Higher- or lower-affinity germinal center (GC) B cells are directed either to plasma cell or GC recycling, respectively; however, how commitment to the plasma cell fate takes place is unclear. We found that a population of light zone (LZ) GC cells, Bcl6CD69 expressing a transcription factor IRF4 and higher-affinity B cell receptors (BCRs) or Bcl6CD69 with lower-affinity BCRs, favored the plasma cell or recycling GC cell fate, respectively. Mechanistically, CD40 acted as a dose-dependent regulator for Bcl6CD69 cell formation. Furthermore, we found that expression of intercellular adhesion molecule 1 (ICAM-1) and signaling lymphocytic activation molecule (SLAM) in Bcl6CD69 cells was higher than in Bcl6CD69 cells, thereby affording more stable T follicular helper (Tfh)-GC B cell contacts. These data support a model whereby commitment to the plasma cell begins in the GC and suggest that stability of Tfh-GC B cell contacts is key for plasma cell-prone GC cell formation.

No abstract

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87ΔEGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.

These animal models histologically recapitulated two invasive and angiogenic phenotypes, namely angiogenesis-dependent and angiogenesis-independent invasion, also observed in human glioblastoma. These cell lines provided a reproducible in vitro and in vivo system to analyze the mechanisms of invasion and angiogenesis in glioma progression.

BACKGROUND: Despite advances in multimodal therapy, patients with malignant glioma have a dismal prognosis. Aberrant angiogenesis and diffuse glioma cell invasion are major obstacles for effective treatment. Therefore, investigation of angiogenesis and invasion is essential for the development of a curative therapy. We established animal models that histologically mimic two invasive and angiogenic phenotypes of glioma, ie, angiogenesis-dependent invasion (J3T-1) and angiogenesis-independent invasion (J3T-2). In our previous study, comparative proteomic analysis showed that annexin A2 was more highly expressed in J3T-1 than in J3T-2. In this study, the function of annexin A2 in