Acid treatment of melanoma cells selects for invasive phenotypes
Acid treatment of melanoma cells selects for invasive phenotypes
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DOI：
10.1007/s10585-008-9145-7
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发表时间：
2008-06-01
影响因子：
4
通讯作者：
Gillies, Robert J.
中科院分区：
文献类型：
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作者：
Moellering, Raymond E.;Black, Kvar C.;Gillies, Robert J.
实体瘤因缺氧和糖酵解上调而呈酸性。我们假设这种酸中毒会导致癌变过程中更具侵略性的侵袭性行为（Nature Reviews Cancer:891-899, 2004）。以前关于这个问题的研究结果好坏参半。虽然有些人观察到酸治疗诱导转移和侵袭，但其他人没有。为了研究这一点，人类黑色素瘤细胞适应低pH生长条件。在驯化过程中发生了显著的细胞死亡，表明酸中毒选择了抗性表型。与未选择的对照细胞相比，维持在酸性条件下的细胞表现出更大的运动范围，在SCID小鼠中形成侧腹肿瘤的能力降低，并且在体外没有更快地入侵。然而，这些选定的细胞对生理pH值的重新驯化产生了稳定的群体，体外入侵率显著提高。这些重新驯化的细胞在多代中保持了较高的侵袭性和运动性。对这三种表型的转录组学分析显示了显著差异，包括对组织重塑、细胞周期控制和增殖重要的相关途径的上调。这些结果强化了酸中毒促进稳定的、更具侵袭性的表型选择的假设，而不是诱导变化，这将是可逆的。
Solid tumors become acidic due to hypoxia and upregulated glycolysis. We have hypothesized that this acidosis leads to more aggressive invasive behavior during carcinogenesis (Nature Reviews Cancer 4:891-899, 2004). Previous work on this subject has shown mixed results. While some have observed an induction of metastasis and invasion with acid treatments, others have not. To investigate this, human melanoma cells were acclimated to low pH growth conditions. Significant cell mortality occurred during acclimation, suggesting that acidosis selected for resistant phenotypes. Cells maintained under acidic conditions exhibited a greater range of motility, a reduced capacity to form flank tumors in SCID mice and did not invade more rapidly in vitro, compared to non-selected control cells. However, re-acclimation of these selected cells to physiological pH gave rise to stable populations with significantly higher in vitro invasion. These re-acclimated cells maintained higher invasion and higher motility for multiple generations. Transcriptomic analyses of these three phenotypes revealed significant differences, including upregulation of relevant pathways important for tissue remodeling, cell cycle control and proliferation. These results reinforce the hypothesis that acidosis promotes selection of stable, more invasive phenotypes, rather than inductive changes, which would be reversible.