Endoglin (CD105) as a urinary and serum marker of prostate cancer

We have previously shown that endoglin (CD105) is upregulated in prostatic fluid of men with large volume prostate cancer. We chose to assess endoglin levels in urine and serum from men with prostate cancer or at increased risk for the disease: Urine samples were collected after digital rectal examination (DRE) from 99 men whose cancer status was confirmed by biopsy, and serum samples were collected from 20 men without prostate cancer at low risk for the disease and from 69 men diagnosed with prostate cancer that subsequently underwent radical prostatectomy (30 pT2, 39 pT3). Endoglin levels were assessed by ELISA. Urinary endoglin was elevated in men with biopsy‐positive prostate cancer compared to biopsy‐negative men (p = 0.0014). Urinary endoglin levels in men with prostate cancer correlated with radical prostatectomy tumor volume. The area under the receiver operating characteristic (ROC) curve was 0.72 for urinary endoglin and 0.50 for serum prostate‐specific antigen (PSA; sensitivity for cancer detection 73%, specificity 63%). There were no differences in serum endoglin between normal and cancer cases, but there were increases in serum endoglin in non‐organ confined (NOC, pT3+) versus organ‐confined (OC, pT2) cases (p = 0.0004). The area under the ROC curve was 0.75 for serum endoglin and 0.63 for PSA for predicting NOC status, with a sensitivity of 67% and a specificity of 80%. In conclusion, elevations in post‐DRE urinary endoglin suggest there may be value in further studying endoglin as a urinary biomarker of prostate cancer. Endoglin levels in both urine and serum may aid in prostate cancer detection and prognostication. © 2008 Wiley‐Liss, Inc.     

Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy

: (1) To determine whether exposure of phosphatidylserine (PS) occurs on vascular endothelium in solid tumors in mice. (2) To determine whether PS exposure can be induced on viable endothelial cells in tissue culture by conditions present in the tumor microenvironment.

: Externalized PS in vivo was detected by injecting mice with a monoclonal anti-PS antibody and examining frozen sections of tumors and normal tissues for anti-PS antibody bound to vascular endothelium. Apoptotic cells were identified by anti-active caspase-3 antibody or by TUNEL assay. PS exposure on cultured endothelial cells was determined by ¹²⁵I-annexin V binding.

: Anti-PS antibody bound specifically to vascular endothelium in six tumor models. The percentage of PS-positive vessels ranged from 4% to 40% in different tumor types. Vascular endothelium in normal organs was unstained. Very few tumor vessels expressed apoptotic markers. Hypoxia/reoxygenation, acidity, inflammatory cytokines, thrombin, or hydrogen peroxide induced PS exposure on cultured endothelial cells without causing loss of viability.

: Vascular endothelial cells in tumors, but not in normal tissues, externalize PS. PS exposure might be induced by tumor-associated oxidative stress and activating cytokines. PS is an abundant and accessible marker of tumor vasculature and could be used for tumor imaging and therapy.     

Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels

Among surface molecules expressed on endothelial cells, endoglin (CD105) is emerging as a prime vascular target for antiangiogenetic cancer therapy. CD105 is a cell membrane glycoprotein mainly expressed on endothelial cells and overexpressed on tumor-associated vascular endothelium, which functions as an accessory component of the transforming growth factor -beta receptor complex and is involved in vascular development and remodelling. Quantification of intratumoral microvessel density by CD105 staining and of circulating soluble CD105 has been suggested to have prognostic significance in selected neoplasias. In addition, the potential usefulness of CD105 in tumor imaging and antiangiogenetic therapy has been well documented utilizing different animal models.     

Endoglin (CD105): a review of its role in angiogenesis and tumor diagnosis, progression and therapy

Endoglin (CD105) is an accessory receptor for transforming growth factor beta (TGF-β) and its expression is up-regulated in actively proliferating endothelial cells. Endoglin has been suggested as an appropriate marker for tumor-related angiogenesis and neovascularization. Several studies demonstrate the potential of endoglin in tumor diagnosis, prognosis, and therapy. This review details the structure and function of endoglin, and investigates the role of endoglin in angiogenesis and tumor diagnosis, prognosis, and therapy.     

CD25: A potential tumor therapeutic target

CD25 is the alpha-chain of the heterotrimer IL-2 receptor. CD25 is expressed on the surface of both immune and non-immune cells with different frequencies. For cancers, CD25 is expressed at high levels in many types of hematological malignancies, but at low levels in most solid tumors. CD25 is also highly expressed in activated circulating immune cells and regulatory T cells (Tregs). Infiltration of Tregs in the tumor microenvironment can lead to an imbalanced ratio of effector T cells (Teffs) and Tregs, which is associated with the progression of cancers. A rescued Teff/Treg cell ratio indicates an efficient anti-tumor response to immunotherapy. CD25 as a potential target for the depletion of Tregs is critical in developing new immunotherapeutic strategies. Few articles have summarized the relationships between CD25 and tumors, or the recent progress of drugs targeting CD25. In this paper, we will discuss the structures of IL-2 and IL-2R, the biological function of CD25 and its important role in tumor therapy. In addition, the latest research on drugs targeting CD25 has been summarized, providing guidance for future drug development.     

Endoglin (CD105) expression in non-neoplastic and neoplastic human tissues and human cancer cell lines

Endoglin is an integral membrane glycoprotein that binds TGF-beta(1,3) with high affinity and is thought to play an important role in modulating the interaction of TGF-beta with its cell surface receptors. In this study a recently characterized monoclonal antibody (29-G8) recognizing endoglin was used to examine expression in a variety of human tissues and human cancer cell lines. Formalin-fixed, paraffin-embedded sections were examined by light microscopy and cell lines were analyzed by now cytometry. Immunostaining was noted in a variety of non-neoplastic epithelia from different organs; most of the neoplastic tissues surveyed also demonstrated prominent immunoreactivity for 29-G8. Flow cytometric analysis of the cell lines revealed strong 29-G8 immunoreactivity in almost all lines examined. Our results suggest that endoglin expression is much more ubiquitous than was previously thought and that endoglin may play a role in modulating TGF-beta binding activity in a variety of normal and neoplastic human tissues.     

Tumour vasculature as a target for anticancer therapy

The development of a blood supply is crucial to the growth and metastasis of cancer. The factors involved in this are complex, however tumour hypoxia and macrophage infiltration are responsible for the synthesis of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF) and the fibroblast growth factors. These factors stimulate proliferation of vascular endothelial cells, the synthesis of proteases such as urokinase type plasminogen activator (uPA) and the matrix metalloproteases, which result in digestion of the extracellular matrix and allow endothelial cell invasion. Endothelial cell motility is promoted by binding of extracellular matrix proteins such as vitronectin and fibronectin to integrins expressed on the plasma membrane of endothelial cells. Interfering with any of these steps may inhibit the process of angiogenesis and drugs aimed at modulation of angiogenesis are currently undergoing evaluation in early clinical studies. This paper reviews our current understanding of angiogenesis and how it may be used as a target for the treatment of cancer.     

Endoglin (CD105) expression in ovarian serous carcinoma effusions is related to chemotherapy status

Endoglin (CD105), a cell surface co-receptor for transforming growth factor-β, is expressed in proliferating endothelial cells, as well as in cancer cells. We studied endoglin expression and its clinical relevance in effusions, primary tumors, and solid metastatic lesions from women with advanced-stage ovarian serous carcinoma. Endoglin expression was analyzed by immunohistochemistry in effusions (n = 211; 174 peritoneal, 37 pleural). Cellular endoglin staining was analyzed for association with the concentration of soluble endoglin (previously determined by ELISA) in 95 corresponding effusions and analyzed for correlation with clinicopathologic parameters, including survival. Endoglin expression was additionally studied in 34 patient-matched primary tumors and solid metastases. Carcinoma and mesothelial cells expressed endoglin in 95/211 (45%) and 133/211 (63%) effusions, respectively. Carcinoma cell endoglin expression was more frequent in effusions from patients aged ≤60 years (p = 0.048) and in post- compared to prechemotherapy effusions (p = 0.014), whereas mesothelial cell endoglin expression was higher in prechemotherapy effusions (p = 0.021). No association was found between cellular endoglin expression and its soluble effusion concentration. Endoglin was expressed in 17/34 (50%) primary tumors and 19/34 (56%) metastases, with significantly higher percentage of immunostained cells in solid metastases compared to effusions (p = 0.036). Endoglin expression did not correlate with survival. Tumor cell endoglin expression is higher in post- vs. prechemotherapy effusions, whereas the opposite is seen in mesothelial cells. Together with its upregulation in solid metastases, this suggests that the expression and biological role of endoglin may differ between cell populations and change along tumor progression in ovarian carcinoma.     

CD133与肿瘤干细胞靶向治疗

CD133是肿瘤干细胞的表面标记物,在多种实体肿瘤中都有表达,且与肿瘤的化疗抵抗和放疗抵抗有关.CD133作为一种跨膜糖蛋白,其潜在的肿瘤干细胞靶向治疗的分子靶点作用备受关注,有望为肿瘤治疗提供新希望.     

CA 125: a potential tumor marker for gallbladder cancer

BACKGROUND: CA 125 is a glycoprotein and a commonly used tumor marker in ovarian carcinoma. Its use in gallbladder carcinoma (GBC) has not yet been reported. We have henceforth examined for the first time the diagnostic utility of CA 125 in patients with gallbladder diseases. PATIENTS AND METHODS: Serum CA 125 was measured in 64 patients with GBC, 47 Gallstone disease (GSD) and 23 healthy volunteers by ELISA. CA 125 level was compared between different cohorts by non-parametric test (Kruskal Wallis and Mann-Whitney test). Receiver operating characteristic curve (ROC) was constructed to see the diagnostic utility of CA 125. Its level was also correlated with age, sex and clinico-pathological parameters of the patients included in the study. RESULTS: Mean value of CA 125 in patients with GBC, GSD and healthy volunteers was 77.44 +/- 141.31 U/ml, 7.85 +/- 5.40 U/ml, and 8.08 +/- 3.26 U/ml respectively and showed a statistically significant difference (P < 0.001). CA 125 at cut off value of 11 U/ml yielded 64% sensitivity and 90% specificity in differentiating benign from malignant gallbladder disease. CA 125 level increased with stage and grade of the GBC though this was not statistically significant. A higher level of CA 125 was found in presence of gallbladder mass, weight loss, ascites and loss of appetite compared to patients with GSD. No association of CA 125 was apparent with either age or sex of the patients. CONCLUSION: CA 125 has a diagnostic potential for GBC and can differentiate GBC from GSD in light of other clinical details.     

Translational regulation of p53 as a potential tumor therapy target

The tumor suppressor p53 is a central player in apoptosis induction in response to oncogenic stimuli and DNA damage. As activation of p53 has been suggested as a prime strategy for future tumor therapy, inhibition of negative regulators of p53 activity would be a similarly desirable strategy. The small worm Caenorhabditis elegans is a model organism in which many conserved biological pathways, including the core apoptotic machinery, were elucidated. The discovery of a worm p53 homolog cep-1/p53 (which stands for C. elegans p53) that specifically induces apoptosis upon DNA damage through a pathway that is conserved from worm to man opened the way for the use of C. elegans genetics to uncover regulatory mechanisms - and hence novel therapeutic targets - of p53-mediated apoptosis. The authors have recently reported a novel mechanism of C. elegans cep-1/p53 regulation through germ line defective-1-mediated translational repression. This review discusses the potential of the worm system to screen for apoptosis-inducing cancer drugs and to identify novel p53 regulators whose human counterparts might become potential tumor therapy targets.     

Eotaxin-2 and colorectal cancer: a potential target for immune therapy.

PURPOSE: To study the production of chemokines by colorectal hepatic metastases. EXPERIMENTAL DESIGN: Biopsies of resected colorectal hepatic metastases and nonneoplastic adjacent liver tissue were screened for chemokines using protein arrays and results were confirmed by ELISA and immunohistochemistry. RESULTS: Two chemokines, eotaxin-2 and MCP-1, were found at elevated levels within the tumor biopsy compared with adjacent liver. The relative increase in expression from tumor was much higher for eotaxin-2 than MCP-1, with 10 of 25 donors having a >100-fold increase in expression compared with 0 of 24 donors for MCP-1. In a parallel analysis, eotaxin-2 was also found at elevated levels in the tumor region of primary colorectal cancer biopsies. Immunohistochemical staining indicated that carcinoembryonic antigen-positive tumor cells stained strongly for eotaxin-2, implicating these cells as the predominant source of the chemokine. In vitro studies confirmed that several colorectal tumor lines produce eotaxin-2 and that secretion of this chemokine could be depressed by IFN-gamma and enhanced by the Th2-type cytokines interleukin-4 and interleukin-13. Jurkat T cells were engineered to express the receptor for eotaxin-2 (CCR3). These cells effectively migrated in response to eotaxin-2 protein, suggesting that immune cells gene modified to express a chemokine receptor may have improved abilities to home to tumor. CONCLUSIONS: Taken together, these observations confirm eotaxin-2 as a chemokine strongly associated with primary and metastatic tumors of colorectal origin. Furthermore, the importance of this result may be a useful tool in the development of targeted therapeutic approaches to colorectal tumors.     

Salivary soluble CD44: a potential molecular marker for head and neck cancer.

OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease which is cured only 50% of the time. If diagnosed early, survival rates could reach 80%, but there is currently no practical method for early detection. CD44 comprises a family of isoforms that, in certain tumors, are alternatively spliced and overexpressed in tissues and circulation. Here we examine salivary soluble CD44 (solCD44) expression in HNSCC patients and normal controls to determine its potential as a screening tool. METHOD: We did a solCD44 ELISA on saliva from 26 HNSCC patients, 10 normal volunteers, conditioned media (CM) of 4 HNSCC cell lines, and 1 CD44-negative cell line (COS-7). Western blot was done on CM from 2 HNSCC cell lines (UMSS11B and FaDu), COS-7, 3 HNSCC, and 2 normal saliva specimens to verify ELISA antibody specificity. SolCD44 levels were significantly elevated in HNSCC patients compared with normal controls (7.85 ng/mL for HNSCC patients and 1.09 ng/mL for normal controls, P < 0.001). RESULTS: The test detected 79% of mucosally invasive HNSCC using preliminary cutoff points. SolCD44 levels did not vary significantly with tumor size, stage, recurrence, history of radiation treatment, or tobacco and alcohol risk factors. A 65 to 75 kDa band, corresponding to solCD44, was detected in all of the HNSCC cell line CM and saliva whereas normal samples showed a fainter band or were undetectable. CONCLUSION: In this preliminary analysis, the salivary solCD44 ELISA seems to effectively detect HNSCC at all stages. Further study is indicated because early detection is clearly important in this disease.     

Endoglin (CD 105) is expressed on endothelial cells in the primary central nervous system lymphomas and correlates with survival

Endoglin (CD105) is predominantly expressed on the cellular lineages within the vascular system and it is overexpressed on proliferating endothelial cells that participate in neoangiogenesis, with a weak or negative expression in the vascular endothelium of normal tissues. To investigate the correlation between the CD105 expression and possible prognostic markers or progression in the primary central nervous system lymphomas (PCNSLs), the present study assessed 26 cases of PCNSL by immunostaining for CD105 and CD34. Intratumoral microvessel density (IMVD) was determined in the hotspots and interfaces at a magnification of x200. According to the mean value, the patients were classified into lower-IMVD and higher-IMVD groups. When CD34 was used as a marker of angiogenesis, the survival rates of these two groups demonstrated no significant difference. In contrast, when CD105 was used as a marker of angiogenesis, the survival rate of the lower-IMVD group was significantly higher than that for the higher-IMVD group (P < 0.01). In the group of CD34-immunostained vessels, no difference was observed in IMVD between the hotspots and interfaces (P = 0.31). In the group with CD105-immunostained vessels, a greater IMVD was observed in the hotspots than in the interfaces (P < 0.01). These results suggested that the growth of PCNSLs was dependent on angiogenesis, that IMVD as determined by anti-CD105 monoclonal antibody was a reliable prognostic marker in PCNSLs, and that PCNSLs may therefore not require sufficient neoangiogenesis at the start of PCNSLs, however, it may instead require a higher rate of neoangiogenesis as they infiltrate and destroy the brain parenchyma.     

Hydralazine-induced tumor hypoxia: a potential target for cancer chemotherapy

Currently available cancer chemotherapeutic agents have been designed to exploit subtle differences in proliferation and biochemistry that are known to exist between host and malignant cells. However, chemotherapeutic agents may also be used to exploit physiological differences between cancer and normal tissue. The present study was conducted to determine whether the reduction in blood flow to the tumor (and thus oxygen delivery) induced by the vasodilator hydralazine would increase the cytotoxicity of drugs known to be more toxic in regions of reduced oxygenation. Results obtained with three murine tumor models clearly demonstrate that hydralazine potentiates the tumor cytotoxicity of such agents to a greater extent than it does their systemic toxicity. This study indicates a potential strategy for increasing the efficacy of certain cancer chemotherapeutic agents in solid tumors.