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

理论基础：与间充质基质细胞(MSC)相关的分子标记被认为是参与脑胶质母细胞瘤发展的脑肿瘤起始细胞的特征，胶质母细胞瘤是最常见和最具侵袭性的原发脑癌。这些发现表明，当转化的干细胞在肿瘤环境中募集时，原发胶质母细胞瘤的一部分可能来自转化的干细胞。这一证据表明，循环中的MSC必须对肿瘤衍生生长因子信号做出反应，从而跨越血脑屏障(BBB)，但更重要的是，MSC还必须在代谢上适应低氧环境和以低氧肿瘤为特征的营养缺乏。从我们上一次NSERC资助的项目中，我们已经确定内质网包埋的葡萄糖-6-磷酸转运蛋白(G6PT)是MSC动员到脑肿瘤的潜在代谢调节因子。事实上，G6PT的强大抑制剂，如Mumbaistatin类似物和绿原酸，导致参与肿瘤发生的几个步骤显著减少，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G6PT通过尚未确定的机制在肿瘤发生中发挥新的作用。长期目标：在分子水平上增加我们对G6PT新角色的理解，G6PT决定了MSC在肿瘤发生中的适应性、代谢和趋化调控。新颖性和预期意义：我们相信，我们的研究将首次证明G6PT在干细胞分化中作为潜在的信号转导蛋白的新角色，以及作为MSC跨越血脑屏障的能力的调节。对这些G6PT介导的生物学机制的控制最终也可能有助于理解MSC在体内的生物分布，以响应不同的微环境线索。此外，G6PT在MSC中的特性和调节打开了将代谢葡萄糖感应和促进肿瘤的机制联系起来的可能性，这两种机制都可能成为可行的抗糖尿病和抗癌药物的靶点。

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.