Interactions between hypoxia, HIF, type 2 IP3 receptors and invasion of glioblastoma

大多数癌症形成实体瘤，其中细胞不适当地增殖。由于有效血液供应的发展滞后于肿瘤的生长，肿瘤细胞暴露于比大多数细胞低得多的氧浓度。这种缺氧导致蛋白质（HIF）的表达，该蛋白质协调对缺氧的适应性反应。HIF导致肿瘤细胞彼此之间的附着力减弱，因此更有可能离开原发肿瘤并迁移到其他地方。这是一个主要的临床问题，因为大多数癌症死亡是由肿瘤扩散到身体其他部位形成新的肿瘤（转移）引起的。胶质母细胞瘤是最常见的原发性脑肿瘤。这些肿瘤很少扩散到大脑以外，但它们确实会侵入周围的脑组织，阻止完全手术切除，通常会在诊断后几个月内导致死亡。与其他实体瘤一样，这种侵袭开始于缺氧环境，其中肿瘤细胞表达HIF。我们对胶质母细胞瘤细胞的分析表明，缺氧和HIF可能导致细胞间粘附破坏，从而增加对周围脑组织的侵袭。令人惊讶的是，该途径涉及下调蛋白质（IP3R2），该蛋白质与其在胶质母细胞瘤细胞中更丰富的近亲差异最小。由于这种蛋白是一个通道，通过它钙离子可以泄漏到细胞中，以调节细胞的活动，我们认为，IP3R2是独特的，在其亲属中选择性地提供其钙信号的目标，调节细胞之间的adhesions.We之间的连接缺氧，通过HIF，下调IP3R2蛋白的机制。然后，我们将探讨这是如何导致细胞间粘附的破坏和侵袭的增加的。我们认为，了解这些早期步骤的入侵可能会发现新的目标，更有效地治疗胶质母细胞瘤。

Most cancers form solid tumours, within which cells inappropriately proliferate. Since the development of an effective blood supply lags behind growth of the tumour, the tumour cells are exposed to much lower oxygen concentrations than most cells. This hypoxia leads to expression of a protein (HIF) that coordinates adaptive responses to the lack of oxygen. HIF causes tumour cells to loosen their attachments to each other, and so become more likely to leave the primary tumour and migrate elsewhere. This is a major clinical problem because most cancer deaths are caused by tumours spreading to form new tumours elsewhere in the body (metastases).Glioblastoma is the most common primary brain tumour. These tumours rarely spread beyond the brain, but they do invade surrounding brain tissue, preventing complete surgical removal and usually leading to death within months of diagnosis. As with other solid tumours, this invasion begins in a hypoxic environment, within which the tumour cells express HIF. Our analyses of glioblastoma cells suggest a pathway through which hypoxia and HIF may lead to disruption of adhesions between the cells and thereby increased invasion of surrounding brain tissue. Surprisingly this pathway involves down-regulation of a protein (IP3R2) that differs minimally from its close relatives that are much more abundant in glioblastoma cells. Since this protein is a channel through which calcium ions can leak into the cell to regulate cellular activities, we suggest that IP3R2 is unique among its relatives in selectively delivering its calcium signals to targets that regulate the adhesions between cells.We will address the mechanisms linking hypoxia, through HIF, to down-regulation of the IP3R2 protein. We will then ask how that leads to disruption of adhesions between cells and to increased invasion. We suggest that understanding these early steps in invasion might identify new targets for more effective treatment of glioblastoma.