Gene expression programs of lactic acidosis in human cancers

描述（由申请人提供）：癌症研究的一个挑战是如何将体外细胞培养获得的发现转化为体内人类癌症的复杂行为。我们先前在培养的细胞中鉴定了缺氧基因特征，使我们能够推断许多人类癌症中缺氧途径活动的水平，以识别具有强烈缺氧反应的患者。通过将体外细胞培养模型与其体内癌症对应物通过“基因签名”的共同语言相关联，我们发现我们可以识别人类癌症中的分子程序，这些分子程序反映了培养物中定义的扰动，以探索其预后意义和表型特征。肿瘤微环境在决定肿瘤行为和治疗反应中起关键作用，并且以缺氧和乳酸酸中毒为特征。尽管据报道乳酸酸中毒与肿瘤侵袭和不良临床结局相关，但我们对细胞如何对乳酸酸中毒做出反应，它们在人类癌症中的预后意义以及识别具有此特征的肿瘤的最佳方法知之甚少。在这项提案中，我们将使用细胞培养和人类癌症中的全局基因表达来了解乳酸酸中毒在人类癌症中的作用。我们将首先确定在各种培养细胞中对乳酸酸中毒的转录反应，以定义反映乳酸酸中毒的“基因签名”。将测试通过抑制酸敏感离子通道（ASIC）或缺氧诱导因子（HIF）蛋白来消除这种反应的可能性。其次，将基于具有测量的乳酸水平的人类癌症的基因表达分析来确定肿瘤中与高乳酸水平相关的基因表达模式。在细胞培养物或肿瘤中获得的乳酸酸中毒基因特征将用作分子计量器，以基于基因表达确定肿瘤中乳酸酸中毒反应的水平。这些基因特征的预后意义将在许多其他基因表达研究中进一步测试，并且乳酸酸中毒肿瘤的分子通路的组成也将通过先进的生物信息学来确定。为了使我们能够识别具有高临床风险的乳酸酸中毒癌症，我们将根据我们的基因表达研究选择分子标记物。将肿瘤组织中标志物表达的空间分布与缺氧标志物（CA9）和测量的肿瘤生理学参数进行比较。这些候选标志物的预后价值将在多个癌症组织微阵列上进一步确定。

DESCRIPTION (provided by applicant): One challenge in cancer research is how to translate the findings obtained with cell culture in vitro to the complex behaviors of human cancers in vivo. We previously identified a hypoxia gene signature in cultured cells to allow us infer the level of hypoxia pathway activities in many human cancers to identify patients with strong hypoxia response. By relating in vitro cell culture models to their in vivo cancer counterparts via the common language of "gene signature", we found we can recognize the molecular programs in human cancers reflecting defined perturbations in culture to explore their prognostic significance and phenotypic characteristics. Tumor microenvironments play critical roles in determining tumor behaviors and treatment responses and are featured by hypoxia and lactic acidosis. Although lactic acidosis is reported to be associated with tumor aggression and poor clinical outcomes, we know little about how cells respond to lactic acidosis, their prognostic significance in human cancers and best ways to identify tumors with this feature. In this proposal, we will use global gene expression in cell culture and human cancers to understand the role lactic acidosis in human cancers. We will first determine the transcriptional responses to lactic acidosis in various cultured cells to define "gene signatures" reflecting lactic acidosis. The possibility of abolishing this response by inhibiting Acid-Sensing Ion Channel (ASICs) or hypoxia-inducible factor (HIF) proteins will be tested. Secondly, the gene expression pattern associated with high lactate levels in tumors will be determined based on gene expression analysis of human cancers with measured lactate levels. The lactic acidosis gene signatures, obtained either in cell culture or tumors, will be used as molecular gauges to determine the level of lactic acidosis response in tumors based on gene expression. The prognostic significances of these gene signatures will be further tested in many other gene expression studies and the composition of molecular pathways lactic acidosis tumors will also be identified with advanced bioinformatics. To allow us to identify lactic acidosis cancers with high clinical risks, we will select molecular markers based on our gene expression studies. The spatial distribution of marker expression in tumor tissues will be compared to hypoxia markers (CA9) and measured tumor physiology parameters. Their prognostic values of these candidate markers will be further determined on multiple cancer tissue microarrays.