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CXCL12, an alpha-chemokine that binds to G-protein-coupled CXCR4, plays an important and unique role in the regulation of stem/progenitor cell trafficking. To elucidate the correlation between the CXCR4/CXCL12 axis and glioblastomas (GBs), the present study assessed CXCR4/CXCL12 expression in 44 astrocytic tumor tissues using immunohistochemical analyses. Several cell lines of brain tumors were also analyzed by RT-PCR analyses. Although low-grade, astrocytic tumors were rarely positive for CXCL12 immunohistochemically, all GBs showed moderate to intense immunostaining with CXCL12, with particularly intense immunostaining being observed in the pseudopalisading cells and the proliferating microvessels. Regarding CXCR4, widespread positive immunoreactivity was noted in the tumor cells in almost all cases of GBs. In contrast, RT-PCR analysis showed low expression of CXCR4/CXCL12 in the aerophilic condition of GB cells and high expression of CXCR4/CXCL12 in the hypoxic condition of GB cells. Taken together, these results suggest that secretion of CXCR4/CXCL12 by hypoxic pseudopalisading and proliferating microvascular cells contributes to an outward migration of tumor cells away from hypoxia, creating a peripherally moving wave and subsequent microvascular proliferation. Pseudopalisades and proliferating microvessels are also considered to be associated with accelerated growth in GBs. These results indicate that expression of CXCL12 is an accelerated growth factor in GBs.

The KIAA 0864 (KA) protein is a putative protein of a cDNA from 100 cDNA clones that was newly determined from a set of size-fractionated human brain cDNA libraries and their coding potentials of large proteins (180-200 kD) by using in vitro transcription assays. To elucidate the correlation between the KA protein and neuroepithelial tumors (NETs), the present study assessed the KA expression by the NETs using immunohistochemical and Western blot analyses with HFB-16 monoclonal antibody. Among the 55 NETs, a moderate-to-intense KA protein immunoreactivity was observed in 8 of 8 medulloblastomas, 1 of 1 central nervous system supratentorial primitive neuroectodermal tumor (CNS supratentorial PNET), 4 of 4 retinoblastomas, 1 of 1 neuroblastoma, 8 of 8 central neurocytomas, 4 of 4 oligodendrogliomas, 4 of 4 oligoastrocytomas, 1 of 1 extraventricular neurocytoma, and 1 of 1 gangliocytoma. No or a weak KA protein immunoreactivity was observed in 11 of 11 glioblastomas (GBs), 4 of 4 anaplastic astrocytomas, 4 of 4 astrocytomas, and 4 of 4 pilocytic astrocytomas. These results indicate that the antibody HFB-16 could be a useful marker for neuronal tumors and primitive neuroectodermal tumors that may originate from immature neural progenitor cells. In addition, it could be a useful tool for performing the differential diagnosis between GBs and CNS supratentorial PNET.

Endoglin (CD105) is predominantly expressed on the cellular lineages within the vascular system and it is overexpressed on proliferating endothelial cells that participate in neoangiogenesis, with a weak or negative expression in the vascular endothelium of normal tissues. To investigate the correlation between the CD105 expression and possible prognostic markers or progression in the primary central nervous system lymphomas (PCNSLs), the present study assessed 26 cases of PCNSL by immunostaining for CD105 and CD34. Intratumoral microvessel density (IMVD) was determined in the hotspots and interfaces at a magnification of x200. According to the mean value, the patients were classified into lower-IMVD and higher-IMVD groups. When CD34 was used as a marker of angiogenesis, the survival rates of these two groups demonstrated no significant difference. In contrast, when CD105 was used as a marker of angiogenesis, the survival rate of the lower-IMVD group was significantly higher than that for the higher-IMVD group (P < 0.01). In the group of CD34-immunostained vessels, no difference was observed in IMVD between the hotspots and interfaces (P = 0.31). In the group with CD105-immunostained vessels, a greater IMVD was observed in the hotspots than in the interfaces (P < 0.01). These results suggested that the growth of PCNSLs was dependent on angiogenesis, that IMVD as determined by anti-CD105 monoclonal antibody was a reliable prognostic marker in PCNSLs, and that PCNSLs may therefore not require sufficient neoangiogenesis at the start of PCNSLs, however, it may instead require a higher rate of neoangiogenesis as they infiltrate and destroy the brain parenchyma.

Some markers of angiogenic endothelial cells are emerging as targets of cancer therapy. The present study compares the expression of CD105 with that of other endothelial markers in all tissue layers during the development of colon cancer. We immunohistochemically analyzed the expression of the colon adenoma-carcinoma sequence by endothelial cells using a panel of eight endothelial markers. We examined sections from endoscopic mucosal resection and surgical resection of tubular adenoma (n=31), carcinoma in adenoma (n=11), and adenocarcinoma (n=34). Cylindrical cores were punched out from donor paraffin blocks of normal mucosa adjacent to tumors, from tumor lesions of mucosa, submucosa, muscularis propria, subserosa, and serosa, and from lymph node metastases. CD31 (PECAM-1) was universally expressed in the blood vessels of adenoma-carcinoma lesions as well as in normal mucosal vessels (80-95%), with no significant differences. In contrast, cancer-associated blood vessels (up to 80%) and cancer cells themselves expressed high levels of CD105. In normal mucosa, CD105 was weakly expressed in endothelial cells of capillaries (< or =21%), and significant differences in its expression in endothelial cells between the normal mucosa and adenoma, carcinoma in adenoma, and adenocarcinoma were found. Flt-1, Flk-1, transforming growth factor-beta1, transforming growth factor-beta receptor II, and CD44 were strongly expressed in the cancer cells but were not expressed in the blood vessels. Vascular endothelial growth factor was expressed at <30% in the blood vessels of adenoma, carcinoma in adenoma, and carcinoma. Moreover, this study provided evidence that CD105 was expressed exclusively in endothelial blood vessels by double immunostaining of CD105 and D2-40. The present study shows that de novo blood vessels of colon cancer specifically express CD105. These findings provide the basis for novel antiangiogenic cancer therapies.

Background: Chronic encephalitis has rarely been seen, probably due to its viral origins, which may produce the disease in healthy or immunocompromised hosts. The etiology and pathophysiology of these types of encephalitis have not yet been clarified., Case Report: A 63-year-old Japanese woman with underlying multiple myeloma developed chronic encephalitis with fever and progressive dementia, bilateral mild thalamic lesions on magnetic resonance imaging, and a prolonged pleocytosis, normal glucose value, and elevated interleukin-6 and interferon-gamma in the cerebrospinal fluid (CSF). The patient died of pneumonia 6 months after the onset of illness, and diffuse microglial nodules were found in the entire brain. No causative viral agents were identified by polymerase chain reaction and serological tests., Conclusions: The patient was presumed to have suffered from chronic viral encephalitis, based on clinical findings, including CSF and cytokine changes. Microglial nodules are observed in flavivirus group encephalitides, Rickettsia infections, and cytomegalovirus encephalitis in immunocompromised hosts. The possible pathogenesis of this rare encephalitis is discussed.

A 76-year old man was referred to our department because of several episodes of generalized convulsion followed by a loss of consciousness and the right hemiparesis. The disturbed consciousness and hemiparesis disappeared soon but the personal change persisted thereafter. T2 and diffusion weighted images of MRI taken on the admission showed high intensity lesions in the left medial temporal lobe including the hippocampus. Antibodies (Abs) against herpes simplex virus were not elevated, however, serum titers of antinuclear and anti-SS-A/Ro Abs were extremely elevated. CSF IgG level and IgQ index were increased, and the CSF reacted with 78-kd bands on Western blots of rat brain homogenate. He died of bacterial pneumonia on the 28th day of illness and was autopsied. Malignant tumors were not found in any organs. In the left hippocampus, degeneration and loss of neurons, infiltration of macrophages, and microgliosis were observed. Vasculitis, however, was not found in the lesion. The immunohistochemical study showed that the CSF recognized the cytoplasm of neurons in the human hippocampus and also Purkinje cells. Those immunological and pathological findings thus suggest an antibody-mediated autoimmune limbic encephalitis in our case.