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1.
bioRxiv ; 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39149249

RESUMO

We employed laser microdissection to selectively harvest tumor cells and stroma from the microenvironment of formalin-fixed, paraffin-embedded head and neck squamous cell carcinoma (HNSCC) tissues. The captured HNSCC tissue fractions were analyzed by quantitative mass spectrometry-based proteomics using a data independent analysis approach. In paired samples, we achieved excellent proteome coverage having quantified 6,668 proteins with a median quantitative coefficient of variation under 10%. We observed significant differences in relevant functional pathways between the spatially resolved tumor and stroma regions. Our results identified extracellular matrix (ECM) as a major component enriched in the stroma, including many cancer associated fibroblast signature proteins in this compartment. We demonstrate the potential for comparative deep proteome analysis from very low starting input in a scalable format that is useful to decipher the alterations in tumor and the stromal microenvironment. Correlating such results with clinical features or disease progression will likely enable identification of novel targets for disease classification and interventions.

2.
Cancers (Basel) ; 15(17)2023 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-37686516

RESUMO

Estimation of cancer risk among astronauts planning to undertake future deep-space missions requires understanding the quantitative and qualitative differences in radiogenic cancers after low- and high-LET radiation exposures. Previously, we reported a multifold higher RBE for high-LET radiation-induced gastrointestinal (GI) tumorigenesis in Apc1638N/+ mice. Using the same model system, i.e., Apc1638N/+ mice, here, we report qualitative differences in the cellular phenotype of low- and high-LET radiation-induced GI tumors. Stem cell (SC) phenotypes were identified using BMI1, ALDH1, CD133, DCLK1, MSI1, and LGR5 markers in low (γ-rays)- and high (56Fe)-LET radiation-induced and spontaneous tumors. We also assessed the expression of these markers in the adjacent normal mucosa. All six of these putative SC markers were shown to be overexpressed in tumors compared to the adjacent normal intestinal tissue. A differential SC phenotype for spontaneous and radiogenic intestinal tumors in Apc1638N/+ mice was observed, where the ALDH1, BMI1, CD133, MSI1, and DCLK1 expressing cells were increased, while LGR5 expressing cells were decreased in 56Fe-induced tumors compared to γ-ray-induced and spontaneous tumors. Furthermore, higher ß-catenin activation (marked by nuclear localization) was observed in 56Fe-induced tumors compared to γ and spontaneous tumors. Since differential tumor cell phenotype along with activated ß-catenin may very well affect malignant progression, our findings are relevant to understanding the higher carcinogenic risk of high-LET radiation. This study has implications for the assessment of GI-cancer risk among astronauts, as well as for the estimation of secondary cancer risk among patients receiving hadron therapy, considering that our results indicate increased stemness properties after radiation.

3.
Lung Cancer ; 184: 107324, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37573703

RESUMO

BACKGROUND: Trophoblastic antigen 2 (Trop2) is a cell surface glycoprotein expressed in multiple types of cancers, including breast cancer, non-small cell lung cancer, and gastrointestinal cancers. Trop2 expression and the use of Trop2-directed therapy such as antibody-drug conjugate (ADC) have not yet been investigated in thymic epithelial tumors (TETs). METHODS: Patients with TETs treated at MedStar Georgetown University Hospital were retrospectively identified. Of the patients for whom tumor samples and normal thymus tissue were available, immunohistochemistry (IHC) membranous staining for Trop2 and PD-L1 were performed. Positivity for Trop2 required at least 10% of the tumor cells to be stained, with an intensity scored of 1+ (weak), 2+ (moderate), and 3+ (strong). Cases with CPS ≥ 5% were considered positive for PD-L1. RESULTS: 30 TET samples from 29 patients (17 patients with thymoma and 12 patients with thymic carcinoma) were identified. One patient with thymic carcinoma had two samples from different time points. From the same set of patients, 13 samples of normal thymus tissue were available. In normal thymus tissue, eight samples (62%) showed no positivity of Trop2, while five samples (38%) showed 1 + IHC staining. In the thymoma samples, four (24%) showed 0 or 1 + IHC staining, while 13 (76%) showed 2 + or 3 + staining. Of the 13 thymic carcinoma samples, three samples (23%) showed 1 + IHC staining while seven (54%) showed 2 + staining and three (23%) showed 3 + staining. There was no statistically significant correlation found between PD-L1 expression and Trop-2 expression in thymoma or thymic carcinoma. CONCLUSIONS: Trop2 is readily expressed in TETS with a higher degree of expression in thymic carcinoma. The expression of Trop-2 was lower in normal thymic tissue compared with TETs. The increased expression of Trop-2 in TETs suggests that Trop2 is an attractive therapeutic target for Trop-2 directed therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias Epiteliais e Glandulares , Timoma , Neoplasias do Timo , Humanos , Timoma/patologia , Antígeno B7-H1/metabolismo , Estudos Retrospectivos , Neoplasias do Timo/patologia
4.
PLoS One ; 17(12): e0279771, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36584137

RESUMO

Space radiation-induced gastrointestinal (GI) cancer risk models for future interplanetary astronauts are being developed that primarily rely on quantitative animal model studies to assess radiation-quality effects of heavy-ion space radiation exposure in relation to γ-rays. While current GI-cancer risk estimation efforts are focused on sporadic GI-cancer mouse models, emerging in-vivo data on heavy-ion radiation-induced long-term GI-inflammation are indicative of a higher but undetermined risk of GI-inflammation associated cancers, such as colitis-associated cancer (CAC). Therefore, we aimed to assess radiation quality effects on colonic inflammation, colon cancer incidence, and associated signaling events using an in-vivo CAC model i.e., Il10-/- mice. Male Il10-/- mice (8-10 weeks, n = 12/group) were irradiated with either sham, γ-rays or heavy-ions (28Si or 56Fe), and histopathological assessments for colitis and CAC were conducted at 2.5 months post-exposure. qPCR analysis for inflammation associated gene transcripts (Ptges and Tgfb1), and in-situ staining for markers of cell-proliferation (phospho-histone H3), oncogenesis (active-ß-catenin, and cyclin D1), and inflammation (phospho-p65NF-κB, iNOS, and COX2) were performed. Significantly higher colitis and CAC frequency were noted after heavy-ion exposure, relative to γ and control mice. Higher CAC incidence after heavy-ion exposure was associated with greater activation of ß-catenin and NF-κB signaling marked by induced expression of common downstream inflammatory (iNOS and COX2) and pro-proliferative (Cyclin D1) targets. In summary, IR-induced colitis and CAC incidence in Il10-/- mice depends on radiation quality and display co-activation of ß-catenin and NF-κB signaling.


Assuntos
Colite , Neoplasias do Colo , Gastrite , Neoplasias Induzidas por Radiação , Camundongos , Masculino , Animais , NF-kappa B/metabolismo , Ciclina D1/genética , beta Catenina/genética , beta Catenina/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Colite/induzido quimicamente , Carcinogênese , Neoplasias do Colo/patologia , Inflamação/complicações , Neoplasias Induzidas por Radiação/genética , Gastrite/complicações , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
5.
Radiat Environ Biophys ; 61(4): 631-637, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36167896

RESUMO

Gastrointestinal (GI) cancer risk among astronauts after encountering galactic cosmic radiation (GCR) is predicted to exceed safe permissible limits in long duration deep-space missions. Current predictions are based on relative biological effectiveness (RBE) values derived from in-vivo studies using single-ion beams, while GCR is essentially a mixed radiation field composed of protons (H), helium (He), and heavy ions. Therefore, a sequentially delivered proton (H) → Helium (He) → Oxygen (O) → Silicon (Si) beam was designed to simulate simplified-mixed-field GCR (Smf-GCR), and Apc1638N/+ mice were total-body irradiated to sham or γ (157Cs) or Smf-GCR followed by assessment of GI-tumorigenesis at 150 days post-exposure. Further, GI-tumor data from equivalent doses of heavy-ions (i.e., 0.05 Gy of O and Si) in 0.5 Gy of Smf-GCR were compared to understand the contributions of heavy-ions in GI-tumorigenesis. The Smf-GCR-induced tumor and carcinoma count were significantly greater than γ-rays, and male preponderance for GI-tumorigenesis was consistent with our earlier findings. Comparison of tumor data from Smf-GCR and equivalent doses of heavy ions revealed an association between higher GI-tumorigenesis where dose received from heavy-ions contributed to > 95% of the total GI-tumorigenic effect observed after Smf-GCR. This study provides the first experimental evidence that cancer risk after GCR exposure could largely depend on doses received from constituent heavy-ions.


Assuntos
Radiação Cósmica , Íons Pesados , Neoplasias Induzidas por Radiação , Exposição à Radiação , Voo Espacial , Camundongos , Masculino , Animais , Íons Pesados/efeitos adversos , Hélio , Radiação Cósmica/efeitos adversos , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/patologia , Carcinogênese , Prótons
6.
Sci Rep ; 12(1): 6159, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459280

RESUMO

Biology and transcriptomes of non-cancerous human mammary epithelial cells at risk for breast cancer development were explored following primary isolation utilizing conditional reprogramming cell technology from mastectomy tissue ipsilateral to invasive breast cancer. Cultures demonstrated consistent categorizable behaviors. Relative viability and mammosphere formation differed between samples but were stable across three different mammary-specific media. E2F cell cycle target genes expression levels were positively correlated with viability and advancing age was inversely associated. Estrogen growth response was associated with Tissue necrosis factor signaling and Interferon alpha response gene enrichment. Neoadjuvant chemotherapy exposure significantly altered transcriptomes, shifting them towards expression of genes linked to mammary stem cell formation. Breast cancer prognostic signature sets include genes that in normal development are limited to specific stages of pregnancy or the menstrual cycle. Sample transcriptomes were queried for stage specific gene expression patterns. All cancer samples and a portion of high-risk samples showed overlapping stages reflective of abnormal gene expression patterns, while other high-risk samples exhibited more stage specific patterns. In conclusion, at-risk cells preserve behavioral and transcriptome diversity that could reflect different risk profiles. It is possible that prognostic platforms analogous to those used for breast cancer could be developed for high-risk mammary cells.


Assuntos
Neoplasias da Mama , Transcriptoma , Mama/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Mastectomia , Gravidez
7.
Life Sci Space Res (Amst) ; 31: 85-91, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34689954

RESUMO

Inevitable exposure to high-LET ionizing radiation (IR) present in galactic cosmic radiation (GCR) could enhance gastrointestinal (GI) cancer incidence among astronauts undertaking deep space exploration and GI-cancer mortality has been predicted to far exceed NASA's limit of < 3% REID (Radiation exposure-induced death) from cancer. Therefore, the development of countermeasure agents against high-LET radiation-induced GI cancer is needed to safeguard astronauts during and after an outer space mission. The cyclooxygenase-2/prostaglandin E2 (COX2/PGE2) mediated activation of pro-inflammatory and oncogenic signaling has been reported to play an important role in persistent inflammation and GI-tumorigenesis after high-LET radiation exposure. Therefore, aspirin, a well-known inhibitor of the COX/PGE2 pathway, was evaluated as a potential countermeasure against 28Si-induced PGE2 and tumorigenesis in Apc1638N/+, a murine model of human GI-cancer. Animals were fed either standard or aspirin supplemented diet (75, 150, or 300 mg/day of human equivalent dose) starting at the age of 4 weeks and continued till the end of the study, while mice were exposed to 28Si-ions (300 MeV/n; 69 keV/µm) at the age of 8 weeks. Serum PGE2 level, GI tumor size (>2mm2), number, and cluster (>5 adjoining tumors) were analyzed at 150 days post-exposure. Aspirin led to a significant reduction in PGE2 in a dose-dependent manner but did not reduce 28Si-induced GI tumorigenesis even at the highest (300 mg/day) dose. In summary, this study suggests that aspirin could reduce high-LET IR-induced pro-inflammatory PGE2 levels, however, lacks the ability to reduce high-LET IR-induced GI tumorigenesis in Apc1638N/+ mice.


Assuntos
Radiação Cósmica , Dinoprostona , Animais , Aspirina , Carcinogênese , Dieta , Camundongos
8.
Cells ; 10(9)2021 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-34571970

RESUMO

Current treatment options for patients infected with hepatitis B virus (HBV) are suboptimal, because the approved drugs rarely induce cure due to the persistence of the viral DNA genome in the nucleus of infected hepatocytes, and are associated with either severe side effects (pegylated interferon-alpha) or require life-long administration (nucleos(t)ide analogs). We report here the evaluation of the safety and therapeutic efficacy of a novel, humanized antibody (hzVSF) in the woodchuck model of HBV infection. hzVSF has been shown to act as a viral entry inhibitor, most likely by suppressing vimentin-mediated endocytosis of virions. Targeting the increased vimentin expression on liver cells by hzVSF after infection with HBV or woodchuck hepatitis virus (WHV) was demonstrated initially. Thereafter, hzVSF safety was assessed in eight woodchucks naïve for WHV infection. Antiviral efficacy of hzVSF was evaluated subsequently in 24 chronic WHV carrier woodchucks by monotreatment with three ascending doses and in combination with tenofovir alafenamide fumarate (TAF). Consistent with the proposed blocking of WHV reinfection, intravenous hzVSF administration for 12 weeks resulted in a modest but transient reduction of viral replication and associated liver inflammation. In combination with oral TAF dosing, the antiviral effect of hzVSF was enhanced and sustained in half of the woodchucks with an antibody response to viral proteins. Thus, hzVSF safely but modestly alters chronic WHV infection in woodchucks; however, as a combination partner to TAF, its antiviral efficacy is markedly increased. The results of this preclinical study support future evaluation of this novel anti-HBV drug in patients.


Assuntos
Alanina/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Antivirais/farmacologia , Vírus da Hepatite B da Marmota/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Fígado/efeitos dos fármacos , Tenofovir/análogos & derivados , Vimentina/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Endocitose/efeitos dos fármacos , Células Hep G2 , Hepatite B/metabolismo , Hepatite B/virologia , Vírus da Hepatite B da Marmota/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Fígado/metabolismo , Fígado/virologia , Marmota , Tenofovir/farmacologia , Vimentina/metabolismo , Carga Viral , Replicação Viral/efeitos dos fármacos
9.
BMJ Case Rep ; 14(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413046

RESUMO

We describe an unusual case of membranous nephropathy precipitated by syphilis infection in a patient without systemic lupus erythematosus (SLE). A previously healthy 20-year-old man presented with leg and facial swelling. Laboratory investigation revealed nephrotic range proteinuria, acute kidney injury, hypocomplementaemia and a highly positive rapid plasma reagin. Kidney biopsy showed membranous nephropathy with 'full-house' immunofluorescence (IgG, IgA, IgM, C1q and C3), mimicking lupus nephritis class Vb. However, the patient had no features of SLE and had negative antinuclear and anti-double-stranded DNA antibodies. He was treated with high-dose methylprednisolone and mycophenolate mofetil for lupus nephritis and with penicillin for syphilis. After 2 months of therapy, his proteinuria resolved, and his renal function and C4 level normalised. This case illustrates that syphilis infection can be a mimicker of lupus nephritis. A literature review suggests that ful-house nephropathy may occur independently of lupus nephritis and may or may not develop into SLE.


Assuntos
Glomerulonefrite Membranosa , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Sífilis , Adulto , Anticorpos Antinucleares , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/tratamento farmacológico , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/complicações , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Masculino , Adulto Jovem
10.
Cancers (Basel) ; 12(2)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059473

RESUMO

Recent studies report that the polarity gene myelin and lymphocyte protein 2 (MAL2), is overexpressed in multiple human carcinomas largely at the transcript level. Because chromosome 8q24 amplification (where MAL2 resides) is associated with hepatocellular- and cholangio-carcinomas, we examined MAL2 protein expression in these human carcinoma lesions and adjacent benign tissue using immunohistochemistry. For comparison, we analyzed renal cell carcinomas that are not associated with chromosome 8q24 amplification. Surprisingly, we found that MAL2 protein levels were decreased in the malignant tissues compared to benign in all three carcinomas, suggesting MAL2 expression may be anti-oncogenic. Consistent with this conclusion, we determined that endogenously overexpressed MAL2 in HCC-derived Hep3B cells or exogenously expressed MAL2 in hepatoma-derived Clone 9 cells (that lack endogenous MAL2) promoted actin-based protrusion formation with a reciprocal decrease in invadopodia. MAL2 overexpression also led to decreased cell migration, invasion and proliferation (to a more modest extent) while loss of MAL2 expression reversed the phenotypes. Mutational analysis revealed that a putative Ena/VASP homology 1 recognition site confers the MAL2-phenotype suggesting its role in tumor suppression involves actin remodeling. To reconcile decreased MAL2 protein expression in human carcinomas and its anti-oncogenic phenotypes with increased transcript levels, we propose a transcriptional regulatory model for MAL2 transient overexpression.

11.
Front Oncol ; 10: 582827, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33585200

RESUMO

Sulfation of heparan sulfate proteoglycans (HSPG) regulates signaling of growth factor receptors via specific interactions with the sulfate groups. 6-O-Sulfation of HSPG is an impactful modification regulated by the activities of dedicated extracellular endosulfatases. Specifically, extracellular sulfatase Sulf-2 (SULF2) removes 6-O-sulfate from HS chains, modulates affinity of carrier HSPG to their ligands, and thereby influences activity of the downstream signaling pathway. In this study, we explored the effect of SULF2 expression on HSPG sulfation and its relationship to clinical outcomes of patients with head and neck squamous cell carcinoma (HNSCC). We found a significant overexpression of SULF2 in HNSCC tumor tissues which differs by tumor location and etiology. Expression of SULF2 mRNA in tumors associated with human papillomavirus (HPV) infection was two-fold lower than in tumors associated with a history of tobacco and alcohol consumption. High SULF2 mRNA expression is significantly correlated with poor progression-free interval and overall survival of patients (n = 499). Among all HS-related enzymes, SULF2 expression had the highest hazard ratio in overall survival after adjusting for clinical characteristics. SULF2 protein expression (n = 124), determined by immunohistochemical analysis, showed a similar trend. The content of 6-O-sulfated HSPG, measured by staining with the HS3A8 antibody, was higher in adjacent mucosa compared to tumor tissue but revealed no difference based on SULF2 staining. LC-MS/MS analysis showed low abundance of N-sulfation and O-sulfation in HS but no significant difference between SULF2-positive and SULF2-negative tumors. Levels of enzymes modifying 6-O-sulfation, measured by RT-qPCR in HNSCC tumor tissues, suggest that HSPG sulfation is carried out by the co-regulated activities of multiple genes. Imbalance of the HS modifying enzymes in HNSCC tumors modifies the overall sulfation pattern, but the alteration of 6-O-sulfate is likely non-uniform and occurs in specific domains of the HS chains. These findings demonstrate that SULF2 expression correlates with survival of HNSCC patients and could potentially serve as a prognostic factor or target of therapeutic interventions.

12.
Int J Radiat Oncol Biol Phys ; 105(3): 525-536, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271826

RESUMO

PURPOSE: Proton radiation is a major component of the radiation field in outer space and is used clinically in radiation therapy of resistant cancers. Although epidemiologic studies in atom bomb survivors and radiologic workers have established radiation as a risk factor for colorectal cancer (CRC), we have yet to determine the risk of CRC posed by proton radiation owing to a lack of sufficient human or animal data. The purpose of the current study was to quantitatively and qualitatively characterize differential effects of acute and fractionated high-energy protons on colorectal carcinogenesis. METHODS AND MATERIALS: We used ApcMin/+ mice, a well-studied CRC model, to examine acute versus fractionated proton radiation-induced differences in intestinal tumorigenesis and associated signaling pathways. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy × 4). Intestinal tumor number and grade were scored 100 to 110 days after irradiation, and tumor and tumor-adjacent normal tissues were harvested to assess proliferative ß-catenin/Akt pathways and DNA damage response and repair pathways relevant to colorectal carcinogenesis. RESULTS: Significantly higher intestinal tumor number and grade, along with decreased differentiation, were observed after acute radiation relative to fractionated radiation. Acute protons induced upregulation of ß-catenin and Akt pathways with increased proliferative marker phospho-histone H3. Increased DNA damage along with decreased DNA repair factors involved in mismatch repair and nonhomologous end joining were also observed after exposure to acute protons. CONCLUSIONS: We show increased γH2AX, 53BP1, and 8-oxo-dG, suggesting that increased ongoing DNA damage along with decreased DNA repair factors and increased proliferative responses could be triggering a higher number of intestinal tumors after acute relative to fractionated proton exposures in ApcMin/+ mice. Taken together, our data suggest greater carcinogenic potential of acute relative to fractionated proton radiation.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo de Erro de Pareamento de DNA , Neoplasias Intestinais/genética , Neoplasias Induzidas por Radiação/genética , Prótons/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Carcinogênese/genética , Diferenciação Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclina D1/metabolismo , Reparo do DNA por Junção de Extremidades , Modelos Animais de Doenças , Fracionamento da Dose de Radiação , Feminino , Expressão Gênica , Genes APC , Histonas/metabolismo , Immunoblotting/métodos , Neoplasias Intestinais/patologia , Intestino Delgado/metabolismo , Intestino Delgado/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Induzidas por Radiação/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doses de Radiação , Exposição à Radiação/efeitos adversos , Voo Espacial , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos da radiação , beta Catenina/metabolismo
13.
Mol Cancer Res ; 17(5): 1207-1219, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30647104

RESUMO

Aberrant regulation of EGFR is common in non-small cell lung carcinomas (NSCLC), and tumor resistance to targeted therapies has been attributed to emergence of other co-occurring oncogenic events, parallel bypass receptor tyrosine kinase pathways including IGF1R, and TNFα-driven adaptive response via NF-κB. TNFAIP8, TNFα-inducible protein 8, is an NF-κB-activated prosurvival and oncogenic molecule. TNFAIP8 expression protects NF-κB-null cells from TNFα-induced cell death by inhibiting caspase-8 activity. Here, we demonstrate that knockdown of TNFAIP8 inhibited EGF and IGF-1-stimulated migration in NSCLC cells. TNFAIP8 knockdown cells showed decreased level of EGFR and increased expression of sorting nexin 1 (SNX1), a key regulator of the EGFR trafficking through the endosomal compartments, and treatment with SNX1 siRNA partially restored EGFR expression in these cells. TNFAIP8 knockdown cells also exhibited downregulation of IGF-1-induced pIGF1R and pAKT, and increased expression of IGF-1-binding protein 3 (IGFBP3), a negative regulator of the IGF-1/IGF1R signaling. Consistently, treatment of TNFAIP8 knockdown cells with IGFBP3 siRNA restored pIGF1R and pAKT levels. TNFAIP8 knockdown cells had enhanced sensitivities to inhibitors of EGFR, PI3K, and AKT. Furthermore, IHC expression of TNFAIP8 was associated with poor prognosis in NSCLC. These findings demonstrate TNFAIP8-mediated regulation of EGFR and IGF1R via SNX1 and IGFBP3, respectively. We posit that TNFAIP8 is a viable, multipronged target downstream of the TNFα/NF-κB axis, and silencing TNFAIP8 may overcome adaptive response in NSCLC. IMPLICATIONS: TNFAIP8 and its effectors SNX1 and IGFBP3 may be exploited to improve the efficacy of molecular-targeted therapies in NSCLC and other cancers.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/5/1207/F1.large.jpg.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , RNA Interferente Pequeno/farmacologia , Receptor IGF Tipo 1/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismo
15.
Case Rep Hematol ; 2018: 7493601, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271641

RESUMO

Lymphadenopathy in chronic myeloid leukemia (CML) is usually due to extramedullary involvement with accelerated or blast phases of the disease. The occurrence of non-Hodgkin lymphoma (NHL) as a synchronous malignancy with CML is rare. We report a case of a 73-year-old male who presented with dyspnea and right-sided lower extremity edema in the setting of leukocytosis. Bone marrow evaluation indicated a chronic phase chronic myeloid leukemia (CML), confirmed by molecular testing. Imaging of the chest for persistent dyspnea revealed supraclavicular and mediastinal lymphadenopathy. Biopsy of the cervical node showed expanded lymphoid follicles with atypical germinal centers that were positive for CD10, BCL-2, and BCL-6, consistent with follicular lymphoma (FL). Nodal PCR demonstrated clonal IGH and IGK gene rearrangements, and FISH analysis was positive for IGH-BCL-2 fusion. Together, these tests supported the diagnosis of FL. Additionally, the lymph node showed paracortical expansion by maturing pan-hematopoietic elements, no blastic groups, and positive RT-PCR analysis for BCR-ABL1, indicating concomitant involvement by chronic phase-CML. To our knowledge, this is the first reported case of a patient with a concurrent diagnosis of CML and FL.

16.
Cancer Prev Res (Phila) ; 11(10): 665-676, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30131435

RESUMO

Obesity is associated with cancer risk and its link with liver cancer is particularly strong. Obesity causes non-alcoholic fatty liver disease (NAFLD) that could progress to hepatocellular carcinoma (HCC). Chronic inflammation likely plays a key role. We carried out a bioassay in the high-fat diet (HFD)-fed C57BL/6J mice to provide insight into the mechanisms of obesity-related HCC by studying γ-OHPdG, a mutagenic DNA adduct derived from lipid peroxidation. In an 80-week bioassay, mice received a low-fat diet (LFD), high-fat diet (HFD), and HFD with 2% Theaphenon E (TE) (HFD+TE). HFD mice developed a 42% incidence of HCC and LFD mice a 16%. Remarkably, TE, a standardized green tea extract formulation, completely blocked HCC in HFD mice with a 0% incidence. γ-OHPdG measured in the hepatic DNA of mice fed HFD and HFD+TE showed its levels increased during the early stages of NAFLD in HFD mice and the increases were significantly suppressed by TE, correlating with the tumor data. Whole-exome sequencing showed an increased mutation load in the liver tumors of HFD mice with G>A and G>T as the predominant mutations, consistent with the report that γ-OHPdG induces G>A and G>T. Furthermore, the mutation loads were significantly reduced in HFD+TE mice, particularly G>T, the most common mutation in human HCC. These results demonstrate in a relevant model of obesity-induced HCC that γ-OHPdG formation during fatty liver disease may be an initiating event for accumulated mutations that leads to HCC and this process can be effectively inhibited by TE. Cancer Prev Res; 11(10); 665-76. ©2018 AACR.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Adutos de DNA/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/prevenção & controle , Extratos Vegetais/administração & dosagem , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Dieta Hiperlipídica/efeitos adversos , Ensaios de Seleção de Medicamentos Antitumorais , Incidência , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas Experimentais/epidemiologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Taxa de Mutação , Obesidade/complicações , Obesidade/etiologia , Obesidade/patologia , Extratos Vegetais/química , Polifenóis/administração & dosagem , Chá/química , Sequenciamento do Exoma
17.
Ann Thorac Surg ; 106(4): 1002-1007, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29859152

RESUMO

BACKGROUND: This study sought to evaluate the effect of tumor-infiltrating lymphocyte (TIL) density and programmed death ligand 1 (PD-L1) expression on the prognosis of esophageal cancer. METHODS: Banked tissue specimens from 53 patients who underwent esophagectomies for malignancy at a single institution over a 6-year period were stained for cluster of differentiation 3 (CD3), CD8, and PD-L1. Tumors were characterized as staining high or low density for CD3 and CD8, as well as positive or negative for PD-L1. TIL density and PD-L1 expression were analyzed in the context of survival, recurrence, and perioperative characteristics. RESULTS: Median follow-up was 823 days, with 92.5% survival and 26.8% recurrence rates. All tumors were adenocarcinomas. Neoadjuvant chemotherapy was given in 56.6% of cases, and neoadjuvant radiotherapy was given in 37.7%. High CD3 density was found in 83%, whereas high CD8 density was found in 56.6%. A total of 18.9% of the tumors stained positive for PD-L1. Survival was significantly shorter in Kaplan-Meier analysis for patients with primary tumors staining positive for PD-L1 (log rank: p = 0.05). Multivariable analysis controlling for neoadjuvant therapy, TIL markers, PD-L1, age, and sex found no significant difference in recurrence or survival. CONCLUSIONS: Positive staining for PD-L1 may be a prognostic marker for decreased survival in esophageal adenocarcinoma. Additional TIL cell types should be investigated for creation of an esophageal cancer Immunoscore. PD-L1 has potential as a therapeutic target.


Assuntos
Adenocarcinoma/imunologia , Antígeno B7-H1/metabolismo , Neoplasias Esofágicas/imunologia , Imunidade Celular/fisiologia , Linfócitos do Interstício Tumoral/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Tempo
18.
Ann Diagn Pathol ; 34: 131-134, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29661719

RESUMO

BACKGROUND: Implant brachytherapy (IBT) is a well-recognized treatment modality for early stage prostate cancer. Rectal ulcer and rectourethral fistula complicating IBT may cause an alteration of the normal anatomic landmarks. In this context, pseudomalignant radiation-induced changes within prostatic epithelium may be misinterpreted as a primary rectal malignancy. Such challenging and misleading findings have not been described, and may not be recognized as such. MATERIALS AND METHODS: We present the clinical and pathologic aspects of two patients who underwent IBT for low stage prostate cancer that was complicated by deep rectal ulcer. Both patients underwent extensive palliative surgical resection for disease control. RESULTS: The histologic changes in both cases were noteworthy for extensive necrosis and inflammation of the prostate, associated with loss of recto-prostatic anatomical landmarks. Prostatic glands showed striking radiation-induced atypia and pseudomalignant epithelial changes extending to the rectal ulcer bed, with no residual viable tumor. The first patient had undergone a biopsy of the rectal ulcer bed that was misinterpreted as a rectal adenocarcinoma prior to surgery. The similarity between atypical glands of the biopsy and the benign prostatic tissue with radiation-induced atypia in resection specimen confirmed their benign nature. CONCLUSIONS: Deep rectal ulcer complicating IBT may lead to distortion of the normal recto-prostatic anatomical landmarks, resulting in detection of pseudo-malignant prostatic glands at the ulcer base. Such findings may be mistaken for a primary rectal malignancy in limited biopsy material if not familiar to the pathologist.


Assuntos
Neoplasias da Próstata/radioterapia , Doenças Retais/diagnóstico , Fístula Retal/diagnóstico , Úlcera/diagnóstico , Fístula Urinária/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Idoso , Braquiterapia , Erros de Diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Próstata/cirurgia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Doenças Retais/patologia , Fístula Retal/patologia , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Úlcera/patologia , Fístula Urinária/patologia
19.
Proc Natl Acad Sci U S A ; 115(18): E4179-E4188, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29581250

RESUMO

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.


Assuntos
Redes Reguladoras de Genes , Histona Desmetilases/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de Próstata Resistentes à Castração/enzimologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/genética , Humanos , Hidrazinas/farmacologia , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Sulfonamidas/farmacologia , Transativadores/genética , Transativadores/metabolismo
20.
Dis Model Mech ; 11(1)2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29419396

RESUMO

Restricted availability of cell and animal models is a rate-limiting step for investigation of salivary gland neoplasm pathophysiology and therapeutic response. Conditionally reprogrammed cell (CRC) technology enables establishment of primary epithelial cell cultures from patient material. This study tested a translational workflow for acquisition, expansion and testing of CRC-derived primary cultures of salivary gland neoplasms from patients presenting to an academic surgical practice. Results showed that cultured cells were sufficient for epithelial cell-specific transcriptome characterization to detect candidate therapeutic pathways and fusion genes, and for screening for cancer risk-associated single nucleotide polymorphisms (SNPs) and driver gene mutations through exome sequencing. Focused study of primary cultures of a low-grade mucoepidermoid carcinoma demonstrated amphiregulin-mechanistic target of rapamycin-protein kinase B (AKT; AKT1) pathway activation, identified through bioinformatics and subsequently confirmed as present in primary tissue and preserved through different secondary 2D and 3D culture media and xenografts. Candidate therapeutic testing showed that the allosteric AKT inhibitor MK2206 reproducibly inhibited cell survival across different culture formats. By contrast, the cells appeared resistant to the adenosine triphosphate competitive AKT inhibitor GSK690693. Procedures employed here illustrate an approach for reproducibly obtaining material for pathophysiological studies of salivary gland neoplasms, and other less common epithelial cancer types, that can be executed without compromising pathological examination of patient specimens. The approach permits combined genetic and cell-based physiological and therapeutic investigations in addition to more traditional pathologic studies, and can be used to build sustainable bio-banks for future inquiries.This article has an associated First Person interview with the first author of the paper.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Mucoepidermoide/tratamento farmacológico , Carcinoma Mucoepidermoide/genética , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/genética , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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