angiotensinogen and Neoplasm-Metastasis

We investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cell (CSC) subpopulations in metastatic head and neck cutaneous squamous cell carcinoma (mHNcSCC). Immunohistochemical staining demonstrated expression of prorenin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme 2; Angiotensinogen; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Microvessels; Middle Aged; Neoplasm Metastasis; Neoplastic Stem Cells; Prorenin Receptor; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Squamous Cell Carcinoma of Head and Neck; Stromal Cells

A number of investigations have addressed the importance of high glucose in breast cancer, however, the involvement of angiotensinogen (AGT) in this scenario is yet to be defined. Here we set out to analyze the potential pro-tumor effects of high glucose in breast cancer, and understand the underlying molecular mechanism. We demonstrated that high glucose promoted cell proliferation, viability, and anchorage-independent growth of breast cancer cells. In addition, the migrative and invasive capacities were significantly enhanced by high glucose medium. Mechanistically, AGT expression was inhibited by high glucose at both transcriptional and translational levels. High AGT remarkably suppressed proliferation, inhibited viability, and compromised migration/invasion of breast cancer cells. Most importantly, ectopic introduction of AGT almost completely abrogated pro-tumor effects of high glucose. Our study has characterized the pro-tumor properties of high glucose in breast cancer cells, which is predominantly attributed to the suppression of AGT.

Topics: Angiotensinogen; Breast Neoplasms; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Glucose; Humans; MCF-7 Cells; Neoplasm Metastasis; Neoplasm Proteins

Bevacizumab improves progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients however currently there are no biomarkers that predict response to this treatment. The aim of this study was to assess if differential protein expression can differentiate patients who respond to chemotherapy and bevacizumab, and to assess if select proteins correlate with patient survival.. Pre-treatment serum from patients with metastatic colorectal cancer (mCRC) treated with chemotherapy and bevacizumab were divided into responders and nonresponders based on their progression free survival (PFS). Serum samples underwent immunoaffinity depletion and protein expression was analysed using two-dimensional difference gel electrophoresis (2D-DIGE), followed by LC-MS/MS for protein identification. Validation on selected proteins was performed on serum and tissue samples from a larger cohort of patients using ELISA and immunohistochemistry, respectively (n = 68 and n = 95, respectively).. 68 proteins were identified following LC-MS/MS analysis to be differentially expressed between the groups. Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies. Increasing APOE expression in the stroma was associated with shorter progression free survival (PFS) (p = 0.0001) and overall survival (OS) (p = 0.01), DBP expression (stroma) was associated with shorter OS (p = 0.037). Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05). Increasing serum AGT concentration was associated with shorter OS (p = 0.009).. APOE, DBP and AGT identified were associated with survival outcomes in mCRC patients treated with chemotherapy and bevacizumab.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apolipoproteins E; Bevacizumab; Biomarkers, Tumor; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Metastasis; Proteomics; Survival Analysis; Treatment Outcome; Vitamin D-Binding Protein

Angiogenesis is essential for tumor growth and metastatic dissemination. We have previously shown that human angiotensinogen (AGT) can in vitro inhibit endothelial cell proliferation and migration, capillary-like tube formation, and neovascularization. To determine whether AGT can exert an antitumoral effect through its antiangiogenic properties, we constructed a recombinant adenovirus carrying the human angiotensinogen gene under the control of the cytomegalovirus promoter (AdAGT). In vitro studies showed that AdAGT selectively inhibited endothelial cell proliferation. In vivo, injections of AdAGT into preestablished human MDA-MB-231 mammary carcinomas in nude mice inhibited tumor growth by 70% compared to controls, with 21% total regression. This effect was associated with the suppression of intratumoral vascularization and marked necrosis. Furthermore, in vitroAdAGT infection of MDA-MB-231 and murine melanoma B16F10 cells strongly blocked their in vivo tumorigenicity. Then, in mice expressing high levels of AGT (i.e., either iv injected with AdAGT or HuAGT transgenic mice), the number of B16F10 pulmonary metastases was 85% lower than in control C57BL/6 mice. Our data demonstrate that AGT is a very potent antiangiogenic factor in vivo, independent of angiotensin II generation. Its delivery by gene transfer represents a promising new strategy to block primary tumor growth and to prevent metastasis.

Topics: Adenoviridae; Angiotensinogen; Animals; Cell Movement; Cell Proliferation; Endothelial Cells; Endothelium, Vascular; Gene Transfer Techniques; Genetic Therapy; HeLa Cells; Humans; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neovascularization, Pathologic; Transplantation, Heterologous