Metabolic and tumorigenic adaptation in mesenchymal stromal cells : a new bioswitch function for the glucose-6-phosphate translocase

原理：与间充质间质细胞（MSC）相关的分子标记物被认为是脑肿瘤起始细胞的特征，胶质母细胞瘤是最常见和侵袭性的原发性脑癌。这些发现表明，原发性胶质母细胞瘤的一个亚群可能来源于转化干细胞在肿瘤环境中的募集。这一证据表明，循环间充质干细胞必须对肿瘤来源的生长因子信号做出反应，从而穿过血脑屏障（BBB），但更重要的是，间充质干细胞还必须通过代谢适应低氧环境和缺氧肿瘤特征的营养剥夺。从我们上一个nserc资助的项目中，我们已经确定了内质网内嵌入的葡萄糖-6-磷酸转运蛋白（G6PT）是骨髓间充质干细胞向脑肿瘤动员的潜在代谢调节剂。事实上，G6PT的强大抑制剂，如孟买抑素类似物和绿原酸，导致肿瘤发生的几个步骤显著减少，如MSC对肿瘤源性生长因子的趋化反应、癌细胞增殖、细胞周期分裂和细胞外基质降解。总之，这些证据支持G6PT在肿瘤发生中的新作用，其机制尚未明确。长期目的：提高我们在分子水平上对G6PT在骨髓间充质干细胞的适应性、代谢和趋化控制中的新作用的理解。新颖性和预期意义：我们相信我们的研究将首次证明G6PT作为干细胞分化中潜在的信号转导蛋白的新作用，以及作为MSC穿越血脑屏障能力的调节剂。这些g6pt介导的生物学机制的控制可能最终也有助于了解MSC响应不同微环境线索在体内的生物分布。此外，MSC中G6PT的表征和调控开辟了将代谢葡萄糖传感和肿瘤促进机制联系起来的可能性，这些机制都可能被可行的抗糖尿病和抗癌药物靶向。

RATIONALE : Molecular markers associated with mesenchymal stromal cells (MSC) are thought to characterize the brain tumor-initiating cells involved in the development of glioblastoma, the most common and aggressive primary brain cancer. These findings suggest that a subset of primary glioblastomas may derive from transformed stem cells upon their recruitment within the tumors' environment. This evidence implies that circulating MSC must respond to tumor-derived growth factor cues and therefore cross the blood-brain barrier (BBB), but more importantly that MSC must also adapt metabolically to the low oxygen environment and to nutrient deprivation that characterizes hypoxic tumors. From our last NSERC-funded program, we have identified the endoplasmic reticulum-embedded glucose-6-phosphate transporter (G6PT) as a potential metabolic regulator of MSC mobilization to brain tumors. Indeed, G6PT's powerful inhibitors such as mumbaistatin analogs and chlorogenic acid led to significant decrease in several steps involved in tumorigenesis such as MSC chemotactic response to tumor-derived growth factors, cancer cells proliferation, cell cycle division, and extracellular matrix degradation. Altogether, this evidence supports a new role for G6PT in tumorigenesis through yet undefined mechanisms. LONG TERM OBJECTIVE : To increase our comprehension at the molecular level of the new role of G6PT dictating the adaptative, metabolic and chemotactic control of MSC in tumorigenesis. NOVELTY AND EXPECTED SIGNIFICANCE : We are convinced that our study will provide the first demonstration for G6PT's new role as a potential signal transducing protein in stem cells differentiation and as a regulator in the ability of MSC to cross the BBB. The control of these G6PT-mediated biological mechanisms may ultimately also help understand MSC biodistribution in vivo in response to different microenvironment cues. Moreover, the characterisation and regulation of G6PT in MSC opens up the possibility to link metabolic glucose-sensing and tumor-promoting mechanisms that can both be potentially targeted by viable anti-diabetic and anti-cancer agents.