RESUMO
BACKGROUND: Angiogenesis is a critical step in colorectal cancer growth, progression and metastasization. CT are routine imaging examinations for preoperative clinical evaluation in colorectal cancer patients. This study aimed to investigate the predictive value of preoperative CT enhancement rate (CER) and CT perfusion parameters on angiogenesis in colorectal cancer, as well as the association of preoperative CER and CT perfusion parameters with serum markers. METHODS: This retrospective analysis included 42 patients with colorectal adenocarcinoma. Median of microvessel density (MVD) as the cut-off value, it divided 42 patients into high-density group (MVD ≥ 35/field, n = 24) and low-density group (MVD < 35/field, n = 18), and 25 patients with benign colorectal lesions were collected as the control group. Statistical analysis of CER, CT perfusion parameters, serum markers were performed in all groups. Receiver operating curves (ROC) were plotted to evaluate the diagnostic efficacy of relevant CT perfusion parameters for tumor angiogenesis; Pearson correlation analysis explored potential association between CER, CT perfusion parameters and serum markers. RESULTS: CER, blood volume (BV), blood flow (BF), permeability surface (PS) and carbohydrate antigen 19 - 9 (CA19-9), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), trefoil factor 3 (TFF3), vascular endothelial growth factor (VEGF) in colorectal adenocarcinoma were significantly higher than those in the control group, the parameters in high-density group were significantly higher than those in the low-density group (P < 0.05); however, the time to peak (TTP) of patients in colorectal adenocarcinoma were significantly lower than those in the control group, and the high-density group showed a significantly lower level compared to the low-density group (P < 0.05). The combined parameters BF + TTP + PS and BV + BF + TTP + PS demonstrated the highest area under the curve (AUC), both at 0.991. Pearson correlation analysis showed that the serum levels of CA19-9, CA125, CEA, TFF3, and VEGF in patients showed positive correlations with CER, BV, BF, and PS (P < 0.05), while these indicators exhibited negative correlations with TTP (P < 0.05). CONCLUSIONS: Some single and joint preoperative CT perfusion parameters can accurately predict tumor angiogenesis in colorectal adenocarcinoma. Preoperative CER and CT perfusion parameters have certain association with serum markers.
Assuntos
Adenocarcinoma , Antígeno Carcinoembrionário , Neoplasias Colorretais , Neovascularização Patológica , Valor Preditivo dos Testes , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Neoplasias Colorretais/irrigação sanguínea , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adenocarcinoma/irrigação sanguínea , Idoso , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/sangue , Tomografia Computadorizada por Raios X/métodos , Antígeno Carcinoembrionário/sangue , Biomarcadores Tumorais/sangue , Adulto , Densidade Microvascular , Antígeno CA-19-9/sangue , Curva ROC , Fator A de Crescimento do Endotélio Vascular/sangue , Volume Sanguíneo , Cuidados Pré-Operatórios/métodosRESUMO
OBJECTIVE: This study aimed to determine whether microvessel density (MVD) in the tumor tissues could be a potential predictive marker for vascular invasion (VI). METHODS: Surgical specimens of 73 patients with colorectal adenocarcinoma in Phramongkutklao Hospital were analyzed. Tissues of patients receiving preoperative radiation or prior anti-angiogenic therapy were excluded. Tumor MVD was determined using the average number of counted CD34-stained endothelial cells from two selected fields at 200x magnification in each slide. The presence of VI was defined by tumor involvement of endothelial cell-lined spaces. The optimal cut-off value of MVD to predict VI was examined using receiver operating characteristic analysis to assess the area under the curve and accuracy. RESULT: VI was detected in 17 of 73 specimens (23.3%). Colorectal cancer (CRC) specimens were classified according to MVD as low (61 specimens, 83.6%) and high density (12 specimens, 16.4%). Average MVD was slightly higher in specimens with VI (81.3±9.3) than those without VI (76.3±7.6), but without statistical significance (p = 0.736). The MVD's cut-off value of 60 vessels/200x field provided 88% sensitivity, 40% specificity, and 57.5% accuracy, with the area under the ROC curve of 0.5788. Patients with CRC having MVD of > 60 vessels/200x field were at significantly higher risk of VI than those with CRC having MVD of <60 vessels/200x field (P=0.009, Fisher's exact test). Univariate analysis revealed that MVD, nodal involvement and AJCC tumor stage were associated with the presence of VI (p <0.05). Further multivariate analysis of these three potential variables demonstrated MVD (OR, 11.994; 95% CI, 2.197 to 65.483; p <0.01) and nodal involvement (OR, 10.767; 95% CI, 1.973 to 58.748; p <0.05) as independent prognostic factors associated with VI. CONCLUSION: Based on our study, MVD immunostaining was an angiogenic marker that potentially be a predictive marker for VI.
Assuntos
Adenocarcinoma , Neoplasias Colorretais , Humanos , Neovascularização Patológica/patologia , Células Endoteliais , Densidade Microvascular , Neoplasias Colorretais/patologia , Adenocarcinoma/irrigação sanguínea , PrognósticoRESUMO
INTRODUCTION AND OBJECTIVES: Prostate cancer is one of the most commonly diagnosed cancers in American men. Apelin is an endogenous peptide identified as the ligand of the G protein-associated apelin receptor. Apelin and apelin receptor have many tissues distribution and they participate in pathological processes, such as cancer. Apelin stimulates cancer angiogenesis. However, there are insufficient data in the literature regarding the role of apelin/apelin receptor in normal tissue, highgrade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma tissues. Therefore, this study aimed to investigate the apelin and apelin receptor expression levels in tissues of normal prostate tissue, high-grade prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. MATERIALS AND METHODS: In this study, 38 samples of patients undergoing radical prostatectomy were used. Among 38 samples; 20 patients were with prostatic adenocarcinoma, 18 patients were with high-grade prostatic intraepithelial neoplasia and adjacent normal prostatic tissue areas. The immunolocalisation of apelin and apelin receptor in these tissues were determined immunohistochemically. RESULTS: Apelin and apelin receptor expressions were higher in prostatic adenocarcinoma than normal prostate tissue and high-grade prostatic intraepithelial neoplasia. Apelin receptor expression was also increased in high-grade prostatic intraepithelial neoplasia compared to normal tissue. CONCLUSION: Apelin and apelin receptor are increase in the process of prostate carcinogenesis. This increase may adversely affect the clinical course of prostate cancer patients by stimulating angiogenesis, which is important for invasion and metastasis in prostate cancer.
Assuntos
Adenocarcinoma , Receptores de Apelina , Apelina , Próstata , Neoplasia Prostática Intraepitelial , Neoplasias da Próstata , Humanos , Masculino , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Apelina/genética , Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Próstata/metabolismo , Próstata/patologia , Próstata/cirurgia , Neoplasia Prostática Intraepitelial/irrigação sanguínea , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasia Prostática Intraepitelial/cirurgia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Prostatectomia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologiaRESUMO
OBJECTIVE: Mast cells (MCs) are known to be involved in several physiological and pathological processes in humans and animals. Recently, their potential role in tumor development and angiogenesis has been investigated, arising interesting results to be potentially applied in clinics. Mast cells' granules contain a huge quantity of protease enzymes that, through different mechanisms, induce the formation of new microvessels, feeding tumor burden. Among them, tryptase and chymase are the most abundant enzymes: tryptase is well known for its multiple activities, on the contrary, the role of chymase in pancreatic cancer angiogenesis has not been investigated yet. PATIENTS AND METHODS: Our research aims to correlate to each other and to angiogenesis four different tissue parameters (MCs density positive to chymase, MCs area positive to chymase, microvascular density and endothelial area) together with the main clinical-pathological characteristics in 52 patients surgically resected for pancreatic ductal adenocarcinoma, employing immunohistochemistry and image analysis system. RESULTS: All reported tissue parameters match to confirm the correlation between chymase enzyme and angiogenesis in pancreatic cancer. CONCLUSIONS: This evidence could become a starting point for a new potential therapeutic route exploiting chymase inhibitors as a novel anti-angiogenetic strategy in pancreatic cancer patients.
Assuntos
Adenocarcinoma , Quimases/metabolismo , Mastócitos/metabolismo , Neovascularização Patológica , Neoplasias Pancreáticas , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Feminino , Humanos , Masculino , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologiaRESUMO
This study was aimed to determine the diagnostic performance of perfusion-related parameters derived from intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) by comparing them with quantitative parameters from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on differentiation grades of rectal cancer. We retrospectively analyzed 98 patients with rectal cancer. Perfusion-related IVIM parameters (D ∗, f, and f·D ∗) and quantitative DCE parameters (K trans, K ep, V e , and V p ) were obtained by plotting the volume-of-interest on in-house software. Furthermore, we compared the difference and diagnostic performance of all well-moderately and poorly differentiated rectal cancer parameters. Finally, we analyzed the correlation between those DCE and IVIM parameters and pathological differentiation grade. The values of f, K trans, and K ep significantly differentiated poor and well-moderate rectal cancers. K trans achieved the highest area under the curve (AUC) value compared to perfusion-related IVIM and DCE parameters. Furthermore, K trans showed a better correlation with pathological differentiation grade than f. The diagnostic efficiency of DCE-MRI was greater than perfusion-related IVIM parameters. The f value derived from perfusion-related IVIM offered a diagnostic performance similar to DCE-MRI for patients with renal insufficiency.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Neoplasias Retais/diagnóstico por imagem , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Biologia Computacional , Meios de Contraste , Imagem de Difusão por Ressonância Magnética/estatística & dados numéricos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Interpretação de Imagem Assistida por Computador/estatística & dados numéricos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Retais/irrigação sanguínea , Neoplasias Retais/patologia , Estudos RetrospectivosRESUMO
PURPOSE: Apatinib, an antiangiogenic drug, has shown beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses. METHODS: Immunocompetent mice with subcutaneous MFC tumors grown were given a combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining. RESULTS: Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTßR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival. CONCLUSION: Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Piridinas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neovascularização Patológica/tratamento farmacológico , Piridinas/efeitos adversos , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) are key angiogenic regulatory factors. The aim of this study was to identify the most useful prognostic angiogenic factors in advanced nonsmall cell lung cancer (NSCLC) without known driver gene mutations. Methods: Eligible patients were pathologically confirmed to have advanced NSCLC without known driver mutations. All patients were treated with standard first-line chemotherapy ± bevacizumab. Serum concentrations of HIF-1α, VEGF, sVEGFR1, sVEGFR2, and endostatin were measured via enzyme-linked immunosorbent assays (ELISAs) prior to and after two cycles of treatment. Area under the curve (AUC) and optimal cutoff values were calculated by receiver operator characteristic curve (ROC) analyses. The parameters that predicted survival were evaluated by univariate and multivariate Cox proportional hazard analyses. Results: A total of 47 patients were included in this study. HIF-1α levels decreased significantly after treatment in the nonprogressing (partial response/stable disease) patient group (707.94 vs. 355.53 pg/mL, p = 0.002), but increased levels were seen in patients with progressive disease, however, the extent of change did not reach significance (173.70 vs. 416.34 pg/mL, p = 0.078). An HIF-1α ratio of 1.18 was chosen as the best point to predict treatment response through ROC analyses. Via univariate and multivariate analyses, we found that patients with a HIF-1α ratio ≥1.18 after treatment were significantly more likely to have a prolonged progression-free survival (PFS, HR 0.303, 95% CI: 0.153-0.603, p = 0.001) and overall survival (OS, HR 0.436, 95% CI: 0.153-0.603, p = 0.025). Conclusions: We identified the pretreatment to posttreatment HIF-1α ratio as a promising predictor for PFS and OS in NSCLC patients without known driver mutations.
Assuntos
Adenocarcinoma/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Neoplasias Pulmonares/sangue , Proteínas de Neoplasias/sangue , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Citocinas/sangue , Endostatinas/sangue , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Neovascularização Patológica/genética , Compostos Organoplatínicos/administração & dosagem , Pemetrexede/administração & dosagem , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Curva ROC , Fumar/epidemiologia , Taxoides/administração & dosagem , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio VascularRESUMO
PURPOSE: Investigation of potential improvements in dynamic CT perfusion measurements by exploitation of improved visualization of contrast agent in virtual monoenergetic reconstructions of images acquired with dual-energy computed tomography (DECT). METHOD: For 17 patients with pancreatic carcinoma, dynamic dual-source DECT acquisitions were performed at 80kVp/Sn140kVp every 1.5 s over 51 s. Virtual monoenergetic images (VMI) were reconstructed for photon energies between 40 keV and 150 keV (5 keV steps). Using the maximum-slope model, perfusion maps of blood flow were calculated from VMIs and 80kVp images and compared quantitatively with regard to blood flow measured in regions of interest in healthy tissue and carcinoma, standard deviation (SD), and absolute-difference-to-standard-deviation ratio (ADSDR) of measurements. RESULTS: On average, blood flow calculated from VMIs increased with increasing energy levels from 114.3 ± 37.2 mL/100 mL/min (healthy tissue) and 45.6 ± 25.3 mL/100 mL/min (carcinoma) for 40 keV to 128.6 ± 58.9 mL/100 mL/min (healthy tissue) and 75.5 ± 49.8 mL/100 mL/min (carcinoma) for 150 keV, compared to 114.2 ± 37.4 mL/100 mL/min (healthy tissue) and 46.5 ± 26.6 mL/100 mL/min (carcinoma) for polyenergetic 80kVp. Differences in blood flow between tissue types were significant for all energies. Differences between perfusion maps calculated from VMIs and 80kVp images were not significant below 110 keV. SD and ADSDR were significantly better for perfusion maps calculated from VMIs at energies between 40 keV and 55 keV than for those calculated from 80kVp images. Compared to effective dose of dynamic 80kVp acquisitions (4.6 ± 2.2mSv), dose of dynamic DECT/VMI acquisitions (8.0 ± 3.7mSv) was higher. CONCLUSIONS: Perfusion maps of blood flow based on low-energy VMIs between 40 keV and 55 keV offer improved robustness and quality of quantitative measurements over those calculated from 80kVp image data (reference standard), albeit at increased patient radiation exposure.
Assuntos
Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/diagnóstico por imagem , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/diagnóstico por imagem , Imagem Radiográfica a Partir de Emissão de Duplo Fóton/métodos , Fluxo Sanguíneo Regional , Tomografia Computadorizada por Raios X/métodos , Idoso , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Razão Sinal-Ruído , Neoplasias PancreáticasRESUMO
PURPOSE: Molecular ultrasound imaging of tumor vasculature is being actively investigated with microbubble contrast agents targeted to neovasculature biomarkers. Yet, a universal method of targeting tumor vasculature independent of specific biomarkers, or in their absence, would be desirable. We report the use of electrostatic interaction to achieve adherence of microbubbles to tumor vasculature and resulting tumor delineation by ultrasound imaging. METHODS AND MATERIALS: Microbubbles were prepared from decafluorobutane gas by amalgamation of aqueous micellar medium. Distearoyl phosphatidylcholine (DSPC) and polyethylene glycol (PEG)-stearate were used as microbubble shell-forming lipids; cationic lipid distearoyl trimethylammoniumpropane (DSTAP) was included to introduce positive electrostatic charge. Microbubbles were subjected to flotation in normal gravity, to remove larger particles. Murine colon adenocarcinoma tumor (MC38, J. Schlom, National Institutes of Health) was inoculated in the hind leg of C57BL/6 mice. Contrast ultrasound imaging was performed under isoflurane anesthesia, using a clinical imaging system in low power mode, with tissue signal suppression (contrast pulse sequencing, 7 MHz, 1 Hz; Mechanical Index, 0.2). The ultrasound probe was positioned to monitor the tumor and contralateral leg muscle; microbubble contrast signal was monitored for 30 minutes or more, after intravenous bolus administration of 2.10 microbubbles. Individual time point frames were extracted from ultrasound video recording and analyzed with ImageJ. RESULTS: Mean bubble diameter was ~1.6 to 2 µm; 99.9% were less than 5 µm, to prevent blocking blood flow in capillaries. For cationic DSTAP-carrying microbubbles, contrast signal was observed in the tumor beyond 30 minutes after injection. As the fraction of positively charged lipid in the bubble shell was increased, adherent contrast signal in the tumor also increased, but accumulation of DSTAP-microbubbles in the normal muscle increased as well. For bubbles with the highest positive charge tested, DSTAP-DSPC molar ratio 1:4, at 10 minutes after intravenous administration of microbubbles, the contrast signal difference between the tumor and normal muscle was 1.5 (P < 0.005). At 30 minutes, tumor/muscle contrast signal ratio improved and reached 2.1. For the DSTAP-DSPC 1:13 preparation, tumor/muscle signal ratio exceeded 3.6 at 10 minutes and reached 5.4 at 30 minutes. Microbubbles with DSTAP-DSPC ratio 1:22 were optimal for tumor targeting: at 10 minutes, tumor/muscle signal ratio was greater than 7 (P < 0.005); at 30 minutes, greater than 16 (P < 0.01), sufficient for tumor delineation. CONCLUSIONS: Cationic microbubbles are easy to prepare. They selectively accumulate in the tumor vasculature after intravenous administration. These microbubbles provide target-to-control contrast ratio that can exceed an order of magnitude. Adherent microbubbles delineate the tumor mass at extended time points, at 30 minutes and beyond. This may allow for an extension of the contrast ultrasound examination time. Overall, positively charged microbubbles could become a universal ultrasound contrast agent for cancer imaging.
Assuntos
Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/diagnóstico por imagem , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/diagnóstico por imagem , Meios de Contraste/química , Microbolhas , Ultrassonografia/métodos , Animais , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/química , Polietilenoglicóis/químicaRESUMO
We report the case of a 63-year-old man who underwent MRI and Ga-PSMA-11 PET/CT for biochemical recurrence localization after radical prostatectomy (serum PSA, 0.25 ng/mL) and describe the incidental discovery of a rectal adenocarcinoma. Immunohistochemical analysis showed PSMA staining in the tumor-associated neovasculature, but not in normal vasculature, or tumor cells. After surgical removal, he was treated with salvage radiotherapy to the postoperative prostate bed. This case example has several implications: the findings confirm the expression of PSMA in the tumor-associated neovasculature of a rectal cancer, nonprostate cancers' stroma may represent a potentially relevant target for nuclear theranostics.
Assuntos
Adenocarcinoma/metabolismo , Antígenos de Superfície/metabolismo , Regulação Neoplásica da Expressão Gênica , Glutamato Carboxipeptidase II/metabolismo , Neovascularização Patológica/metabolismo , Medicina Nuclear , Neoplasias Retais/metabolismo , Nanomedicina Teranóstica , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/terapia , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prostatectomia , Neoplasias Retais/irrigação sanguínea , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapiaRESUMO
Cyclovirobuxine D (CVBD) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVBD has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVBD on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVBD and further elucidate its molecular mechanism(s). DLD1 and LoVo cell lines were selected to evaluate the antitumor effect of CVBD. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVBDtreated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVBD in vivo. It was identified that CVBD inhibited the proliferation, migration, stemness, angiogenesis and epithelialmesenchymal transition of CRC cells, and induced apoptosis and Sphase arrest. In addition, CVBD significantly inhibited the growth of xenografts. It is notable that CVBD exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVBD exerted anticancer effects through the CTHRC1AKT/ERKSnail signaling pathway. Targeted therapy combining CTHRC1 with CVBD may offer a promising novel therapeutic approach for CRC treatment.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Proteínas da Matriz Extracelular/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/patologia , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo , RNA-Seq , Fatores de Transcrição da Família Snail/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Anti-angiogenic agents combined with chemotherapy is an important strategy for the treatment of solid tumors. However, survival benefit is limited, urging the improvement of combination therapies. We aimed to clarify the effects of vascular endothelial growth factor receptor 2 (VEGFR2) targeting on hemodynamic function and penetration of drugs in esophagogastric adenocarcinoma (EAC). Patient-derived xenograft (PDX) models of EAC were subjected to long-term and short-term treatment with anti-VEGFR2 therapy followed by chemotherapy injection or multi-agent dynamic contrast-enhanced (DCE-) MRI and vascular casting. Long-term anti-VEGFR2-treated tumors showed a relatively lower flow and vessel density resulting in reduced chemotherapy uptake. On the contrary, short-term VEGFR2 targeting resulted in relatively higher flow, rapid vasodilation, and improved chemotherapy delivery. Assessment of the extracellular matrix (ECM) revealed that short-term anti-angiogenic treatment drastically remodels the tumor stroma by inducing nitric oxide synthesis and hyaluronan degradation, thereby dilating the vasculature and improving intratumoral chemotherapy delivery. These previously unrecognized beneficial effects could not be maintained by long-term VEGFR2 inhibition. As the identified mechanisms are targetable, they offer direct options to enhance the treatment efficacy of anti-angiogenic therapy combined with chemotherapy in EAC patients.
Assuntos
Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/metabolismo , Animais , Neoplasias Esofágicas/irrigação sanguínea , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Camundongos Nus , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
The antiangiogenic therapy for prostate cancer with Nintedanib, a potent inhibitor of important growth factor receptors, has been proven to delay tumor progression and arrest tumor growth; thus, the aim herein is to evaluate Nintedanib effects on tumor cells, besides angiogenesis and apoptosis processes, metalloproteinases and hypoxia factor in an animal model. Nintedanib promoted growth inhibition and cell death in a dose-dependent manner, showing no tumor selectivity. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) were treated with Nintedanib (10 mg/kg/day) in different stages of tumor development and the ventral prostate was examined for protein levels by means of immunohistochemistry and Western blotting and apoptosis evaluation. In vitro antiproliferative activity of Nintedanib was also assessed in nine human tumor cell lines. Early Nintedanib treatment has shown decreased levels of FGF-2, VEGFR-1, MMP-9 and HIF-1α and a significantly increased apoptosis of epithelial cells. Furthermore, late Nintedanib treatment decreased FGF-2, VEGFR-1 and FGFR-3 levels. Importantly, even after treatment discontinuation, treated animals displayed a significant decrease in VEGFR-1 as well as MMP-9. Although Nintedanib treatment in late stages of tumor growth has shown some good results, it is noteworthy that the drug presents the best tissue response when administered in the early stages of disease development. Nintedanib treatment has shown to be a promising approach for prostate cancer therapy, especially in the early stages of the disease, interfering in different carcinogenesis progression pathways.
Assuntos
Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Apoptose , Hipóxia/patologia , Indóis/uso terapêutico , Próstata/patologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/patologia , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Indóis/farmacologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estadiamento de Neoplasias , Neoplasias da Próstata/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismoAssuntos
Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/radioterapia , Embolização Terapêutica , Sintomas do Trato Urinário Inferior/terapia , Próstata/irrigação sanguínea , Hiperplasia Prostática/terapia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/radioterapia , Radiocirurgia , Adenocarcinoma/diagnóstico por imagem , Idoso , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico por imagem , Masculino , Próstata/diagnóstico por imagem , Hiperplasia Prostática/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Resultado do TratamentoRESUMO
Early growth response-1 (EGR1) is a transcription factor correlated with prostate cancer (PC) progression in a variety of contexts. For example, EGR1 levels increase in response to suppressed androgen receptor signaling or loss of the tumor suppressor, PTEN. EGR1 has been shown to regulate genes influencing proliferation, apoptosis, immune cell activation, and matrix degradation, among others. Despite this, the impact of EGR1 on PC metastatic colonization is unclear. We demonstrate using a PC model (DU145/RasB1) of bone and brain metastasis that EGR1 expression regulates angiogenic and osteoclastogenic properties of metastases. We have shown previously that FN14 (TNFRSF12A) and downstream NF-κB signaling is required for metastasis in this model. Here we demonstrate that FN14 ligation also leads to NF-κB-independent, MEK-dependent EGR1 expression. EGR1-depletion in DU145/RasB1 cells reduced both the number and size of metastases but did not affect primary tumor growth. Decreased EGR1 expression led to reduced blood vessel density in brain and bone metastases as well as decreased osteolytic bone lesion area and reduced numbers of osteoclasts at the bone-tumor interface. TWEAK (TNFSF12) induced several EGR1-dependent angiogenic and osteoclastogenic factors (e.g., PDGFA, TGFB1, SPP1, IL6, IL8, and TGFA, among others). Consistent with this, in clinical samples of PC, the level of several genes encoding angiogenic/osteoclastogenic pathway effectors correlated with EGR1 levels. Thus, we show here that EGR1 has a direct effect on prostate cancer metastases. EGR1 regulates angiogenic and osteoclastogenic factors, informing the underlying signaling networks that impact autonomous and microenvironmental mechanisms of cancer metastases.
Assuntos
Adenocarcinoma/patologia , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Neovascularização Patológica/genética , Osteogênese/genética , Neoplasias da Próstata/patologia , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/genética , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Proteína 1 de Resposta de Crescimento Precoce/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Metástase Neoplásica , Neovascularização Patológica/patologia , Células PC-3 , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/genética , Células RAW 264.7 , Transdução de Sinais/genética , Células Tumorais Cultivadas , Microambiente Tumoral/genéticaRESUMO
Objective: To evaluate the ability of pulsatility index (PI), resistance index (RI), and hypoxia inducible factor-1α (HIF-1α) expression in predicting the clinical response after radiation in patients with cervical cancer. Methods: A prospective cohort was carried on in Department of Obstetric and Gynecology Dr. Hasan Sadikin Hospital/ Faculty of Medicine, Padjadjaran University, during the period of July 2017 to March 2018 which include 51 samples with stage IIB to IVA cervical cancer. Tumor perfusion and oxygenation were evaluated using color Doppler ultrasound indices (pulsatility index and resistance index) and the expression of hypoxia inducible factor-1α (HIF-1α). The clinical response was assessed 2 months after external radiation. Result: Among 51 patients, 31 patients demonstrated good response and 20 patients demonstrated poor response to radiation. The mean value of PI was significantly lower in patients who demonstrated good response as compared to patients with poor response (0.84±0.916 vs. 1.70±1.260, p = 0.004). The mean value of RI did not differ significantly (0.29±0.112 vs. to 0.36±0.189 p =0.173). HIF-1α expression was significantly lower in patients who demonstrated good response as compared to patients with poor response (1.83±1.529 vs. 6.55±2.625, p = 0.0001). In multivariate model, PI and HIF-1α expression both predicted the clinical response after radiation. Conclusion: PI and HIF-1α expression predict the clinical response after radiation in patients with cervical cancer.
Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Hipóxia Celular , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Radioterapia/métodos , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/metabolismo , Adenocarcinoma/radioterapia , Adulto , Idoso , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Ultrassonografia Doppler , Neoplasias do Colo do Útero/irrigação sanguínea , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapiaRESUMO
The origin of blood and lymphatic vessels in high-grade serous adenocarcinoma of ovary (HGSOC) is uncertain. We evaluated the potential of cancer stem cells (CSCs) in HGSOC to contribute to their formation. Using spheroids as an in vitro model for CSCs, we have evaluated their role in primary malignant cells (PMCs) in ascites from previously untreated patients with HGSOC and cell lines. Spheroids from PMCs grown under specific conditions showed significantly higher expression of endothelial, pericyte and lymphatic endothelial markers. These endothelial and lymphatic cells formed tube-like structures, showed uptake of Dil-ac-LDL and expressed endothelial nitric oxide synthase confirming their endothelial phenotype. Electron microscopy demonstrated classical Weibel-Palade bodies in differentiated cells. Genetically, CSCs and the differentiated cells had a similar identity. Lineage tracking using green fluorescent protein transfected cancer cells in nude mice confirmed that spheroids grown in stem cell conditions can give rise to all three cells. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor inhibited the differentiation of spheroids to endothelial cells in vitro. These results suggest that CSCs contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary, which can be inhibited.
Assuntos
Adenocarcinoma/patologia , Linfangiogênese , Neoplasias Císticas, Mucinosas e Serosas/patologia , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/ultraestrutura , Ascite/metabolismo , Ascite/patologia , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Biomarcadores Tumorais/metabolismo , Vasos Sanguíneos/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias Císticas, Mucinosas e Serosas/irrigação sanguínea , Neoplasias Císticas, Mucinosas e Serosas/ultraestrutura , Células-Tronco Neoplásicas/ultraestrutura , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/ultraestrutura , Pericitos/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVES: We investigated the prognostic value of tumor blood supply in patients with advanced gastric cancer (GC) receiving neoadjuvant chemotherapy. METHODS: We retrospectively reviewed 53 patients with advanced GC treated with FLEEOX chemotherapy. The tumor computed tomography (CT) enhancement value was measured before chemotherapy (CT1; arterial phase CT-plain phase CT). The liver parenchyma CT enhancement value (CT2) was also measured using the same method, to eliminate individual differences. Tumor blood supply was defined as good or poor based on the median CT1/CT2 values. We evaluated the relationships between tumor blood supply and response to chemotherapy, clinicopathologic characteristics, and overall survival (OS). RESULTS: A good blood supply (GBS) was associated with significantly better clinical and pathological responses to chemotherapy than a poor blood supply (PBS). The 3-year OS was 65.8% for the entire cohort. Patients with a GBS had a significantly higher OS (78.57%) than those with a PBS (54.44%). Additionally, patients with Bormann type III GC had a better blood supply than those with type II GC. CONCLUSION: Patients with advanced GC and a GBS are more likely to benefit from neoadjuvant chemotherapy than those with a PBS. Blood supply may thus be a predictor for chemotherapy response.
Assuntos
Adenocarcinoma/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células em Anel de Sinete/mortalidade , Terapia Neoadjuvante/mortalidade , Neoplasias Gástricas/mortalidade , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma de Células em Anel de Sinete/irrigação sanguínea , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Carcinoma de Células em Anel de Sinete/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
In lung cancer, antiangiogenic strategies targeting tumor-derived endothelial cells (TECs) afford a survival advantage, but the characteristics of TECs have not been comprehensively elucidated. Herein, high-purity (> 98%) TECs were obtained, and these cells retained expression of EC markers and exhibited high viability. ITRAQ-2DLC-MS/MS was performed to profile the proteome and the heterogeneity of ECs. Only 31 of 1820 identified proteins were differentially expressed between adenocarcinoma (ADC)- and squamous cell carcinoma (SCC)-derived TECs (TEC-A and TEC-S, respectively), and cadherin-2 (CDH2) was the most significantly upregulated protein in TEC-A samples. Positive immunostaining for CDH2 (score > 3) was significantly more frequent in the endothelium of ADC tissues than in that of SCC tissues. Loss- or gain-of-function analysis showed that CDH2 significantly promoted in vitro and in vivo angiogenesis and sensitivity to the antagonist exherin. The MAPK/ERK and MAPK/JNK signaling pathways may play crucial roles in CDH2-induced HIF-1α/VEGF-mediated angiogenesis. Moreover, high CDH2 expression in TECs was significantly associated with tumor stage, visceral pleural metastasis, and decreased overall survival in patients with ADC but not SCC. Together, these data indicate the importance of CDH2 in angiogenesis and highlight its potential both for antiangiogenic therapy and as a candidate prognostic marker for ADC.
Assuntos
Adenocarcinoma/irrigação sanguínea , Antígenos CD/metabolismo , Caderinas/metabolismo , Carcinoma de Células Escamosas/irrigação sanguínea , Endotélio Vascular/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/irrigação sanguínea , Neovascularização Patológica/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Endotélio Vascular/metabolismo , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Objective: Despite the existence of detailed consensus guidelines, challenges remain regarding the role angiogenetic factors on non-small cell lung cancer (NSCLC). This study was conducted to determine the role of the vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and angiopoietin2 (Ang2) in patients with NSCLC. Methods: This study included 64 consecutive patients with non-small cell lung cancer, who admitted to clinic. Pre-treatment serum VEGF, IL-8 and Ang2 levels were evaluated. Patients were treated according to internationally accepted guidelines. Results: VEGF and IL-8 serum levels of patients with both squamous cell carcinoma and adenocarcinoma were significantly higher than controls (p<0.05). In addition, IL-8 levels were lower among treatment-responders than non-responders (p:0.031). Impact of elevated or decreased levels of VEGF, Ang2 and IL-8 on survival was evaluated, accepting median level as reference. There was no correlation between the serum levels of VEGF, Ang2, IL-8 and survival. Conclusion: We found that the levels of angiogenic markers were significantly different between non-small cell lung cancer patients and controls. These markers could elicit more information related to stage and prognosis.