Regulation of proliferation-survival decisions during tumor cell hypoxia
Regulation of proliferation-survival decisions during tumor cell hypoxia
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DOI：
10.1128/mcb.18.5.2845
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发表时间：
1998-05-01
影响因子：
5.3
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
Schmaltz, C;Hardenbergh, PH;Fisher, DE
缺氧可能以矛盾的相反方式影响肿瘤生物学：作为直接应激触发因素，缺氧是致命的，但实体瘤中的缺氧区含有对治疗特别有抗性的活细胞，并对疾病复发有重要作用。为了研究缺氧时生长-存活决定的潜在机制，我们在体外比较了遗传相关的转化和未转化的成纤维细胞的增殖、存活、克隆形成、细胞周期和p53表达。缺氧诱导原代成纤维细胞的G（0）/G（1）停滞，但触发癌基因转化衍生物的凋亡。出乎意料的是，细胞凋亡的机制被认为需要积累酸中毒，并通过增强缓冲来拯救。在非酸性条件下缺氧的直接作用对于转化细胞是独特的，因为它们克服了原代细胞的缺氧G（0）/G（1）停滞。此外，当与酸中毒解偶联时，相对于常氧，缺氧增强肿瘤细胞活力和集落形成。p53在缺氧诱导的酸中毒时相应上调，但在无酸中毒的缺氧期间下调。因此，低氧可能既产生处理抗性又产生生长优势。鉴于强有力的证据表明，实体瘤中的缺氧区域通常是非酸性的（G。Helmlinger，F. Yuan，M. Dellian和R. K. Jain，Nat.Med.3：177-182，1997），这种行为可能影响复发并暗示这些细胞是潜在的重要治疗靶点。
Hypoxia may influence tumor biology in paradoxically opposing ways: it is lethal as a direct stress trigger, yet hypoxic zones in solid tumors harbor viable cells which are particularly resistant to treatment and contribute importantly to disease relapse. To examine mechanisms underlying growth-survival decisions during hypoxia, we have compared genetically related transformed and untransformed fibroblast cells in vitro for proliferation, survival, clonogenicity, cell cycle, and p53 expression, Hypoxia induces G(0)/G(1) arrest in primary fibroblasts but triggers apoptosis in oncogene-transformed derivatives. Unexpectedly, the mechanism of apoptosis is seen to require accumulated acidosis and is rescued by enhanced buffering. The direct effect of hypoxia under nonacidotic conditions is unique to transformed cells in that they override the hypoxic G(0)/G(1) arrest of primary cells. Moreover, when uncoupled from acidosis, hypoxia enhances tumor cell viability and clonogenicity relative to normoxia. p53 is correspondingly upregulated in response to hypoxia-induced acidosis but downregulated during hypoxia without acidosis. Hypoxia may thus produce both treatment resistance and a growth advantage. Given strong evidence that hypoxic regions in solid tumors are often nonacidotic (G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3:177-182, 1997), this behavior may influence relapse and implicates such cells as potentially important therapeutic targets.