Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer.
Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer.
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DOI：
10.4161/cc.24092
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Martinez-Outschoorn UE
中科院分区：
文献类型：
--
作者：
Curry JM;Tuluc M;Whitaker-Menezes D;Ames JA;Anantharaman A;Butera A;Leiby B;Cognetti DM;Sotgia F;Lisanti MP;Martinez-Outschoorn UE
在这里，我们询问了头颈癌（HNSCC）标本（n = 12），以检查不同的代谢区室（氧化与糖酵解）是否共存于人类肿瘤中。采用了一大批成熟的生物标志物来确定增殖性癌细胞的代谢状态。有趣的是，如通过Ki-67免疫染色所标记的，癌细胞中的细胞增殖与氧化线粒体代谢（OXPHOS）和线粒体燃料的摄取严格相关，如通过MCT 1表达所检测的（p < 0.001）。更具体地说，描述了三个代谢肿瘤区室：（1）增殖性和富含肿瘤细胞的癌细胞（Ki-67+/TOMM 20 +/考克斯+/MCT 1+）;（2）非增殖性和缺乏肿瘤细胞的癌细胞（Ki-67−/TOMM 20 −/考克斯−/MCT 1 −）;和（3）非增殖性和缺乏肿瘤细胞的基质细胞（Ki-67−/TOMM 20 −/考克斯−/MCT 1 −）。此外，高氧化应激（MCT 4+）对癌组织非常特异。因此，我们接下来在第二个独立的患者队列（n = 40）中评估了MCT 4的预后价值。最重要的是，非增殖性上皮癌细胞中的氧化应激（MCT 4+）预测不良临床结果（肿瘤复发; p < 0.0001;对数秩检验），并且在功能上与FDG-PET亲合力相关（p < 0.04）。类似地，肿瘤基质细胞中的氧化应激（MCT 4+）与较高的肿瘤分期特异性相关（p < 0.03），并且是癌症相关成纤维细胞的高度特异性标志物（p < 0.001）。我们认为，氧化应激是肿瘤组织的一个关键标志，通过线粒体燃料（如L-乳酸和酮体）的旁分泌转移，驱动邻近增殖的富含肿瘤细胞的高能代谢。应该开发新的抗氧化剂和MCT 4抑制剂，以代谢靶向头颈癌中的“三室肿瘤代谢”。值得注意的是，肿瘤内的两个“非增殖”细胞群（Ki-67−/MCT 4+）实际上可以决定临床结果，可能是通过为增殖性癌细胞提供高能线粒体“燃料”来燃烧。最后，我们还表明，在正常粘膜组织中，基底上皮“干细胞”层是过度增殖的（Ki-67+），富含线粒体（TOMM 20 +/考克斯+），并在代谢上被编程为使用线粒体燃料（MCT 1+），如酮体和L-乳酸。因此，氧化线粒体代谢（OXPHOS）是（1）正常干细胞和（2）增殖癌细胞的共同特征。因此，我们应该考虑用线粒体抑制剂（如Metabolic）和/或MCT 1和MCT 4抑制剂的组合对癌症患者进行代谢治疗，以靶向“代谢共生”。
Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67−/TOMM20−/COX−/MCT1−); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67−/TOMM20−/COX−/MCT1−). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target “three-compartment tumor metabolism” in head and neck cancers. It is remarkable that two “non-proliferating” populations of cells (Ki-67−/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial “fuels” for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial “stem cell” layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target “metabolic symbiosis.”
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DOI：
10.1016/s0360-3016(01)01630-3
发表时间：
2001-10-01
影响因子：
7
作者：
Brizel, DM;Schroeder, T;Mueller-Klieser, W
通讯作者：
Mueller-Klieser, W
影响因子：
8.8
作者：
Halfpenny, W;Hain, S F;Biassoni, L;Maisey, M N;Sherman, J A;McGurk, M
通讯作者：
McGurk, M
影响因子：
4.3
作者：
Bonuccelli, Gloria;Tsirigos, Aristotelis;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.
影响因子：
4.1
作者：
Dimmer, KS;Friedrich, B;Bröer, S
通讯作者：
Bröer, S
影响因子：
5.5
作者：
Brooks, George A.
通讯作者：
Brooks, George A.