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Endoglin (ENG) is expressed on the surface of endothelial cells (ECs) where it efficiently binds circulating BMP9 and BMP10 ligands to initiate activin A receptor like type 1 (ALK1) protein signalling to protect the vascular architecture. Patients heterozygous for ENG or ALK1 mutations develop the vascular disorder known as hereditary haemorrhagic telangiectasia (HHT). Many patients with this disorder suffer from anaemia, and are also at increased risk of stroke and high output heart failure. Recent work using animal models of HHT has revealed new insights into cellular and molecular mechanisms causing this disease. Loss of the ENG (HHT1) or ALK1 (HHT2) gene in ECs leads to aberrant arteriovenous connections or malformations (AVMs) in developing blood vessels. Similar phenotypes develop following combined EC specific loss of SMAD1 and 5, or EC loss of SMAD4. Taken together these data point to the essential role of the BMP9/10-ENG-ALK1-SMAD1/5-SMAD4 pathway in protecting the vasculature from AVMs. Altered directional migration of ECs in response to shear stress and increased EC proliferation are now recognised as critical factors driving AVM formation. Disruption of the ENG/ALK1 signalling pathway also affects EC responses to vascular endothelial growth factor (VEGF) and crosstalk between ECs and vascular smooth muscle cells. It is striking that the vascular lesions in HHT are both localised and tissue specific. Increasing evidence points to the importance of a second genetic hit to generate biallelic mutations, and the sporadic nature of such somatic mutations would explain the localised formation of vascular lesions. In addition, different pro-angiogenic drivers of AVM formation are likely to be at play during the patient's life course. For example, inflammation is a key driver of vessel remodelling in postnatal life, and may turn out to be an important driver of HHT disease. The current wealth of preclinical models of HHT has led to increased understanding of AVM development and revealed new therapeutic approaches to treat AVMs, and form the topic of this review.
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The outcome of colorectal cancer (CRC) can be improved by the identification of prognostic biomarkers. This systematic review of observational cohort and case-control studies was conducted to investigate the role of Endoglin (CD105) in the prognosis of CRC. The databases PubMed, Web of Science, Scopus, and Cochrane CENTRAL were searched to identify the qualified studies using the relevant keywords. After the removal of duplicate articles, the screening was implemented on the titles, abstracts, and potential full-text articles. Afterward, the eligible cohort and case-control studies were identified, and the data were extracted into an Excel datasheet. In total, 11 observational cohort studies and 1 case-control study were identified to be eligible for this systematic review. The majority of the included studies achieved a moderate to high-degree quality according to the Newcastle-Ottawa Scale. Moreover, the eligible studies included a total of 1,400 patients with CRC and mean age of 60 years, the majority of whom were male. Endoglin was observed to be more upregulated in colorectal carcinomas and associated with poor survival outcomes, compared to healthy controls. The levels of Endoglin seem to reflect the degree of cancer invasiveness, therefore predicting dismal prognosis in patients with CRC. Larger and well-designed clinical studies with longer follow-up intervals are needed to investigate the role of Endoglin and its association with cancer metastasis.
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Background: Breast cancer is the leading cause of cancer-related deaths in Asia and is emerging as the commonest female malignancy. Angiogenesis or neovascularization is important for the growth and spread of malignant tumors, and quantitative assessment of angiogenesis may prove valuable in prognostication. This study was undertaken to quantify and explore angiogenesis with immunohistochemistry with CD 34, CD 105, and vascular endothelial growth factor (VEGF), as well as morphometric analysis and correlate with the grades of the invasive breast carcinoma. Methods: Angiogenesis was assessed by morphometry and immunohistochemistry. Seventy cases of invasive ductal carcinoma (IDC) and twenty-five benign cases as controls were included in the study. Morphometry was performed on the CD34 and CD105 (Endoglin) stained representative histologic sections with the use of a computerized digital photomicrograph system using image analyzing software. Morphometric analysis and evaluation of vascular parameters, i.e. microvessel density (MVD), microvessel caliber (VC), and total microvessel boundary density (TVBD), were calculated. Semiquantitative assessment of angiogenesis of VEGF-stained sections was done by scoring. Immunohistochemical staining was correlated with the histological grade of the tumors. MVD, mean VC, TVBD with their mean values, SD, and range were calculated using Statistical Package for The Social Sciences (Version 20). One-way analysis of variance (ANOVA) with Tukey HSD was performed to assess the difference of the parameters for the groups. Spearman rank correlation coefficients ρ were calculated. Results: The vascular parameters were significantly more in malignant lesions as compared to benign lesions and showed differences with increasing grade. Grades of breast carcinoma showed a mild positive correlation with VEGF (ρ = 0.467), MVD-CD34 (ρ = 0.422) and VC-CD34 (ρ = 0.482); and moderate positive correlation with TVBD-CD34 (ρ = 0.615), VC-CD105 (ρ = 0.527), and TVBD-CD105 (ρ = 0.354). When these parameters were compared with each other for all four groups, VEGF showed a mild positive correlation with MVD-CD34 (ρ = 0.295), TVBD-CD34 (ρ = 0.339), and TVBD-CD105 ((ρ = 0.277). MVD-CD105 showed a mild positive correlation with MVD-CD34 TVBD-CD105 also showed a strong positive correlation with MVD-CD34. VC-CD105 showed a moderate positive correlation with VC-CD34. CD 105 stained fewer but larger caliber vessels. Conclusions: In this study, vascular parameters showed significant differences in three grades of IDC with CD34. Differences were seen in vascular parameters stained with CD105 in three grades of IDC. Expression of VEGF also showed significant differences with positive correlations in the three grades of IDC. CD34 highlighted both old and newly formed microvessels. CD 105 stained fewer but larger caliber microvessels. VC-CD105 can be an extremely useful adjunct along with VEGF and CD34 to study angiogenesis of vessels in IDC.
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Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal-dominant genetic disorder involving defects in two predominant genes known as endoglin (ENG; HHT-1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT-2). It is characterized by mucocutaneous telangiectases that, due to their fragility, frequently break causing recurrent epistaxis and gastrointestinal bleeding. Because of the severity of hemorrhages, the study of the hemostasis involved in these vascular ruptures is critical to find therapies for this disease. Our results demonstrate that HHT patients with high bleeding, as determined by a high Epistaxis Severity Score (ESS), do not have prolonged clotting times or alterations in clotting factors. Considering that coagulation is only one of the processes involved in hemostasis, the main objective of this study was to investigate the overall mechanisms of hemostasis in HHT-1 (Eng +/-) and HHT-2 (Alk1 +/-) mouse models, which do not show HHT vascular phenotypes in the meaning of spontaneous bleeding. In Eng +/- mice, the results of in vivo and in vitro assays suggest deficient platelet-endothelium interactions that impair a robust and stable thrombus formation. Consequently, the thrombus could be torn off and dragged by the mechanical force exerted by the bloodstream, leading to the reappearance of hemorrhages. In Alk1 +/- mice, an overactivation of the fibrinolysis system was observed. These results support the idea that endoglin and Alk1 haploinsufficiency leads to a common phenotype of impaired hemostasis, but through different mechanisms. This contribution opens new therapeutic approaches to HHT patients' epistaxis.
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BACKGROUND: The most commonly used prognostic factors in acute myeloid leukemia (AML) are cytogenetic, molecular, and morphological markers. However, AML prognosis is still unfavorable particularly in adults. So, further reliable markers are urgently needed to improve the risk stratification and treatment decisions. CUB domain-containing protein 1 (CDCP1; CD318) and endoglin (CD105) are new markers correlated with poor prognosis in different solid tumors, but their role in AML prognosis is not fully evaluated. OBJECTIVES: This work aimed to evaluate the prognostic role of CD318 and CD105 in AML and their impact on the outcomes. METHODS: Sixty-five newly diagnosed AML patients were included in this study. CD318 and CD105 expression was assessed by quantitative real-time polymerase chain reaction. Patients were followed up for â¼ 2 years to evaluate the prognostic impact of gene expression on the outcomes. RESULTS: Patients with high CD318 and CD105 showed higher white blood cell (WBC) count, M2 subtype, poor cytogenetic risk, reduced complete remission, and a greater number of deaths compared to low CD318 and CD105. CD318 was correlated with CD105, and both were correlated with WBC count, bone marrow blasts, and peripheral blood blasts. After a follow-up period of up to 24 months, relapse-free survival for high CD318 and CD105 was significantly different (42.1% and 52.6% vs. 64.5% and 58.1% for low CD318 and CD105, respectively). Survival was worse in patients with high CD318 and CD105, as the mean survival time was 13.9 and 13.3 months compared to 24 and 22.7 months in low CD318 and CD105, respectively. CONCLUSIONS: CD318 and CD105 are upregulated in AML patients. Their overexpression was associated with poor response to treatment and poor outcomes. Therefore, CD318 and CD105 can be useful prognostic markers in AML.
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Antígenos de Neoplasias , Moléculas de Adhesión Celular , Endoglina , Leucemia Mieloide Aguda , Adulto , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Médula Ósea/metabolismo , Médula Ósea/patología , Moléculas de Adhesión Celular/metabolismo , Endoglina/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Pronóstico , Inducción de RemisiónRESUMEN
Microvascular proliferation is a key feature of glioblastoma and neovascularization has been implicated in tumor progression. Glioblastomas use pro-angiogenic factors such as vascular endothelial growth factor (VEGF) for new blood vessel formation. Yet, anti-VEGF therapy does not prolong overall survival so that alternative angiogenic pathways may need to be explored as drug targets. Both glioma cells and glioma-associated endothelial cells produce TGF-ß superfamily ligands which bind TGF-ß receptors (TGF-ßR). The TGF-ßR type III endoglin (CD105), is a marker of proliferating endothelium that has already been studied as a potential therapeutic target. We studied endoglin expression in glioblastoma tissue and in glioma-associated endothelial cells in a cohort of 52 newly diagnosed and 10 recurrent glioblastoma patients by immunohistochemistry and by ex vivo single-cell gene expression profiling of 6 tumors. Endoglin protein levels were similar in tumor stroma and endothelium and correlated within tumors. Similarly, endoglin mRNA determined by ex vivo single-cell gene expression profiling was expressed in both compartments. There was positive correlation between endoglin and proteins of TGF-ß superfamily signaling. No prognostic role of endoglin expression in either compartment was identified. Endoglin gene silencing in T98G glioma cells and in human cerebral microvascular endothelial cells (hCMEC) did not affect constitutive or exogenous TGF-ß superfamily ligand-dependent signaling, except for a minor facilitation of pSmad1/5 signaling in hCMEC. These observations challenge the notion that endoglin might become a promising therapeutic target in glioblastoma.
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Neoplasias Encefálicas/metabolismo , Endoglina/fisiología , Glioblastoma/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Línea Celular Tumoral , Humanos , Neovascularización PatológicaRESUMEN
BACKGROUND: Colorectal cancer (CRC) is an important current problem concerning public health due to its high incidence and mortality. Advances in molecular and cellular knowledge and the detection of new disease biomarkers are very important to improve prognosis, prediction, and early diagnosis. In this study, we aimed to analyze the gene and protein expression levels of two angiogenic markers, VEGF and soluble Endoglin, during different tumor stages as well as at different stages of cancer treatment, to predict the diagnosis and evolution of colon and rectal cancer. MATERIAL AND METHODS: This study includes 133 CRC patients (93 with colon cancer and 40 with rectal cancer) on which the gene and protein expression of Endoglin (membrane and soluble form) and VEGF were analyzed by molecular and immunohistochemical techniques on different tumor stage samples and plasma obtained preoperatively as well as 3, 6, and 9 months after resection of the tumor. RESULTS: VEGF and Endoglin gene expressions were higher in tumor tissue than in surrounding non-tumoral tissue for both types of cancer. The VEGF levels in plasma were found to decrease in less aggressive tumors, whereas soluble Endoglin was increased in preoperative samples of patients with metastasis. Membrane Endoglin expression was higher on the vascular endothelium of more aggressive tumors. In contrast, Endoglin expression was mainly in the colon epithelium in less aggressive stage tumors. CONCLUSION: Endoglin and VEGF are proteins with a major role in the tumor angiogenesis process. This study performed with a wide cohort of human samples shows that both proteins seem to be valuable biomarkers in the diagnosis and prognosis of CRC.
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Biomarcadores de Tumor/sangre , Neoplasias del Colon/diagnóstico , Endoglina/sangre , Neovascularización Patológica/diagnóstico , Neoplasias del Recto/diagnóstico , Factor A de Crecimiento Endotelial Vascular/sangre , Anciano , Biomarcadores de Tumor/metabolismo , Colectomía , Colon/patología , Colon/cirugía , Neoplasias del Colon/sangre , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Endoglina/metabolismo , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neovascularización Patológica/sangre , Neovascularización Patológica/patología , Neovascularización Patológica/cirugía , Proctectomía , Pronóstico , Estudios Prospectivos , Neoplasias del Recto/sangre , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Recto/patología , Recto/cirugía , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
: Most high-grade serous ovarian cancers (HGSCs) initiate from the fallopian tube epithelium and then metastasize to the ovary and throughout the abdomen. Genomic analyses suggest that most HGSCs seed the ovary prior to abdominal dissemination. Similarly, animal models support a critical role for the ovary in driving abdominal dissemination. Thus, HGSC cell recruitment to the ovary appears to be a critical component of HGSC cell metastasis. We sought to identify factors driving HGSC recruitment to the ovary. We identified CD105 (endoglin, or ENG, a TGF-ï¢ receptor family member) as a mediator of HGSC cell ovarian recruitment. We found that CD105 was expressed on both serous tubal intraepithelial carcinoma (STIC) cells (STICs-HGSC precursors in the fallopian tube epithelium) and HGSC cells. Using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), we showed that high CD105 expression by HGSC cells correlated with a metastatic signature. Furthermore, intravenous injection of CD105(+) HGSC tumor cells, but not CD105(-), resulted in ovarian-specific metastasis and abdominal dissemination of disease. CD105 knockdown or blockade with a clinically relevant CD105-neutralizing mAb (TRC105), inhibited HGSC metastasis, reduced ascites, and impeded growth of abdominal tumor nodules, thereby improving overall survival in animal models of ovarian cancer. CD105 knockdown was associated with a reduction in TGF-ï¢ï signaling. Together, our data support CD105 as a critical mediator of ovarian cancer spread to the ovary and implicate it as a potential therapeutic target.
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The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor ß (TGF-ß) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma Hepatocelular , Endoglina/biosíntesis , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hepáticas , Proteínas de Neoplasias/biosíntesis , Neovascularización Patológica , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patologíaRESUMEN
BACKGROUND: The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31. METHODS: Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients. RESULTS: We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%-97%) compared to patients with higher values (40%, 95%CI, 12%-67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio. CONCLUSION: CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.
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Endoglina/genética , Neovascularización Patológica/genética , Rabdomiosarcoma/genética , Adolescente , Biomarcadores de Tumor/genética , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Recién Nacido , Masculino , Neovascularización Patológica/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Rabdomiosarcoma/patología , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
OBJECTIVE: To assess the expression of Endoglin (CD-105) and Microvessel Density in clinically normal oral mucosa of non-tobacco and tobacco habituated patients & also histopathologically confirmed cases of oral squamous cell carcinoma (OSCC) patients. MATERIALS AND METHODS: Twenty cases of clinically normal oral mucosa with tobacco habituation in the form of chewing or smoking, 20 histopathologically confirmed cases of OSCC and twelve normal healthy oral mucosal cases without tobacco habituation in any form, served as control group, were immunohistochemically analysed for expression of Endoglin (CD-105). Chi-square test is used to determine statistical analysis and significance. RESULT & CONCLUSION: The finding of 65% of Endoglin CD - 105 positivity and microvessel density (MVD) in the mucosal specimens of tobacco users may be attributed as neoangiogenesis or angiogenic squamous dysplasia like phenomenon occurring as important pathological biomarker preceding oral cancer development, and may therefore be useful as a predictive marker of malignancy.
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BACKGROUND: Angiogenic molecular markers such as vascular endothelial growth factor and tumor microvessel density reflect prognosis of human cancers. The present study clarified the usefulness of endothelial marker endoglin (CD 105) by assessing microvessel density in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: We immunohistochemically investigated CD105, CD31, and vascular endothelial growth factor-A VEGF-A expression in primary esophageal squamous cell carcinoma specimens from 142 patients. RESULTS: Microvessel density was 35.9±21.2 for CD105 and 46.3±25.4 for CD31. CD105 microvessel density was significantly associated with tumor length, tumor invasion depth, lymph node metastasis, stage, lymphatic invasion, venous invasion, and VEGF-A expression; its correlation with almost all clinicopathological parameters was stronger than CD31 microvessel density. And significantly better prognosis was achieved in patients with low, compared to high CD105, microvessel density. CONCLUSION: CD105 microvessel density reflected the degree of angiogenesis and prognosis in patients with esophageal squamous cell carcinoma.
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Antígenos CD/biosíntesis , Carcinoma de Células Escamosas/irrigación sanguínea , Neoplasias Esofágicas/irrigación sanguínea , Receptores de Superficie Celular/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/biosíntesis , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Endoglina , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/biosíntesis , Pronóstico , Estudios Retrospectivos , Factor A de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
BACKGROUND: The purpose of this study was to examine endoglin (CD105) expression on microvessel endothelial cells (ECs) in juvenile nasopharyngeal angiofibroma (JNA) and its relationship with recurrence. METHODS: Immunohistochemistry was performed to detect CD105 expression in a tissue microarray from 70 patients with JNA. Correlation between CD105 expression on microvessel ECs and clinicopathological features, as well as tumor recurrence, were analyzed. RESULTS: Immunohistochemistry revealed CD105 expression on ECs but not in stroma of patients with JNA. Chi-square analysis indicated CD105-based microvessel density (MVD) was correlated with JNA recurrence (p = .013). Univariate and multivariate analyses determined that MVD was a significant predictor of time to recurrence (p = .009). The CD105-based MVD was better for predicting disease recurrence (AUROC: 0.673; p = .036) than other clinicopathological features. CONCLUSIONS: MVD is a useful predictor for poor prognosis of patients with JNA after curative resection. Angiogenesis, which may play an important role in the occurrence and development of JNA, is therefore a potential therapeutic target for JNA.
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Angiofibroma/irrigación sanguínea , Antígenos CD/metabolismo , Células Endoteliales/metabolismo , Microvasos/citología , Neoplasias Nasofaríngeas/irrigación sanguínea , Receptores de Superficie Celular/metabolismo , Adolescente , Adulto , Angiofibroma/metabolismo , Angiofibroma/patología , Angiofibroma/cirugía , Niño , Endoglina , Humanos , Inmunohistoquímica , Masculino , Análisis Multivariante , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/cirugía , Recurrencia Local de Neoplasia/metabolismo , Pronóstico , Curva ROC , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
The pseudocapsule (PC) of the uterine leiomyoma (UL) is an anatomic entity that surrounds the myoma separating it from the myometrium (UM). Although a number of microarray experiments have identified differences in gene expression profile in the UL when compared with the UM, there is a lack of systematic studies on the PC. In this study, quantitative RT-PCR analysis was performed on 18 matched PC, UL and UM specimens and results showed that the PC displays a specific gene expression profile. The low expression level of insulin-like growth factor (IGF-2), a fibroid specific marker, that we found in the PC and the UM when compared with the UL, clearly indicates that the PC is in structural continuity with the UM. However, the significant increase in endoglin expression level in PC with respect to the UL and UM indicates that an active neoangiogenesis is present in PC. Conversely, other angiogenic factors such as von Willebrand factor (vWF) and vascular endothelial growth factor A (VEGF-A) seem to have little influence on the PC angiogenesis. Because the endoglin is preferentially expressed in proliferating endothelial cells, whereas the vWF and VEGF-A are preferentially expressed in preexisting endothelial cells, our idea is that the angiogenic activity in the PC is linked to wound healing. The angiogenic activity is also sustained by intermediate expression level of cystein-rich angiogenesis inducer 61, connective tissue growth factor and collagen 4α2 genes all involved in the neoangiogenesis, that we detected in the PC. Taken together our data demonstrate that the specific expression pattern observed in the PC could be the response of the uterine wall's smooth cells to the tension imposed by the tumor. As a consequence, a neovascular structure is generated involving regenerative processes. For these reasons, we suggest that the laparoscopic intracapsular myomectomy (LIM), a new surgical technique that preserves the PC during the UL removal, should always be preferred, to favor a faster and proper uterine healing.
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Antígenos CD/genética , Expresión Génica , Factor II del Crecimiento Similar a la Insulina/genética , Leiomioma/irrigación sanguínea , Miometrio/irrigación sanguínea , Receptores de Superficie Celular/genética , Neoplasias Uterinas/irrigación sanguínea , Adulto , Anciano , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Proteína 61 Rica en Cisteína/genética , Proteína 61 Rica en Cisteína/metabolismo , Endoglina , Femenino , Perfilación de la Expresión Génica , Humanos , Factor II del Crecimiento Similar a la Insulina/metabolismo , Leiomioma/genética , Leiomioma/patología , Leiomioma/cirugía , Persona de Mediana Edad , Miometrio/metabolismo , Miometrio/patología , Miometrio/cirugía , Neovascularización Patológica , Receptores de Superficie Celular/metabolismo , Miomectomía Uterina/métodos , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugía , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismoRESUMEN
Endoglin (CD105) is an accessory receptor of transforming growth factor B. The highest synthesis, as well as expression, of endoglin has been found in vascular endothelial cells. The involvement of endoglin in angiogenesis and in angiogenesis-dependent processes has been observed. Endoglin promotes angiogenesis not only by activation of vascular endothelial cell proliferation but also by induction of the antiapoptotic pathway in hypoxic endothelial cells. The potential application of endoglin as a tumour angiogenesis marker, useful for cancer diagnostics and clinical application, is anticipated. Endoglin expression may be useful as an indicator of disease progression and helpful for estimation of recurrence and metastasis risk.
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The type 2 ribosome-inactivating proteins (RIPs) isolated from some species belonging to the Sambucus genus, have the characteristic that although being even more active than ricin inhibiting protein synthesis in cell-free extracts, they lack the high toxicity of ricin and related type 2 RIPs to intact cells and animals. This is due to the fact that after internalization, they follow a different intracellular pathway that does not allow them to reach the cytosolic ribosomes. The lack of toxicity of type 2 RIPs from Sambucus make them good candidates as toxic moieties in the construction of immunotoxins and conjugates directed against specific targets. Up to now they have been conjugated with either transferrin or anti-CD105 to target either transferrin receptor- or endoglin-overexpressing cells, respectively.