Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and a subpopulation of glioma stem-like cells (GSCs) is likely responsible for the invariable recurrence following maximum resection and chemoradiotherapy. As most GSCs that are located in the perivascular and perinecrotic niches should be removed during tumor resection, it is very important to know where surviving GSCs are localized. Here, we investigated the existence and functions of GSCs in the tumor periphery, which is considered to constitute the invasion niche for GSCs in GBM, by analyzing expression of stem cell markers and stem cell-related molecules and measuring particular activities of cultured GSCs. In addition, the relationship between GSCs expressing particular stem cell markers and pathological features on MRI and prognosis in GBM patients was analyzed. We showed that GSCs that express high levels of CD44 are present in the tumor periphery. We also found that vascular endothelial growth factor (VEGF) is characteristically expressed at a high level in the tumor periphery. Cultured GSCs obtained from the tumor periphery were highly invasive and have enhanced migration phenotype, both of which were markedly inhibited by CD44 knockdown. Higher expression of CD44 in the tumor periphery than in the core was correlated with a highly invasive feature on MRI and was associated with early tumor progression and worse survival, whereas lower expression of CD44 in the tumor periphery corresponded to low invasion and was associated with longer survival. The low invasion type on MRI tended to show high levels of VEGF expression in the tumor periphery, thus presenting the tumor with high proliferative activity. These results imply the significance of GSCs with high levels of CD44 expression in the tumor periphery compared to the core, not only in tumor invasion but also rapid tumor progression and short survival in patients with GBM.

2019) Chloride intracellular channel protein 2 in cancer and noncancer human tissues: relationship with tight junctions, Tissue Barriers, 7:1, 1593775, ABSTRACT Chloride intracellular channel protein 2 (CLIC2) belongs to the CLIC family of conserved metazoan proteins. Although CLICs have been identified as chloride channels, they are currently considered multifunctional proteins. CLIC2 is the least studied family member. We investigated CLIC2 expression and localization in human hepatocellular carcinoma, metastatic colorectal cancer in the liver, and colorectal cancer. Significant expression of mRNAs encoding CLIC1, 2, 4, and 5 were found in the human tissues, but only CLIC2 was predominantly expressed in non-cancer tissues surrounding cancer masses. Fibrotic or dysfunctional (aspartate aminotransferase ≥40) non-cancer liver tissues and advanced stage HCC tissues expressed low levels of CLIC2. Endothelial cells lining blood vessels but not lymphatic vessels in non-cancer tissues expressed CLIC2 as well as high levels of the tight junction proteins claudins 1 and 5, occludin, and ZO-1. Most endothelial cells in blood vessels in cancer tissues had very low expressions of CLIC2 and tight junction proteins. CD31 + /CD45 − endothelial cells isolated from non-cancer tissues expressed mRNAs encoding CLIC2, claudin 1, occludin and ZO-1, while similar cell fractions from cancer tissues had very low expressions of these molecules. Knockdown of CLIC2 expression in human umbilical vein endothelial cells (HUVECs) allowed human cancer cells to transmigrate through a HUVEC monolayer. These results suggest that CLIC2 may be involved in the formation and/or maintenance of tight junctions and that cancer tissue vasculature lacks CLIC2 and tight junctions, which allows the intravasation of cancer cells necessary for hematogenous metastasis. ARTICLE HISTORY

Endoscopic endonasal transsphenoidal surgery (ETSS) has been widely applied to pituitary adenomas. However, anatomical orientation is difficult when structures of the sphenoidal sinus are complicated. This study investigated the usefulness of three-dimensional computed tomography (3D-CT) modeling in planning surgical procedures for ETSS and providing anatomical guidance during surgery. CT data from 99 consecutive patients with pituitary adenoma treated between January 2008 and March 2014 were used to reconstruct 3D-CT models. Based on these images, the architecture of sphenoidal sinus, particularly structures surrounding the sellar floor, was visualized for preoperative simulation of surgical procedures. These 3D-CT images were also compared to surgical views during ETSS to evaluate applicability of the images. These models clearly demonstrated the morphology of the nasal cavity and structures of the sphenoidal sinus, including bony prominences of the internal carotid arteries (ICAs) and optic canals by successively eliminating sphenoidal structures. The 3D-CT images permitted determination of the maximum marginal line of the opening of the sellar floor by presenting vital structures such as ICAs and optic canals. With this 3D-CT model, the surgeon could access the sella more easily, open the floor widely enough for each individual patient, and resect the tumor maximally without complications. Preoperative 3D-CT models distinctly visualized the optic canals, bilateral ICAs, and complicated structures of sphenoidal septa. The 3D-CT images were useful for preoperative planning and as a road map during endoscopic surgery for pituitary adenoma, facilitating maximum tumor resection without complications.

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