Targeting the metabolic microenvironment of tumors.
Targeting the metabolic microenvironment of tumors.
复制标题
DOI：
10.1016/b978-0-12-397927-8.00004-x
复制
发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Gillies, Robert J
中科院分区：
文献类型：
--
作者：
Bailey, Kate M;Wojtkowiak, Jonathan W;Hashim, Arig Ibrahim;Gillies, Robert J
1924年Otto Warburg对肿瘤细胞有氧糖酵解的观察，以及随后通过PET-CT对肿瘤患者葡萄糖摄取成像的创新，重新激起了人们对肿瘤代谢改变的兴趣。当肿瘤原位生长时，一部分肿瘤远离其血液供应，导致氧浓度降低（缺氧），从而诱导HIF1α、mTOR和UPR的缺氧反应途径。在正常组织中，这些反应可减轻缺氧应激并诱导新生血管生成。在肿瘤中，由于血管不成熟和混乱，这些通路失调，导致灌注减少和缺氧加剧。缺氧选择糖酵解表型和由此导致的肿瘤微环境酸化，促进质子转运蛋白上调。酸化选择通过离子捕获增强转移潜能和降低药物功效。本文综述了针对有氧糖酵解、酸中毒、缺氧和缺氧反应途径的临床前和临床药物的研究进展。缺氧和酸中毒可以控制，为具有这些常见表型的癌症提供进一步的治疗益处。
The observation of aerobic glycolysis by tumor cells in 1924 by Otto Warburg, and subsequent innovation of imaging glucose uptake by tumors in patients with PET-CT has incited a renewed interest in the altered metabolism of tumors. As tumors grow in situ, a fraction of it is further away from their blood supply, leading to decreased oxygen concentrations (hypoxia), which induces the hypoxia response pathways of HIF1α, mTOR and UPR. In normal tissues, these responses mitigate hypoxic stress and induce neo-angiogenesis. In tumors, these pathways are dysregulated and lead to decreased perfusion and exacerbation of hypoxia as a result of immature and chaotic blood vessels. Hypoxia selects for a glycolytic phenotype and resultant acidification of the tumor microenvironment, facilitated by upregulation of proton transporters. Acidification selects for enhanced metastatic potential and reduced drug efficacy through ion trapping. In this review, we provide a comprehensive summary of pre-clinical and clinical drugs under development for targeting aerobic glycolysis, acidosis, hypoxia and hypoxia-response pathways. Hypoxia and acidosis can be manipulated, providing further therapeutic benefit for cancers that feature these common phenotypes.