism , Brain Neoplasms/pathology , Glioma/pathology , Meningeal Neoplasms/pathology , Meningioma/pathology , Neoplasm Proteins/metabolism , Brain Neoplasms/metabolism , Brain Neoplasms/mortality , Cell Line, Tumor , Glioma/metabolism , Glioma/mortality , Humans , Meningeal Neoplasms/metabolism , Meningeal Neoplasms/mortality , Meningioma/metabolism , Meningioma/mortality , Neoplasm Grading , Survival Rate , Tissue Array AnalysisABSTRACT
Tn antigen (GalNAc-α-O-Ser/Thr), a mucin-type O-linked glycan, is a well-established cell surface marker for tumors and its elevated levels have been correlated with cancer progression and prognosis. There are also reports that Tn is elevated in inflammatory tissues. However, the molecular mechanism for its elevated levels in cancer and inflammation is unclear. In the current studies, we have explored the possibility that cytokines may be one of the common regulatory molecules for elevated Tn levels in both cancer and inflammation. We showed that the Tn level is elevated by the conditioned media of HrasG12V-transformed-BEAS-2B cells. Similarly, the conditioned media obtained from LPS-stimulated monocytes also elevated Tn levels in primary human gingival fibroblasts, suggesting the involvement of cytokines and/or other soluble factors. Indeed, purified inflammatory cytokines such as TNF-α and IL-6 up-regulated Tn levels in gingival fibroblasts. Furthermore, TNF-α was shown to down-regulate the COSMC gene as evidenced by reduced levels of the COSMC mRNA and protein, as well as hypermethylation of the CpG islands of the COSMC gene promoter. Since Cosmc, a chaperone for T-synthase, is known to negatively regulate Tn levels, our results suggest elevated Tn levels in cancer and inflammation may be commonly regulated by the cytokine-Cosmc signaling axis.
Subject(s)
Antigens, Tumor-Associated, Carbohydrate/metabolism , Gene Expression Regulation, Neoplastic , Interleukin-6/metabolism , Molecular Chaperones/metabolism , Tumor Necrosis Factor-alpha/metabolism , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , Bronchi/metabolism , Cell Line , CpG Islands , Culture Media, Conditioned , DNA Methylation , Disease Progression , Female , Fibroblasts/metabolism , Genes, ras , Gingiva/cytology , Humans , Inflammation , Male , Prognosis , Promoter Regions, Genetic , Prostatic Neoplasms/immunology , Prostatic Neoplasms/metabolism , Signal Transduction , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/metabolismABSTRACT
A tobacco-specific component, 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK), is a major risk factor for many cancers. Recent reports have demonstrated that NNK exposure may be associated with tumor progression and chemoresistance in certain cancers. However, the underlying NNK-induced mechanism contributing to the aggressiveness of colorectal cancer (CRC) has not been thoroughly studied. In this study, we used HT29 cells treated with NNK to simulate the long-term exposure of cigarette smoke. A comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as epithelial-mesenchymal transition (EMT) markers and drug-resistance genes expression, cancer stem cell (CSC) properties, and anti-apoptotic activity. Signaling pathways related to chemoresistance were also investigated. As a result, NNK exposure dose-dependently stimulates cell proliferation, enhance abilities of migration and invasion, induce EMT phenomenon, and attenuate apoptosis. Furthermore, NNK exposure also promotes the capabilities of sphere formation, upregulation of Snail, and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of Raf kinase inhibitor protein (RKIP), increased apoptosis, reversal of EMT phenomenon, and reducation of expression of CSC markers, all of which contribute to a decrease of chemoresistance. Our study demonstrates a number of related mechanisms that mediate the effect of NNK exposure on increasing CRC therapeutic resistance via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of CRC.
Subject(s)
Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm , Nitrosamines/pharmacology , Organoplatinum Compounds/pharmacology , Phosphatidylethanolamine Binding Protein/antagonists & inhibitors , Snail Family Transcription Factors/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor/metabolism , Carcinogens/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Epithelial-Mesenchymal Transition/drug effects , Humans , Oxaliplatin , Signal Transduction , Tumor Cells, CulturedABSTRACT
UNLABELLED: Treatment failure followed by relapse and metastasis in patients with non-small cell lung cancer is often the result of acquired resistance to cisplatin-based chemotherapy. A cancer stem cell (CSC)-mediated anti-apoptotic phenomenon is responsible for the development of drug resistance. The underlying molecular mechanism related to cisplatin resistance is still controversial, and a new strategy is needed to counteract cisplatin resistance. We used a nonadhesive culture system to generate drug-resistant spheres (DRSPs) derived from cisplatin-resistant H23 lung cancer cells. The expressions of drug-resistance genes, properties of CSCs, and markers of anti-apoptotic proteins were compared between control cells and DRSPs. DRSPs exhibited upregulation of cisplatin resistance-related genes. Gradual morphological alterations showing epithelial-to-mesenchymal transition phenomenon and increased invasion and migration abilities were seen during induction of DRSPs. Compared with control cells, DRSPs displayed increased CSC and anti-apoptotic properties, greater resistance to cisplatin, and overexpression of p-Hsp27 via activation of p38 MAPK signaling. Knockdown of Hsp27 or p38 decreased cisplatin resistance and increased apoptosis in DRSPs. Clinical studies confirmed that the expression of p-Hsp27 was closely associated with prognosis. Overexpression of p-Hsp27 was usually detected in advanced-stage patients with lung cancer and indicated short survival. SUMMARY: DRSPs were useful for investigating drug resistance and may provide a practical model for studying the crucial role of p-Hsp27 in the p38 MAPK-Hsp27 axis in CSC-mediated cisplatin resistance. Targeting this axis using siRNA Hsp27 may provide a treatment strategy to improve prognosis and prolong survival in lung cancer patients.
Subject(s)
Adenocarcinoma/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/pharmacology , Drug Resistance, Neoplasm , HSP27 Heat-Shock Proteins/metabolism , Lung Neoplasms/pathology , p38 Mitogen-Activated Protein Kinases/metabolism , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic/drug effects , HSP27 Heat-Shock Proteins/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Male , Middle Aged , Prognosis , Survival Rate , Tumor Cells, Cultured , p38 Mitogen-Activated Protein Kinases/geneticsABSTRACT
Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor-initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFα expression and activation of its downstream p38-MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFα-p38-MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET-TNFα-p38-MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy.
Subject(s)
Breast Neoplasms/genetics , Cell Hypoxia/physiology , DNA Methylation , DNA-Binding Proteins/physiology , Dioxygenases/physiology , Neoplasm Proteins/physiology , Proto-Oncogene Proteins/physiology , Tumor Necrosis Factor-alpha/physiology , p38 Mitogen-Activated Protein Kinases/physiology , 5-Methylcytosine/analogs & derivatives , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Hypoxia/genetics , Cell Line, Tumor , Chromatin Immunoprecipitation , Cytosine/analogs & derivatives , Cytosine/biosynthesis , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Dioxygenases/biosynthesis , Dioxygenases/genetics , Female , Gene Expression Regulation, Neoplastic , Heterografts , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Mice , Mice, Nude , Mixed Function Oxygenases , Molecular Sequence Data , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplastic Stem Cells/cytology , Neoplastic Stem Cells/enzymology , Prognosis , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/genetics , Recombinant Fusion Proteins/biosynthesis , Retrospective Studies , Signal Transduction/physiology , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Massive localized lymphedema (MLL) is an uncommon benign skin lesion typically presenting with prominent edema and vascular proliferation in the adipose tissue of lower limbs. When rarely occurring in scrotum, it instead is characterized by a striking proliferation of dermal smooth muscle bundles mimicking acquired smooth muscle hamartoma of dartos. The authors report a rare case of scrotal MLL. A 57-year-old obese man with a history of previous surgery for rectal adenocarcinoma, 20 years earlier, presented with progressive nodular enlargement of the scrotum for 2 years, causing discomfort, difficulty in ambulation, and cosmetic problems. The preoperative radiographic investigation revealed thickening of the scrotal wall with multiple soft-tissue nodules. The patient underwent a wide excision of the scrotal wall, perineum, and penile skin. The pathological examination showed a scrotal MLL associated with well-differentiated squamous cell carcinoma. The authors speculate that prior radiotherapy and surgery together with morbid obesity led to long-standing lymphedema that triggered the proliferation of smooth muscle cells, chronic epidermal change, and finally squamous cell carcinoma.
Subject(s)
Carcinoma, Squamous Cell/pathology , Genital Neoplasms, Male/pathology , Hamartoma/pathology , Lymphedema/pathology , Scrotum , Skin Neoplasms/pathology , Carcinoma, Squamous Cell/complications , Diagnosis, Differential , Genital Neoplasms, Male/complications , Humans , Lymphedema/complications , Magnetic Resonance Imaging , Male , Middle Aged , Muscle, Smooth/pathology , Skin Neoplasms/complicationsABSTRACT
BACKGROUND: Recent studies suggest that long-term exposure of the carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) found in tobacco smoke is involved in the progression of head and neck squamous cell carcinoma (HNSCC). The underlying nicotine-mediated mechanism remains unclear. METHODS: An analysis of SCC-25 and Fadu cells with or without NNK exposure focusing on the evaluation of migration and invasion abilities, the expression of epithelial-mesenchymal transition, drug-resistance-related genes, properties of cancer stem cells (CSCs), and anti-apoptosis was performed. RESULTS: Long-term NNK exposure enhances migration and invasion with morphological alterations in a dose-dependently manner. Furthermore, NNK exposure also upregulates Snail, promotes sphere-forming ability, and overexpresses aldehyde dehydrogenase 1 (ALDH1), Nanog, OCT4, ABCG2, and MDR1. CONCLUSION: The current study confirmed that long-term NNK exposure plays a role in HNSCC by increasing anti-apoptosis and therapeutic resistance via the Snail-RKIP signaling pathway. Our data also suggest that α7 nicotinic acetylcholine receptor (α7-nAChR) inhibition or targeting Snail may provide a feasible rationale for preventing the progression of HNSCC.
Subject(s)
Carcinogens/pharmacology , Carcinoma, Squamous Cell/pathology , Head and Neck Neoplasms/pathology , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Nitrosamines/pharmacology , Transcription Factors , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Aldehyde Dehydrogenase 1 Family , Apoptosis/drug effects , Carcinoma, Squamous Cell/metabolism , Cell Culture Techniques/methods , Cell Line, Tumor , Cell Movement/drug effects , Disease Progression , Drug Resistance, Neoplasm/genetics , Epithelial-Mesenchymal Transition/drug effects , Head and Neck Neoplasms/metabolism , Humans , Hypopharyngeal Neoplasms/pathology , Isoenzymes/drug effects , Isoenzymes/metabolism , Mouth Neoplasms/pathology , Neoplasm Invasiveness/genetics , Neoplasm Staging , Neoplastic Stem Cells/drug effects , Retinal Dehydrogenase/drug effects , Retinal Dehydrogenase/metabolism , Signal Transduction/drug effects , Snail Family Transcription Factors , Tongue Neoplasms/pathology , Transcription Factors/drug effects , Transcription Factors/metabolism , Up-Regulation , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitorsABSTRACT
Low HDL-C levels are associated with atherosclerosis and non-alcoholic steatohepatitis, and increased levels may reduce the risk of these diseases. Inhibition of cholesteryl ester transfer protein (CETP) activity is considered a promising strategy for increasing HDL-C levels. Since CETP is a self-antigen with low immunogenicity, we developed a novel CETP vaccine (Fc-CETP6) to overcome the low immunogenicity of CETP and for long-term inhibition of CETP activity. The vaccine consists of a rabbit IgG Fc domain for antigen delivery to antigen-presenting cells fused to a linear array of 6 repeats of a CETP epitope to efficiently activate B cells. Rabbits were fed a high fat/cholesterol (HFC) diet to induce atherosclerosis and NASH, and immunized with Fc-CETP6 vaccine. The Fc-CETP6 vaccine successfully elicited anti-CETP antibodies and lowered plasma CETP activity. The levels of plasma HDL-C and ApoA-I were higher, and plasma ox-LDL lower, in the Fc-CETP6-immunized rabbits as compared to the unimmunized HFC diet-fed rabbits. Pathological analyses revealed less lipid accumulation and inflammation in the aorta and liver of the Fc-CETP6-immunized rabbits. These results show that the Fc-CETP6 vaccine efficiently elicited antibodies against CETP and reduced susceptibility to both atherosclerosis and steatohepatitis induced by the HFC diet. Our findings suggest that the Fc-CETP6 vaccine may improve atherosclerosis and NASH and has high potential for clinical use.
Subject(s)
Atherosclerosis/etiology , Atherosclerosis/prevention & control , Cholesterol Ester Transfer Proteins/immunology , Diet, High-Fat/adverse effects , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/prevention & control , Vaccines/immunology , Animals , Antibodies/blood , Antibodies/immunology , Apolipoprotein A-I/metabolism , Atherosclerosis/pathology , Cholesterol/blood , Cholesterol/metabolism , Cholesterol Ester Transfer Proteins/genetics , Cholesterol Ester Transfer Proteins/metabolism , Disease Models, Animal , Female , Fibrosis , Gene Expression , Humans , Immunoglobulin Fc Fragments/genetics , Immunoglobulin Fc Fragments/immunology , Lipoproteins, LDL/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Rabbits , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Vaccines/geneticsABSTRACT
Stem cell markers are upregulated in various cancers and have potential as prognostic indicators. The objective of this study was to determine the expression of three stem cell markers, aldehyde dehydrogenase 1 (ALDH-1), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), and Nanog, in esophageal squamous cell carcinoma (ESCC) tissues. Immunohistochemistry was used to measure the expression of ALDH-1, Bmi-1, and Nanog in ESCC tissues from 41 patients who received pre-operative chemoradiation. We evaluated the relationship between expression of these markers, and clinicopathological features, tumor regression grade (TRG), and 5-year overall survival (OS). There were no significant associations of ALDH-1 or Bmi-1 expression with age, gender, clinical stage, and treatments (p>0.05). However, patients with Nanog-positive tumors were significantly older than those whose tumors were Nanog-negative (pâ=â0.033). TRG after treatment was significantly associated with expression of ALDH-1 (pâ=â0.001), Bmi-1 (pâ=â0.004), and Nanog (p<0.001). Although OS was significantly better in patients with low TRGs (pâ=â0.001), there were no significant correlations between ALDH-1, Bmi-1, or Nanog with OS. Expression of ALDH-1, Bmi-1, and Nanog correlated with TRG, but not OS. Further large studies are necessary to fully elucidate the prognostic value of these stem cell markers for ESCC patients.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell , Esophageal Neoplasms , Homeodomain Proteins/metabolism , Isoenzymes/metabolism , Neoplasm Proteins/metabolism , Neoplastic Stem Cells , Polycomb Repressive Complex 1/metabolism , Retinal Dehydrogenase/metabolism , Adult , Aged , Aldehyde Dehydrogenase 1 Family , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Disease-Free Survival , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Nanog Homeobox Protein , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Retrospective Studies , Survival RateABSTRACT
Endometrial stromal tumors (ESTs) with limited infiltration were first proposed by Dionigi et al.(1) However, the prognostic significance of these tumors is unclear. We report a case of a 60-year-old woman who presented with a prolapsed uterine corpus and then underwent laparoscopic-assisted vaginal hysterectomy. A very small EST was incidentally found. The tumor manifested focal irregularity and finger-like permeation into the adjacent myometrium not exceeding 3 mm but exceeding 3 in number, features intermediate between a low-grade endometrial stromal sarcoma and an endometrial stromal nodule. By definition, we rendered a descriptive diagnosis of "endometrial stromal tumor with limited infiltration." A subsequent staging operation confirmed metastasis and, hence, a malignant potential.
Subject(s)
Endometrial Neoplasms/pathology , Endometrial Stromal Tumors/pathology , Female , Humans , Middle AgedABSTRACT
AIMS: In order to determine whether the expression of tumour-associated carbohydrate antigens (Tn/sTn) and a representative inflammation marker, nuclear factor-κB (NF-κB), is associated with the invasiveness of oral squamous cell carcinoma (OSCC), this study has attempted to investigate the correlation of the aforementioned markers with the well-established invasive pattern grading score (IPGS) and clinicopathological parameters. METHODS AND RESULTS: Specimens from 143 OSCC patients with classified clinicopathological parameters and IPGS were stained immunohistochemically using anti-Tn, sTn and NF-κB antibodies. Our results showed that the expression of both Tn and NF-κB was correlated positively with staging (P = 0.036; P = 0.015), recurrence (P < 0.001; P < 0.001) and distant metastasis (P = 0.005; P = 0.009), as well as with IPGS, while the expression of sTn was correlated inversely. In addition, poor survival was associated with overexpression of Tn and NF-κB but not with expression of sTn. CONCLUSIONS: Our results indicate that a reciprocal relationship between Tn and sTn expression may serve as a reliable indicator for OSCC prognostic evaluation. In addition, expression of Tn rather than sTn may play an important role in deeply invasive OSCC via regulation of NF-κB signalling.