Targeting lactate transport suppresses in vivo breast tumour growth.
Targeting lactate transport suppresses in vivo breast tumour growth.
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DOI：
10.18632/oncotarget.3910
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发表时间：
2015-08-07
期刊：
影响因子：
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通讯作者：
Pinheiro C
中科院分区：
文献类型：
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作者：
Morais-Santos F;Granja S;Miranda-Gonçalves V;Moreira AH;Queirós S;Vilaça JL;Schmitt FC;Longatto-Filho A;Paredes J;Baltazar F;Pinheiro C
大多数癌症，包括乳腺癌，都有很高的葡萄糖消耗率，这与乳酸的产生有关，这一过程被称为“华宝效应”。乳酸转运体(MCTs)通过乳酸排出使肿瘤微环境酸化，与更高的细胞增殖、迁移、侵袭、血管生成和提高细胞存活率有关。在此之前，我们已经描述了乳腺癌样本中MCT1的上调，并证明了体外抑制MCT的重要性。在这项研究中，我们在常氧和低氧条件下对基底样乳腺癌细胞进行MCT1和MCT4的siRNA敲除，以验证乳酸运输抑制在乳腺癌治疗中的潜力。观察MCT基因敲除对裸鼠体内乳酸外流、细胞增殖、细胞生物量、迁移侵袭和诱导移植瘤生长的影响。MCT基因敲除导致体外肿瘤细胞侵袭力下降，乳酸转运、细胞增殖、迁移和侵袭减少，更重要的是，抑制了体内肿瘤的形成和生长。这项工作支持MCT作为癌症治疗的有希望的靶点，展示了MCT对癌细胞侵袭性的贡献，更重要的是，首次展示了通过靶向乳酸运输来破坏体内乳腺肿瘤的生长。
Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as “Warburg effect”. Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment. The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth. This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of in vivo breast tumour growth by targeting lactate transport.