Immunoelectron Microscopic Characterization of Human Dermal Lymphatic Microvascular Endothelial Cells: Differential Expression of CD31, CD34, and Type IV Collagen with Lymphatic Endothelial Cells vs Blood Capillary Endothelial Cells in Normal Human Skin, Lymphangioma, and Hemangioma In Situ
Abstract:We performed a comparative investigation of the immunomorphological characteristics of lymphatic and blood microvascular endothelial cells in normal human skin, cutaneous lymphangiomas, and hemangiomas, employing a pre-embedding immunogold electron microscopic technique. We stained for cell membrane proteins that are commonly used for light microscopic characterization of blood endothelial cells. With blood microvascular endothelial cells, we observed uniform labeling of the luminal cell membranes with monoclo… Show more
“…Double staining for CD31 and LYVE-1 showed that a small population of cells in the periphery was doubly positive for both (Fig. 4B), consistent with previous findings (26,27). Importantly, E7080 treatment dramatically inhibited the numbers of CD31-and LYVE-1-positive cells (Fig.…”
Section: E7080 Inhibition Of Angiogenesis and Lymphangiogenesis In Mesupporting
While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve the prognosis of patients with EGFR mutant lung cancer, the prognosis of patients with nonmutant EGFR lung cancer, especially those with metastases, is still extremely poor. We have assessed the therapeutic efficacy of E7080, an orally available inhibitor of multiple tyrosine kinases including VEGF receptor 2 (VEGFR-2) and VEGFR-3, in experimental multiple organ metastasis of lung cancer cell lines without EGFR mutations. E7080 markedly inhibited the in vitro proliferation of VEGF-stimulated microvascular endothelial cells. Intravenous inoculation into natural killer cell-depleted severe combined immunodeficient mice of the small cell lung cancer cell lines H1048 (producing low amounts of VEGF) and SBC-5 (producing intermediate amounts of VEGF) resulted in hematogenous metastases into multiple organs, including the liver, lungs, kidneys, and bones, whereas intravenous inoculation of PC14PE6, a non-small cell lung cancer cell line producing high amounts of VEGF, resulted in lung metastases followed by massive pleural effusion. Daily treatment with E7080 started after the establishment of micrometastases significantly reduced the number of large (>2 mm) metastatic nodules and the amount of pleural effusion, and prolonged mouse survival. Histologically, E7080 treatment reduced the numbers of endothelial and lymph endothelial cells and proliferating tumor cells and increased the number of apoptotic cells in metastatic nodules. These results suggest that E7080 has antiangiogenic and antilymphangiogenic activity and may be of potential therapeutic value in patients with nonmutant EGFR lung cancer and multiple organ metastases.
“…Double staining for CD31 and LYVE-1 showed that a small population of cells in the periphery was doubly positive for both (Fig. 4B), consistent with previous findings (26,27). Importantly, E7080 treatment dramatically inhibited the numbers of CD31-and LYVE-1-positive cells (Fig.…”
Section: E7080 Inhibition Of Angiogenesis and Lymphangiogenesis In Mesupporting
While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors improve the prognosis of patients with EGFR mutant lung cancer, the prognosis of patients with nonmutant EGFR lung cancer, especially those with metastases, is still extremely poor. We have assessed the therapeutic efficacy of E7080, an orally available inhibitor of multiple tyrosine kinases including VEGF receptor 2 (VEGFR-2) and VEGFR-3, in experimental multiple organ metastasis of lung cancer cell lines without EGFR mutations. E7080 markedly inhibited the in vitro proliferation of VEGF-stimulated microvascular endothelial cells. Intravenous inoculation into natural killer cell-depleted severe combined immunodeficient mice of the small cell lung cancer cell lines H1048 (producing low amounts of VEGF) and SBC-5 (producing intermediate amounts of VEGF) resulted in hematogenous metastases into multiple organs, including the liver, lungs, kidneys, and bones, whereas intravenous inoculation of PC14PE6, a non-small cell lung cancer cell line producing high amounts of VEGF, resulted in lung metastases followed by massive pleural effusion. Daily treatment with E7080 started after the establishment of micrometastases significantly reduced the number of large (>2 mm) metastatic nodules and the amount of pleural effusion, and prolonged mouse survival. Histologically, E7080 treatment reduced the numbers of endothelial and lymph endothelial cells and proliferating tumor cells and increased the number of apoptotic cells in metastatic nodules. These results suggest that E7080 has antiangiogenic and antilymphangiogenic activity and may be of potential therapeutic value in patients with nonmutant EGFR lung cancer and multiple organ metastases.
“…4A-C). CD31 (PECAM-1, platelet endothelial cell adhesion molecule-1) is a marker of both BECs and LECs, and is also present on leukocytes of the periphery (Sauter et al, 1998). The leukocyte common antigen CD45, a transmembrane glycoprotein with a molecular weight of 180 -220 kDa, is a marker for cells of hematopoietic origin except for erythrocytes.…”
The development of lymphatic endothelial cells (LECs) from deep embryonic veins or mesenchymal lymphangioblasts is controversially discussed. Studies employing quail-chick grafting experiments have shown that various mesodermal compartments of the embryo possess lymphangiogenic potential, whereas studies on murine embryos have been in favor of a venous origin of LECs. We have investigated NMRI mice from embryonic day (ED) 9.5 to 13.5 with antibodies against the leukocyte marker CD45, the pan-endothelial marker CD31, and the lymphendothelial markers Prox1 and Lyve-1. Early signs of the development of lymphatics are the Lyve-1-and Prox1-positive segments of the jugular and vitelline veins. Then, lymph sacs, which are found in the jugular region of ED 11.5 mice, express Prox1, Lyve-1, and CD31.
“…Several different negative controls are currently used in the different studies, ranging from isotype specific antibodies labeled with the same colors as the specific antibodies (8)(9)(10), addition of no antibodies at all to see the autofluorescence of the cells, to the fluorescence minus one (FMO) strategy [reviewed in (11)]. Another factor complicating the characterization of EPCs is the fact that the expression of the often used stem cell marker CD34 is not only restricted to stem cells, but is also expressed on mature microvascular endothelial cells (12,13). Therefore, CD133, a more immature hematopoietic stem cell marker that is absent on mature endothelial cells and monocytic cells (14) was introduced as a better marker for EPCs.…”
Endothelial progenitor cells (EPCs) reside in the bone marrow and are mobilized into the circulation by specific stimuli such as certain drugs, ischemia, and exercise training.
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