Hypoxia Contributes to Melanoma Heterogeneity by Triggering HIF1α-Dependent Phenotype Switching
Hypoxia Contributes to Melanoma Heterogeneity by Triggering HIF1α-Dependent Phenotype Switching
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DOI：
10.1038/jid.2013.115
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发表时间：
2013-10-01
影响因子：
6.5
通讯作者：
Levesque, Mitchell P.
中科院分区：
文献类型：
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作者：
Widmer, Daniel S.;Hoek, Keith S.;Levesque, Mitchell P.
我们之前报道过一种黑色素瘤进展模型，其中以侵袭或增殖为特征的黑色素瘤细胞表型之间的振荡是肿瘤异质性和疾病进展的基础。在这项研究中，我们通过促进从增殖表型向侵袭表型的转变，研究了缺氧作为驱动转移进展的微环境影响因素之一的可能作用。原发性人皮肤黑色素瘤活检的免疫组织化学显示表达黑素细胞标记物的细胞具有瘤内异质性，并且这些标记物的缺失与缺氧区域相关。此外，我们发现黑素细胞标记物的下调依赖于缺氧诱导因子 1 α (HIF1 α)，这是一种已知的缺氧反应调节因子。体外侵袭测定表明，缺氧环境以 HIF1 α 依赖性方式增加增殖性黑色素瘤细胞培养物的侵袭性。相比之下，侵袭性表型黑色素瘤细胞在暴露于缺氧时并未表现出侵袭潜力的增加。因此，以 HIF1 α 依赖性方式，将增殖性黑色素瘤细胞暴露于缺氧微环境足以下调黑色素细胞标志物的表达并增加其侵袭潜力。
We have previously reported a model for melanoma progression in which oscillation between melanoma cell phenotypes characterized by invasion or proliferation is fundamental to tumor heterogeneity and disease progression. In this study we examine the possible role of hypoxia as one of the microenvironmental influences driving metastatic progression by promoting a switch from a proliferative to an invasive phenotype. Immunohistochemistry on primary human cutaneous melanoma biopsies showed intratumoral heterogeneity for cells expressing melanocytic markers, and a loss of these markers correlated with hypoxic regions. Furthermore, we show that the downregulation of nnelanocytic markers is dependent on hypoxia inducible factor 1 alpha (HIF1 alpha), a known regulator of the hypoxic response. In vitro invasion assays showed that a hypoxic environment increases the invasiveness of proliferative melanoma cell cultures in a HIF1 alpha-dependent manner. In contrast, invasive phenotype melanoma cells showed no increase in invasive potential upon exposure to hypoxia. Thus, exposure of proliferative melanoma cells to hypoxic microenvironments is sufficient, in a HIF1 alpha-dependent manner, to downregulate melanocytic marker expression and increase their invasive potential.