Gene expression programs of lactic acidosis in human cancers

描述(申请人提供)：癌症研究中的一个挑战是如何将体外细胞培养获得的结果转化为体内人类癌症的复杂行为。我们以前在培养的细胞中发现了一个缺氧基因信号，以允许我们推断许多人类癌症中缺氧途径活动的水平，以确定具有强烈缺氧反应的患者。通过将体外细胞培养模型与体内癌症模型通过共同语言“基因签名”联系起来，我们发现我们可以识别反映培养中明确扰动的人类癌症的分子程序，以探索它们的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着至关重要的作用，其特点是缺氧和乳酸酸中毒。尽管乳酸酸中毒被报道与肿瘤侵袭性和不良的临床结果有关，但我们对乳酸酸中毒细胞如何反应，它们在人类癌症中的预后意义，以及识别具有这一特征的肿瘤的最佳方法知之甚少。在这项提案中，我们将利用细胞培养和人类癌症中的全球基因表达来了解乳酸酸中毒在人类癌症中的作用。我们将首先确定不同培养细胞对乳酸酸中毒的转录反应，以确定反映乳酸酸中毒的“基因标志”。通过抑制酸敏感离子通道(ASICs)或低氧诱导因子(HIF)蛋白来消除这种反应的可能性将被测试。其次，将根据测量的乳酸水平对人类癌症的基因表达进行分析，确定与肿瘤中高乳酸水平相关的基因表达模式。在细胞培养或肿瘤中获得的乳酸酸中毒基因特征将被用作基于基因表达来确定肿瘤乳酸酸中毒反应水平的分子标尺。这些基因标记的预后意义将在许多其他基因表达研究中得到进一步验证，乳酸酸中毒肿瘤的分子通路的组成也将利用先进的生物信息学进行鉴定。为了使我们能够识别具有高临床风险的乳酸中毒癌症，我们将根据我们的基因表达研究来选择分子标记。肿瘤组织中标志物表达的空间分布将与缺氧标志物(CA9)和测量的肿瘤生理参数进行比较。这些候选标记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.