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1.
Cancer Sci ; 112(2): 781-791, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33315285

RESUMO

Malignant pleural effusion is a common complication in metastatic breast cancer (MBC); however, changes in the pleural microenvironment are poorly characterized, especially with respect to estrogen receptor status. Histologically, MBC presents with increased microvessels beneath the parietal and visceral pleura, indicating generalized angiogenic activity. Breast cancer-associated pleural fluid (BAPF) was collected and cultured with HUVECs to recapitulate the molecular changes in subpleural endothelial cells. The clinical progression of triple-negative breast cancer (TNBC) is much more aggressive than that of hormone receptor-positive breast cancer (HPBC). However, BAPF from HPBC (BAPF-HP) and TNBC (BAPF-TN) homogeneously induced endothelial proliferation, migration, and angiogenesis. In addition, BAPF elicited negligible changes in the protein marker of endothelial-mesenchymal transition. Both BAPF-HP and BAPF-TN exclusively upregulated JNK signaling among all MAPKs in HUVECs. By contrast, the response to the JNK inhibitor was insignificant in Transwell and tube formation assays of the HUVECs cultured with BAPF-TN. The distinct contribution of p-JNK to endothelial angiogenesis was consequently thought to be induced by BAPF-HP and BAPF-TN. Due to increased angiogenic factors in HUVECs cultured with BAPF, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor was applied accordingly. Responses to VEGFR2 blockade were observed in both BAPF-HP and BAPF-TN concerning endothelial migration and angiogenesis. In conclusion, the above results revealed microvessel formation in the pleura of MBC and the underlying activation of p-JNK/VEGFR2 signaling. Distinct responses to blocking p-JNK and VEGFR2 in HUVECs cultured with BAPF-HP or BAPF-TN could lay the groundwork for future investigations in treating MBC based on hormone receptor status.


Assuntos
Neoplasias da Mama/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neovascularização Patológica/metabolismo , Derrame Pleural Maligno/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Idoso , Neoplasias da Mama/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Derrame Pleural Maligno/patologia
2.
Cancer Sci ; 111(10): 3747-3758, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32706142

RESUMO

Malignant pleural effusion (MPE) and paramalignant pleural effusion (PPE) remain debilitating complications in lung cancer patients with poor prognosis and limited treatment options. The role of vascular endothelial cells has not been explored in the pleural environment of lung cancer. By integrating MPE and PPE as malignant-associated pleural fluid (MAPF), the current study aimed to evaluate the effect of MAPF on cell proliferation, migration and angiogenesis of HUVEC. First, increased capillaries were identified in the subpleural layer of lung adenocarcinoma. Compatible with pathological observations, the ubiquitous elevation of HUVEC survival was identified in MAPF culture regardless of the underlying cancer type, the driver gene mutation, prior treatments and evidence of malignant cells in pleural fluid. Moreover, MAPF enhanced HUVEC motility with the formation of lamellipodia and filopodia and focal adhesion complex. Tube formation assay revealed angiogenic behavior with the observation of sheet-like structures. HUVEC cultured with MAPF resulted in a significant increase in MAPK phosphorylation. Accompanied with VEGFR2 upregulation in MAPF culture, there was increased expressions of p-STAT3, HIF-1α and Nf-kB. VEGF/VEGFR2 blockade regressed endothelial migration and angiogenesis but not cell proliferation. Our data indicate the angiogenic activities of MAPF on vascular endothelial cells that revealed increased pleural capillaries in lung cancer. Targeting the VEGF/VEGFR2 pathway might modulate the angiogenic propensity of MAPF in future clinical investigations.


Assuntos
Neoplasias Pulmonares/genética , Derrame Pleural Maligno/genética , Fator de Transcrição STAT3/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , NF-kappa B/genética , Neovascularização Patológica/complicações , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Derrame Pleural/genética , Derrame Pleural Maligno/complicações , Derrame Pleural Maligno/patologia
3.
Cancers (Basel) ; 14(11)2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35681743

RESUMO

Lung cancer-related pleural fluid (LCPF) presents as a common complication with limited treatment. Beyond its function in lipid digestion, bile acid was identified as a potent carcinogen to stimulate tumor proliferation. Previous research indicated a correlation between serum bile acid levels and the risk of developing several gastrointestinal cancers. Our study identified elevated bile acid levels in LCPF and increased farnesoid X receptor (FXR) expression as bile acid nuclear receptors in pleural microvessels of lung adenocarcinoma. Additionally, LCPF stimulated the expression of proteins involved in bile acid synthesis and cholesterol metabolism in HUVECs including CYP7A1, StAR, HMGCR, and SREBP2. LCPF-induced endothelial motility and angiogenesis were counteracted by using ß-muricholic acid as an FXR antagonist. Moreover, we investigated the efficacy of cholesterol-lowering medications, such as cholestyramine, fenofibrate, and atorvastatin, in regulating LCPF-regulated angiogenesis. Along with suppressing endothelial proliferation and angiogenesis, atorvastatin treatment reversed cholesterol accumulation and endothelial junction disruption caused by LCPF. Statin treatment inhibited LCPF-induced endothelial FXR expression as well as the downstream proteins RXR and SHP. Based on the positive findings of suppressing endothelial angiogenesis, our group further incorporated the effect of statin on clinical patients complicated with LCPF. A Kaplan-Meier analysis revealed the clinical benefit of statin exposure in patients with lung adenocarcinoma with LCPF. Conclusively, our study demonstrated the ability of statin to alleviate LCPF-induced angiogenesis in patients with LCPF via FXR modulation.

4.
Cells ; 11(5)2022 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-35269438

RESUMO

Impaired wound healing is an ongoing issue that cancer patients undergoing chemotherapy or radiotherapy face. Our previous study regarding lung-cancer-associated pleural fluid (LCPF) demonstrated its propensity to promote endothelial proliferation, migration, and angiogenesis, which are crucial features during cutaneous wound healing. Therefore, the current study aimed to investigate the effect of pleural fluid on cutaneous wound closure in vitro and in vivo using HaCaT keratinocytes and a full-thickness skin wound model, respectively. Both heart-failure-associated pleural fluid (HFPF) and LCPF were sequentially centrifuged and filtered to obtain a cell-free status. Treatment with HFPF and LCPF homogeneously induced HaCaT proliferation with cell cycle progression, migration, and MMP2 upregulation. Western blotting revealed increased PI3K/Akt phosphorylation and VEGFR2/VEGFA expression in HaCaT cells. When treated with the PI3K inhibitor, LCPF-induced keratinocyte proliferation was attenuated with decreased pS6 levels. By applying the VEGFR2 inhibitor, LCPF-induced keratinocyte proliferation was ameliorated by pS6 and MMP2 downregulation. The effect of LCPF-induced cell junction rearrangement was disrupted by co-treatment with a VEGFR2 inhibitor. Compared with a 0.9% saline dressing, LCPF significantly accelerated wound closure and re-epithelization when used as a dressing material in a full-thickness wound model. Histological analysis revealed increased neo-epidermis thickness and dermis collagen synthesis in the LCPF-treated group. Furthermore, LCPF treatment activated basal keratinocytes at the wound edge with the upregulation of Ki-67, VEGFA, and MMP2. Our preliminaries provided the benefit of wet dressing with pleural fluid to improve cutaneous wound closure through enhanced re-epithelization and disclosed future autologous application in cancer wound treatment.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Proliferação de Células , Humanos , Queratinócitos/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cicatrização/fisiologia
5.
Biomedicines ; 9(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34680445

RESUMO

Malignant-associated pleural fluid (MAPF) represented an unsolved problem in advanced lung cancer. Our previous work characterized increased pleural angiogenesis in lung adenocarcinoma and the propensity of MAPF on endothelial angiogenesis. This study investigated the combined efficacy of the tyrosine kinase inhibitor (gefitinib) and bevacizumab in opposing MAPF-induced angiogenesis. In lung adenocarcinoma patients with malignant pleural effusion (MPE), Kaplan-Meier analysis revealed the benefit of cotreatment with target therapy and bevacizumab. Increased EGFR expression was observed in the pleural microvessels of patients with lung adenocarcinoma both with and without mutations in EGFR. MAPF was obtained from lung adenocarcinoma patients both wild-type and mutant EGFRs. Total and phosphorylated EGFR were upregulated in HUVEC cultured with MAPF. Treatment with gefitinib as an EGFR inhibitor suppressed MAPF-induced endothelial migration and partially attenuated endothelial proliferation in both wild-type and mutant EGFR lung adenocarcinoma. Cotreatment with gefitinib and bevacizumab produced better inhibition of MAPF-induced endothelial angiogenesis than gefitinib alone in the mutant EGFR subgroup. Protein analysis of MAPF-derived exosomes revealed abundant EGFR and p-EGFR components that implied possible transfer to endothelial cells. Concluding Kaplan-Meier analysis and in vitro studies, the results indicated that the addition of bevacizumab on gefitinib treatment could suppress MAPF-induced angiogenesis in lung adenocarcinoma patients.

6.
PLoS One ; 15(1): e0226879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995577

RESUMO

BACKGROUND: Chronic lymphocytic leukemia (CLL) is incurable through conventional chemoimmunotherapy regimens. Despite durable responses to front-line therapy and sustained remission rates in patients with CLL, a majority of patients eventually relapse in 5 years of initial treatment. The depth of the response may affect the length of response. Maintenance therapies were aimed to deep remissions and extend the period of disease quiescence. Lenalidomide, rituximab and ofatumumab had demonstrated some efficacy as a maintenance therapy compared to no intervention for CLL patients. The relative effect on disease control and safety between different maintenance therapies were unclear. METHODS: We performed a systematic literature review and network meta-analysis to evaluate relative effect on disease control and safety of current available maintenance therapies. We searched PubMed, Embase and Cochrane database up to March 6, 2019. Relevant reference of review article and conference abstract including European Hematology Association Annual Meeting (EHA 2018), American Society of Hematology Annual Meeting (ASH 2018) and American Society of Clinical Oncology Annual Meeting (ASCO 2018) were searched. Randomized controlled trials (RCT) involving current available maintenance therapy including "Lenalidomide", "Rituximab", "Ofatumumab", "Ibrutinib", "Idelalisib", "Venetoclax"and "Obinutuzumab"were eligible. Outcomes of interest included progression-free survival (PFS), overall survival (OS) and serious adverse events (SAE) in CLL patients received subsequent maintenance therapy. Two authors CHL and CL) independently assessed eligibility for all identified citations and extracted data from the original trial reports. The selected studies' risk of bias was assessed following the guidelines of Cochrane Collaboration Handbook. RESULTS: In total, six phase III RCTs with total 1,615 CLL patients were identified. Maintenance therapy using lenalidomide, rituximab, and ofatumumab demonstrated a statistically significant effect in prolongation of progression-free survival (HR:0.37, 95% CI: 0.27-0.50 of lenalidomide; HR:0.50, 95% CI: 0.38-0.66 of rituximab; HR:0.52, 95% CI:0.41-0.66 of ofatumumab, separately) compared with no intervention; however, for overall survival, the effect of maintenance therapy showed no significant difference versus no intervention (HR: 0.89, 95% CI: 0.70-1.14). Lenalidomide showed the best efficacy for PFS (HR: 0.37, 95% CI: 0.27-0.50, Probability of being best treatment: 96%). CONCLUSIONS: Our network meta-analysis provided an integrated overview of relative efficacy and safety of different maintenance therapies in CLL. All maintenance therapies were effective in reducing the risk of disease progression versus no intervention. Based on current best evidence, maintenance therapy with lenalidomide is the most efficacious option.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Humanos , Lenalidomida/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
7.
Oncotarget ; 9(37): 24642-24652, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29872494

RESUMO

Numerous evidence has indicated that excess weight is associated with an increased risk of mortality in patients in several cancer types including breast, colorectal, pancreatic, endometrial, and prostate cancer However, with respect to non-small cell lung cancer and upper aero-digestive cancer, evidence suggests that low body mass index (BMI) may increase the risk of mortality of these cancers, but a definitive link between premorbid BMI and overall survival in small cell lung cancer patients has yet to be fully explored. To investigate this possibility, we conducted a retro-spective of 173 small-cell lung cancer patients. Multivariate Cox analysis indicated that pretreatment overweight (BM I ≥ 23) was an independent prognostic factor for overall survival (OS) (Hazard ratio, = 0.58, 95% CI = 0.39-0.87, p = 0.008). In addition, meta-regression revealed that per-formance status (≤ 2) marginally interacted with increased BMI (p = 0.068). However, subgroup analysis showed that patients with a BMI ≥ 23 and performance status ≤ 2 had the best OS (Hazard ratio: 0.31, 95% CI: 0.16-0.61, p = 0.001). Premorbid BMI and performance status level are easy to measure and may provide physicians an additional measurement to predict a small-cell lung cancer patient's survival. The data from the present study indicates that a, further large scale prospective study is warranted to better assess the association of pretreatment BMI and OS in small-cell lung cancer. .

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