Angiogenesis plays critical roles in organ development during embryonic and fetal life, wound healing and in a variety of pathological conditions. Vascular endothelial growth factor (VEGF) is a secreted growth factor specific for vascular endothelial cells which induces angiogenesis in vivo. To gain a better understanding of the physiological role of VEGF, we have generated and characterized four murine monoclonal antibodies (mAbs) using the 165 amino acid species of recombinant human VEGF as immunogen. These mAbs (A3.13.1, A4.6.1, B4.3.1 and B2.6.2) belong to IgG1 isotype and have high affinities for VEGF (dissociation constants range from 2.2 x 10(-9) to 4 x 10(-10) M). Two different epitopes were detected with these mAbs. One epitope is recognized by mAbs A3.13.1 and B2.6.2, and the other recognized by mAbs A4.6.1 and B4.3.1. The epitope recognized by mAb A4.6.1 appears to be continuous while mAb B2.6.2 recognizes a discontinuous epitope. MAb A4.6.1 recognized three species of VEGF generated by alternative splicing, VEGF121, VEGF165 and VEGF189 while mAb B2.6.2 binds only VEGF165 and VEGF189. Results using an in vitro bovine adrenal cortex endothelial cell proliferation assay, in in vivo vascular permeability assay and an in vivo embryonic chicken angiogenesis assay showed that mAb A4.6.1 has potent VEGF neutralizing activities. MAb A4.6.1 was shown to block the binding of VEGF to its receptor(s) suggesting the inhibitory mechanism for VEGF activities. These well-defined mAbs should be very powerful tools to understand the structure-function relationship of various domains of VEGF and may have therapeutic potential.
Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.
In patients receiving anti-TNF therapy, 3HR seems to be the most acceptable treatment regimen for LTBI, given its high completion rate and acceptable rate of adverse drug reactions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.