2022

ENG

endoglin;ENG;endoglin

CD105 antigen

9q34.11

protein-coding

Our purpose was to determine the respective prognostic significance of CD105 and CD31 immunoexpression in node negative patients with breast carcinoma, since angiogenesis induces blood borne metastases and death in carcinomas. CD105 (endoglin) has been reported as expressed by activated endothelial cells and consequently should better reflect neoangiogenesis in malignant tumors. Comparison of CD31 and CD105 immunocytochemical expression was undertaken in a series of 905 breast carcinomas. Results were compared to patients' long-term (median = 11.3 years) outcome. Univariate (Kaplan-Meier) analysis showed that the number of CD105+ microvessels (cut-off 15 vessels) correlated significantly with poor overall survival (p=0.001). This correlation was less significant in node negative patients (p=0.035). The number of CD31+ microvessels (cut-off 25 vessels) similarly correlated with poor survival (p=0.032) but not in the subgroup of node negative patients. Marked CD105 expression also correlated with a high risk for metastasis in all patients (p=0.0002) and in the subset of node negative patients (p=0.001). Similarly metastasis risk in node negative patients correlated with marked CD31 immunocytochemical expression (p=0.02). Multivariate analysis (Cox model) identified CD105, but not CD31 immunoexpression, as an independent prognostic indicator. Our results suggest that: i) in breast carcinomas, immunoselection of microvessels containing activated CD105 labelled endothelial cells is endowed with a stronger prognostic significance, as compared to CD31 vessels labelling; ii) the CD105 immunoexpression may be considered as a potential tool for selecting node negative patients with a poorer outcome and higher metastasis risk; iii) in these patients specific antiangiogenic therapy targeted by anti-CD105 conjugates can be further developed.

Background Endoglin (CD105) is a co-receptor for TGF-beta, is expressed by human vascular endothelial cells, and plays a major role in angiogenesis. Materials and methods Pretreatment EDTA plasma from 224 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial and 50 control subjects were assayed for endoglin using an ELISA. Results The female control group (n = 50) plasma endoglin upper limit of normal was defined as the mean + 2 SD (8.7 ng/ml). The breast cancer patient plasma endoglin was 6.40 +/- 2.23 ng/ml (range 3.00-19.79 ng/ml). Elevated plasma endoglin levels were detected in 26 of 224 patients (11.6%). Patients with elevated plasma endoglin had a reduced clinical benefit rate (CR + PR + Stable) (15 vs. 42%) (P = 0.01) to hormone therapy. TTP was shorter for patients with elevated plasma endoglin, but did not reach statistical significance (P = 0.2). Patients with elevated plasma endoglin had decreased overall survival (median 645 vs. 947 days) (P = 0.005). Conclusion Elevated pretreatment plasma endoglin levels predicted for decreased clinical benefit and a shorter overall survival in metastatic breast cancer patients treated with 2nd-line hormone therapy.

The aim of this study was to investigate the midkine and endoglin expression in breast carcinomas with five different immunohistochemical profiles and their relevance to histopathologic and clinicopathologic features. We analyzed 161 archival tissues immunohistologically. The level of midkine expression in breast cancer significantly correlated with lymph node metastasis (p = 0.001) and TNM staging (p = 0.003). High microvessel density (MVD) was associated with higher midkine reactivity group (p = 0.036). Although the basal-like subtype had higher midkine expression level and MVD, no significant difference with the other breast cancer subtypes was found. In conclusion, midkine was a promising target for tumor prognosis in clinical diagnosis and treatment. This study found no significant differences in tumor angiogenesis in different molecular subtypes of breast cancer.

The liver is the most common and critical site for the development of colon cancer metastases. tumor angiogenesis in liver metastasis from colon carcinoma is a controversial subject. Liver microenvironment, immunophenotypical and morphological particularities of hepatic vessels are only few aspects, which establish difficulties in quantification of tumor vascularisation from liver metastasis. The aim of this work is to study the distribution of CD105 positive vessels and the proliferation rate of endothelial cells from liver metastasis of colon carcinoma based on double immunostaining CD105/Ki67. In liver metastasis from well-differentiated adenocarcinoma we found a high number of CD105+/Ki67- vessels. On the other hand, in liver metastasis from poorly differentiated adenocarcinoma we noticed rare CD105+/Ki67+ vessels. It is hypothesized that neoangiogenesis of liver metastasis is performed through intussusceptive mechanism rather than sprouting and could be supported by the presence of kissing phenomenon, CD105 positive transcapillary pillars and the absence of endothelial cells proliferation in this vessels. We conclude that in liver metastasis principal mechanism of neovascularisation formation is based on intussusception.

In this study, we analyzed the microvessel density (MVD) for CD105+ and alpha-SMA+ vessels and the VEGF immunoexpression in 38 gastric carcinomas. CD105+ MVD had superior values at the advancing edge compared with the intratumoral area, no matter of the analyzed clinico-pathological parameters, the difference being significant only in intestinal type, moderate differentiated carcinomas as well as in T2-T3 carcinomas, without lymph node metastases (p<0.05). Intratumoral expression of CD105+ MVD indicated significant differences related to histological type (p=0.006), depth of invasion (p=0.027) and lymph node metastases (p=0.009), but without statistical association in case of the advancing edge or metastases. The assesses of alpha-SMA+ MVD indicated no differences between intratumoral and advancing edge areas, no matter of the analyzed parameters, excepting intestinal type carcinomas, which presented significant high values (p=0.003) at the advancing edge. VEGF score revealed significant differences related to histological type (p=0.020), differentiation degree of the intestinal type carcinomas (p=0.036) and depth of invasion (p=0.049). In case of metastases, the levels of VEGF expression were higher in the primary tumor, without statistically significant differences (p>0.05). It were significant differences of intratumoral VEGF expression depending on CD105+ MVD values (p=0.019), but not with alpha-SMA+ MVD (p>0.05). Angiogenesis evaluated through the VEGF and MVD (CD105+ and alpha-SMA+) expression is correlated with the progression and metastasis of gastric cancer and could be considered a prognostic marker of these tumors.

The presence of cervical metastasis is responsible for high morbidity and mortality rates in individuals with head and neck squamous cell carcinoma (HNSCC). S100A4, a pleiotropic EF-hand calcium-binding protein, is expressed in various normal and cancer cell types. During cancer progression, molecular disturbances in S100A4 can modulate the activity and expression of pre-metastatic and metastatic genes. In this study, we investigated the association between S100A4 methylation status and protein expression as well as the expression of the S100A4 related-proteins annexin A2 (ANXA2), matrix metallopeptidase-9, and endoglin, for metastasis and other clinicopathological parameters in HNSCC. Formalin-fixed, paraffin-embedded blocks of metastatic and non-metastatic HNSCC and matched cervical lymph node (LN) samples (metastatic LN = mLN, non-metastatic = nmLN, and control LN (lymphadenitis) = cLN) were submitted for methylation specific-polymerase chain reaction and immunohistochemistry. Our results showed that S100A4 methylation status failed to demonstrate association with cervical metastasis and other clinicopathological factors related to HNSCC. HNSCC samples from patients that presented with metastatic disease showed high S100A4 and endoglin expression (p < 0.05). In conclusion, molecular disturbances in S100A4 and endoglin expression might regulate the formation of cervical metastasis in HNSCC.

OBJECTIVE: To explore the expressions of thymidine phosphorylase (TP), midkine (MK) and MVD marked with CD105 antibody in laryngeal squamous cell carcinoma (LSCC) and their clinical significance. METHOD: The expressions of TP, MK and CD105 in LSCC tissues of 43 cases were studied by immunohistochemical staining. RESULT: The positive expression rates of TP and MK in LSCC were 67.4% and 60.5% respectively, the mean value of MVD was 6.01 +/- 1.78. MVD was significantly higher in tumor tissue with both positive TP and MK than in that with both negative TP and MK (7.07 +/- 3.26 vs. 4.03 +/- 1.90, P < 0.05). The expression of TP, MK and CD105 were all correlated with T-stage and lymph node metastasis. Positive TP, MK expression and high MVD were all associated with a poor survival, and positive expression of both TP and MK in tumors conferred a poorer prognosis than negative expression of those factors in tumors, but only the lymph node metastasis and MVD were independent prognostic factors on multivariate analysis. CONCLUSION: Both TP and MK are important for angiogenesis in LSCC. TP, MK and angiogenesis are all closely correlated with the progress of LSCC and the lymph node metastasis. The lymph node metastasis and MVD marked with CD105 antibody were independent prognostic factors. TP and MK may affect the progression and prognosis of tumor by promotion of angiogenesis. A combinative detection of TP, MK and CD105 can be as valuable tumor marker and prognostic factor for LSCC.

OBJECTIVE: To investigate the expression of endoglin (ENG) in human non small cell lung cancer (NSCLC) cell lines, cancer and adjacent non-cancer tissues, and its role in NSCLC development, progression, metastasis and recurrence. METHODS: Five strains of NSCLC cells and one strain of normal human bronchial epithelial (HBE) cells were cultured in vitro. Human NSCLC tissues and their corresponding adjacent lung tissues were taken from 22 NSCLC cases to detect the mRNA and protein levels of ENG using real-time PCR and Western blotting, respectively. Chi-square test was performed to analyze the correlations between the ENG expression and clinical data. RESULTS: The mRNA and protein levels of ENG were up-regulated in 3 NSCLC cell strains of high metastasis. However, the expression of ENG was missing in the other low-metastatic NSCLC cell strains and the HBE cell strain. Besides, the mRNA and protein levels of ENG were up-regulated in the 19 out of 22 lung cancer tissues (86.36%), which were significantly higher than those in the adjacent non-cancer tissues (P<0.01). The over-expression of ENG was significantly correlated positively with lymph node metastasis (P<0.01), but not with age, sex, tumor size, clinical stage, pathological grade or histopathological type. CONCLUSION: The expression of ENG in NSCLC is significantly correlated positively with lymph node metastasis, and it might be a biomarker for the metastasis and prognosis of NSCLC.

PURPOSE: Current predictive tools and imaging modalities are not accurate enough to preoperatively diagnose lymph node metastases in patients with prostate cancer. The aim of the study was to evaluate whether preoperative plasma endoglin improves the prediction of lymph node metastases in patients with clinically localized prostate cancer. EXPERIMENTAL DESIGN: Endoglin levels were measured using a commercially available ELISA assay in banked plasma from 425 patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma at two university hospitals between July 1994 and November 1997. Logistic regression analyses were undertaken to evaluate whether endoglin improves the accuracy of a standard preoperative model for prediction of lymph node metastasis and to build a predictive nomogram. RESULTS: Preoperative plasma endoglin levels were higher in patients with higher preoperative total serum prostate-specific antigen (PSA; Spearman correlation coefficient 0.296, P < 0.001), positive surgical margins (P = 0.03), higher pathologic Gleason sum (P = 0.04), and lymph node metastasis (P < 0.001). In a preoperative multivariable logistic regression analysis that included PSA and clinical stage, only preoperative endoglin (odds ratio, 1.17; 95% confidence interval, 1.09-1.26; P < 0.001) and biopsy Gleason sum (odds ratio, 18.57; 95% confidence interval, 1.08-318.36; P = 0.04) were associated with metastasis to lymph nodes. The addition of endoglin to a standard preoperative model (including PSA, clinical stage, and biopsy Gleason sum) significantly improved its accuracy for prediction of lymph node metastasis from 89.4% to 97.8% (P < 0.001). CONCLUSIONS: Preoperative plasma endoglin improves the accuracy for prediction of pelvic lymph node metastasis in patients treated with radical prostatectomy for clinically localized prostate cancer by a statistically and clinically significant margin.

Endoglin is a transmembrane receptor that suppresses human prostate cancer (PCa) cell invasion. Small molecule therapeutics now being tested in humans can activate endoglin signaling. It is not known whether endoglin can regulate metastatic behavior, PCa tumor growth, nor what signaling pathways are linked to these processes. This study sought to investigate the effect of endoglin on these parameters. We used a murine orthotopic model of human PCa metastasis, designed by us to measure effects at early steps in the metastatic cascade, and implanted PCa cells stably engineered to express differing levels of endoglin. We now extend this model to measure cancer cells circulating in the blood. Progressive endoglin loss led to progressive increases in the number of circulating PCa cells as well as to the formation of soft tissue metastases. Endoglin was known to suppress invasion by activating the Smad1 transcription factor. We now show that it selectively activates specific Smad1-responsive genes, including JUNB, STAT1, and SOX4. Increased tumor growth and increased Ki67 expression in tissue was seen only with complete endoglin loss. By showing that endoglin increased TGFbeta-mediated suppression of cell growth in vitro and TGFbeta-mediated signaling in tumor tissue, loss of this growth-suppressive pathway appears to be implicated at least in part for the increased size of endoglin-deficient tumors. Endoglin is shown for the first time to suppress cell movement out of primary tumor as well as the formation of distant metastasis. It is also shown to co-regulate tumor growth and metastatic behavior in human PCa.