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

基本原理：与间充质基质细胞（MSC）相关的分子标记物被认为是参与胶质母细胞瘤（最常见和最具侵袭性的原发性脑癌）发展的脑肿瘤起始细胞的特征。这些发现表明，原发性胶质母细胞瘤的一个子集可能来源于转化的干细胞，当它们在肿瘤环境中募集时。这一证据表明，循环中的MSC必须对肿瘤源性生长因子的信号作出反应，从而穿过血脑屏障（BBB），但更重要的是，MSC还必须在代谢上适应低氧环境和缺氧肿瘤特有的营养缺乏。从我们最后一个NSERC资助的项目中，我们已经确定了内质网嵌入的葡萄糖-6-磷酸转运蛋白（G6 PT）作为MSC动员到脑肿瘤的潜在代谢调节因子。事实上，G6 PT的强效抑制剂如孟买他汀类似物和绿原酸导致肿瘤发生中涉及的几个步骤的显著减少，如MSC对肿瘤衍生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，这一证据支持G6 PT通过尚未确定的机制在肿瘤发生中的新作用。长期目标：在分子水平上加深我们对G6 PT在肿瘤发生中决定MSC的适应性、代谢性和趋化性控制的新作用的理解。新奇和预期意义：我们相信我们的研究将首次证明G6 PT作为干细胞分化中的潜在信号转导蛋白以及作为MSC穿过BBB能力的调节剂的新作用。这些G6 PT介导的生物学机制的控制可能最终也有助于了解MSC在体内响应不同微环境线索的生物分布。此外，MSC中G6 PT的表征和调节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，这些机制都可以被可行的抗糖尿病和抗癌药物潜在地靶向。

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.