Organ distribution of asialo-red blood cell ghosts: an attempt at targeting to the liver.

We investigated the organ distribution of four types of red blood cells (RBC) preparations: native RBC, asialo-RBC, native ghosts and asialo-ghosts. Intravenously injected asialo-ghosts were rapidly removed from the blood stream and accumulated mainly in the liver 120 min after the injection. Our results suggest that asialo-ghosts are a simple and effective carrier for targeting of drugs to the liver.</p

A case of gastrointestinal stromal tumor (GIST) with peritoneal dissemination : Imatinib re-challenged case

Unresectable, metastatic, recurrent gastrointestinal stromal tumor (GIST) is primarily treated with a molecular-targeted therapeutic agent, imatinib. However, after an initial response, a secondary resistance to the drug often occurs after a few years. We report here a case of a resected giant GIST of the jejunum that disseminated following treatment with imatinib. A 59-year-old male presented with a giant tumor in the abdominal cavity, which was diagnosed as GIST by needle biopsy; he was administered 400 mg/day imatinib. Eight months later, the tumor had considerably decreased, but multiple tumors in small intestine and mesenterium, indicating dissemination, appeared. Administration of imatinib was continued for 36 months from the initial treatment and the dissemination gradually reduced and almost disappeared except for a tumor in the right upper abdomen. Three years later, follow-up computed tomography revealed that the disseminated lesions had enlarged; a part of the intrapelvic tumor was suspected to be viable. We deduced that the tumor developed partial resistance to imatinib: therefore, we surgically removed as many disseminated tumors as possible. Pathologically, resected tumors appeared to have no viable tumor cells except for a small part of the primary tumor in which mitosis was 0-1/50 high-power fields. Genetic analysis of surgically resected specimen for c-kit mutation revealed an exon 11 c554-559 deletion. 17 months after operation, another disseminated tumor was detected. Imaninib therapy was re-introduced. The dissemination was diminished after three months re-challenged imatinib and continues to be recurrence-free for two years. When partial resistance to imatinib is observed, combined modality therapy that involves chemotherapy with surgical intervention at early stages is expected to improve the outcome

Human bone marrow VCAM-1+ macrophages provide a niche for reactive and neoplastic erythropoiesis

Resident bone marrow macrophages provide a microenvironment for erythropoiesis, forming erythroblastic islands (EBIs) via adhesion molecules. In this study, we examined vascular cell adhesion molecule-1 (VCAM-1) expression in human bone marrow specimens using immunohistochemistry. VCAM-1 was strongly expressed in CD169+ macrophages in EBIs and weakly in sinusoidal vascular endothelial cells. In reactive erythropoiesis, including hemolytic and megaloblastic anemia, the extended cytoplasm of VCAM-1+ CD169+ macrophages circumscribed the erythroid cells. The strong affinity between VCAM-1+ macrophages and erythroid cells was also observed in polycythemia vera (PV), essential thrombocythemia (ET), and chronic myelogenous leukemia (CML). VCAM-1 density was significantly higher in PV than in ET and CML (p < 0.001), and correlated with blood erythrocyte count in all three neoplasms (p < 0.001). In ET, the VCAM-1 density was higher in cases with the JAK2 mutation than with the CALR mutation. In myelodysplastic syndrome with erythroid predominance but unclear EBI formation, punctate VCAM-1+ cytoplasmic processes of macrophages were seen between erythroblasts, similar to those seen between granulocytic precursors in CML, suggesting incomplete contact of VCAM-1+ macrophages with dysplastic erythroid cells. These results suggest that VCAM-1+ macrophages create a niche for reactive and neoplastic erythropoiesis and may be a therapeutic target in PV

"Pseudo-cap" formation in Ehrlich ascites tumor cells induced by cytochalasin B.

Cytochalasin B (CB) treatment induces or accelerates the capping phenomenon in some cells. In Ehrlich ascites tumor cells (EATC) CB treatment apparently induced the capping of Con A binding sites as observed under a fluorescent microscope. However, electron microscopic examinations revealed that the CB treatment did not induce a rearrangement of Con A binding sites, but rather it only induced a change in cell shape. On the contrary, CB treatment inhibited the capping phenomenon induced by treatment with Con A. Electron microscopic observations may give exact information on the distribution of lectin binding sites.</p

Sphingosine-1-phosphate receptor 1 expression in angiosarcoma : Possible role in metastasis and a potential therapeutic target

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that has been implicated in the migration of lymphocytes and endothelial cells through S1P receptors. S1PR1 is strongly expressed in angiosarcoma, a malignant tumor of endothelial cell origin that has a high propensity for metastasis and poor prognosis; however, the pathological significance of S1PR1 expression is not clear. In this study, we investigated the effect of S1PR1 modulation on cell migration, and examined its potential role as a therapeutic target against metastatic dissemination of angiosarcoma. S1PR1 expression in the human angiosarcoma cell line MO-LAS was assessed by immunocytochemical examination and Western blotting. Effects of S1PR1- specific small interfering RNA (siRNA) and that of FTY720-P (a functional S1PR1-antagonist) on MO-LAS cell chemotactic migration towards sphingosine-1-phosphate (S1P) or 10% fetal bovine serum (FBS) were assessed by Transwell migration assay; wound healing assays for random cell migration were performed using a live cell analyzer. Immunostaining revealed high expression of S1PR1 on the MO-LAS cell membrane. Transwell and wound-healing assays showed that S1P enhanced chemotactic and random migration of MO-LAS cells, respectively. Inhibition of S1PR1 expression with siRNA significantly attenuated chemotaxis of cells towards S1P and 10% FBS. Further, FTY720-P strongly induced the internalization and degradation of S1PR1 even in the presence of serum containing S1P. It attenuated chemotactic cell migration of MO-LAS towards both S1P and serum, as well as the random motility of cells at nanomolar concentrations. These results suggest that the S1P/S1PR1 axis may be a potential therapeutic target for inhibition of angiosarcoma metastasis by controlling its cell motility