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Regulation of Proliferation-Survival Decisions during Tumor Cell Hypoxia

机译：肿瘤细胞缺氧过程中增殖-生存决定的调节

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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 G0/G1 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 G0/G1 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.
机译：缺氧可能以相反的相反方式影响肿瘤生物学：它是致命的直接应激触发物，然而实体瘤中的低氧区却带有活细胞，这些细胞对治疗特别有抵抗力，并且对疾病的复发起重要作用。为了检查低氧期间生长生存决定的潜在机制，我们比较了体外遗传相关的转化和未转化成纤维细胞的增殖，存活，克隆形成性，细胞周期和p53表达。缺氧诱导原代成纤维细胞中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累积的酸中毒，并通过增强缓冲来挽救。在非酸性条件下，缺氧的直接作用是转化细胞所特有的，因为它们可以克服低氧对原代细胞的G 0 / G 1 停滞。此外，当与酸中毒脱钩时，相对于正常性缺氧，缺氧可增强肿瘤细胞的生存能力和成克隆性。响应于缺氧引起的酸中毒，p53相应上调，但在无酸中毒的缺氧过程中p53下调。缺氧可能因此产生治疗抗性和生长优势。鉴于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RK Jain，Nat。Med。3：177-182，1997），这种行为可能会影响复发，并暗示细胞作为潜在的重要治疗靶标。

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