Purpose: Endosialin/CD248/tumor endothelial marker 1 is expressed in stromal cells, endothelial cells, and pericytes in various tumors;
however, few studies have focused on expression in malignant ...cells.
Experimental Design: We studied expression of endosialin in clinical specimens, cell culture, and animal models and designed an anti-endosialin
therapeutic prototype.
Results: Fifty human tumor cell lines and 6 normal cell types in culture were assayed by reverse transcription-PCR and/or flow cytometry
for endosialin. Cell surface protein was found on 7 sarcoma lines, 1 neuroblastoma, and 4 normal cell types in culture. A
fully human anti-endosialin antibody bound to human A-673 Ewing's sarcoma cells and SK-N-AS neuroblastoma cells but not HT-1080
cells. Exposure of cells to an anti-human IgG conjugated to saporin resulted in growth inhibition only of endosialin-expressing
cells. Endosialin expression was assessed by immunohistochemistry in 250 clinical specimens of human cancer including 20 cancer
subtypes. Endosialin is frequently found in human cancers. Endosialin expression is mainly a perivascular feature in carcinomas,
with some expression in stromal cells. In sarcomas, endosialin is expressed by malignant cells, perivascular cells, and stromal
cells. Development and characterization of experimental models for studying endosialin biology in sarcomas and evaluating
anti-endosialin therapies is presented.
Conclusions: Findings suggest that an anti-endosialin immunotoxin might be a promising therapeutic approach for endosialin-positive neoplasia,
especially synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma, liposarcoma, and osteosarcoma. Thus, a diagnostic/therapeutic
targeted therapeutic approach to treatment of endosialin-expressing tumors may be possible.
Endosialin emerged recently as a potential therapeutic target for sarcoma. Since some sarcoma subtypes, such as Ewing's sarcoma, show characteristics of neuroendocrine differentiation, we wondered ...whether cancers with neuro-endocrine properties and/or neuroectodermal origin, such as neuroblastoma, small cell lung cancer and melanoma, may express endosialin. Endosialin protein expression was surveyed in neuroblastoma, small cell lung cancer and melanoma in human clinical specimens by immunohistochemistry (IHC) and in human cell lines by flow cytometry. Side population cells were examined to determine whether cancer stem cells can express endosialin. Endosialin-expressing neuroblastoma cell lines were implanted in immunodeficient mice and allowed to grow. The xenograft tumors were resected and tested for endosialin expression by IHC. In human clinical specimens, vascular endosialin staining was observed in neuroblastoma, small cell lung cancer and melanoma. Malignant cell staining was strongest in neuroblastoma, weak in melanoma and rare in small cell lung cancer. In human cell lines, endosialin was detected in neuroblastoma cell lines, including cancer stem cell-like side population (SP) cells, but was absent in melanoma and was both rare and weak in small cell lung cancer. Human neuroblastoma xenograft tumors were found to be positive for endosialin. Our work suggests that endosialin may be a suitable therapeutic target for neuroblastoma.
Abstract
Hypothesis: Endosialin emerged recently as a potential marker and therapeutic target for adult and pediatric sarcoma. Given evidence of a possible common progenitor cell for mesenchymal and ...neural cell lineages, we wondered whether expression of endosialin may be shared by sarcomas and neuroblastomas, which are cancers of mesenchymal origin and neural crest origin, respectively.
Methods: Endosialin protein expression was studied in live human neuroblastoma cell lines by flow cytometry using a fully human monoclonal antibody against human endosialin. Endosialin-positive human neuroblastoma cells were subsequently implanted at different anatomic sites in nu/nu mice and allowed to grow. Tumors were collected, formalin fixed and subjected to immunohistochemistry using a fully human monoclonal antibody against human endosialin. Using the same IHC assay, endosialin protein expression was also studied in formalin-fixed paraffin-embedded human clinical specimens of neuroblastoma.
Results: We tested 10 human neuroblastoma cell lines for endosialin protein expression by flow cytometry and found that 9/10 expressed endosialin. Several of the positive cell lines were derived from bone marrow metastases, suggesting that endosialin expression is maintained in advanced disease. We modeled endosialin-positive neuroblastoma in vivo by implanting SK-N-AS cells in mice subcutaneously and in the subrenal capsule, kidney being a site where neuroblastoma sometimes originates. Immunohistochemical analysis revealed that SK-N-AS cells, which are positive for endosialin in vitro and derived from the bone marrow metastasis of an adrenal primary tumor, formed endosialin-positive subcutaneous tumors and endosialin-positive renal tumors, demonstrating that endosialin expression is supported by different microenvironments in various anatomic locations.
Immunohistochemistry of human clinical specimens of neuroblastoma showed expression of endosialin. All specimens of neuroblastoma were bone marrow metastases, demonstrating that endosialin is expressed in advanced disseminated neuroblastoma.
Conclusions: Our work demonstrates that endosialin expression is shared by sarcomas and neuroblastomas. The expression of endosialin in neuroblastoma potentially opens up a new therapeutic horizon for neuroblastoma patients, including those suffering from advanced disease.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5251.
Diffuse or multifocal invasion of the leptomeninges by malignant glioma (meningeal gliomatosis) is believed to be rare. From 1971 through 1977, 11 of 52 patients with intracranial malignant gliomas ...examined at autopsy were found to have meningeal gliomatosis, and 1 additional patient was diagnosed clinically without autopsy (12 cases total). Eight of the 12 patients were diagnosed antemortem with positive cerebrospinal fluid (CSF) cytology, while the other 4 patients were diagnosed at autopsy only. All 11 autopsied patients had multifocal or diffuse meningeal tumor distant from the primary site; 8 patients had spinal subarachnoid seeding with tumor encroachment of cauda equina and spinal nerve roots, and 9 patients had tumor invasion into the lateral ventricles. Three patients had symptomatic spinal cord compression at the thoracic or lumbar level, and 10 patients had hydrocephalus. These 12 patients with meningeal gliomatosis were compared with the other 41 autopsied malignant glioma patients without the complication (controls); the patients with meningeal gliomatosis were significantly younger (mean age, 40 versus 57 years; p less than 0.005). Patients with meningeal gliomatosis lived somewhat longer (median, 49 weeks) compared to controls (35 weeks), but the difference was not statistically significant. With the advance of chemotherapy, patients with malignant glioma are living longer and the incidence of meningeal gliomatosis may rise. The diagnosis of meningeal gliomatosis can be suspected, especially if hydrocephalus is present, and can often be confirmed by CSF cytology.
Nucleophilic substitution at phosphorus Wadsworth, William S; Larsen, Samuel; Horten, H. Lee
Journal of organic chemistry,
01/1973, Letnik:
38, Številka:
2
Journal Article
PDF
