Brown Robert E, McGuire Mary F
Department of Pathology and Laboratory Medicine, University of Texas Health Science Center-Medical School at Houston, 77030, USA.
Ann Clin Lab Sci. 2012 Summer;42(3):243-57.
Hypoxia (3 to 5% oxygen) is essential in maintaining the plasticity of embryonic stem cells and permitting their transformation via epithelial-mesenchymal transition(EMT) and mesenchymal-epithelial transition(MET) into tissues and organs of the developing fetus. Similarly, a relatively hypoxic microenvironment supports the development of tumor cells with stemness and epithelial-mesenchymal properties and capabilities. At the same time, such adaptation results in the tumor cells becoming relatively resistant to chemotherapy and radiation therapy and promotes intravasation into blood vessels with metastasis. In this context, current therapeutic strategies designed to target tumoral angiogenesis could promote stemness and EMT by rendering tumor cells more hypoxic, leading to chemoradioresistance and metastatic and recurrent disease.
The purpose of this report is to present a conceptual model that illustrates the impact of an hypoxic microenvironment on the signal transduction pathways involved in the hypoxia pathway. We will show the molecular connectivity and correlative association of these pathways with protein analytes in both embryogenesis and oncogenesis in order to strengthen our hypothesis that oncogenesis recapitulates embryogenesis. Finally, we propose to use the model as a basis for the construction of combinatorial, therapeutic options from existing pharmaceutical and nutraceutical agents that may obviate tumoral adaptation to hypoxia.
Morphoproteomics and biomedical analytics. APPLICATION AND RESULTS: Archival data retrieved from morphoproteomic analysis of glioblastoma multiforme(GBM) cases revealed proteomic correlates of tumoral necrosis and associated hypoxia pathway signaling. Biomedical analytics using Ingenuity Pathway Analysis (IPA) showed comparative validation of the hypoxia pathway, as demonstrated by morphoproteomics in GBM, both with the hypoxia-induced genes in neuroblastoma and with the networks associated with embryogenesis. Additionally, therapeutic agents known to have activity against various components of the hypoxia pathway (identified by morphoproteomic analysis in GBM) were validated using UNIPROT identifiers entered into IPA and Path Designer. These therapies also connected with the hypoxia signature in neuroblastoma and embryogenesis.
The application of morphoproteomics to define the presence of an adaptive hypoxia pathway in GBM accords with biomedical analytics in the demonstration of concordant interaction with the hypoxia signature in neuroblastoma and embryogenesis, providing proof of concept that oncogenesis recapitulates embryogenesis. This approach also validates a new combinatorial therapeutic strategy targeting the hypoxia pathway and designed to prevent tumoral adaptation, chemoradioresistance and recurrent disease.
低氧环境（3%至5%的氧气含量）对于维持胚胎干细胞的可塑性以及使其通过上皮-间质转化（EMT）和间质-上皮转化（MET）转变为发育中胎儿的组织和器官至关重要。同样，相对低氧的微环境支持具有干性以及上皮-间质特性和能力的肿瘤细胞的发育。同时，这种适应性导致肿瘤细胞对化疗和放疗产生相对抗性，并促进其通过血管内渗发生转移。在此背景下，当前旨在靶向肿瘤血管生成的治疗策略可能会通过使肿瘤细胞更加低氧，从而促进干性和EMT，导致放化疗耐药以及转移性和复发性疾病。
本报告的目的是提出一个概念模型，以说明低氧微环境对低氧途径中涉及的信号转导通路的影响。我们将展示这些通路在胚胎发生和肿瘤发生过程中与蛋白质分析物的分子连接性和相关性，以强化我们的假说，即肿瘤发生重现胚胎发生。最后，我们建议将该模型作为构建组合治疗方案的基础，这些方案来自现有的药物和营养保健品，可能会消除肿瘤对低氧的适应性。
形态蛋白质组学和生物医学分析。
从多形性胶质母细胞瘤（GBM）病例的形态蛋白质组学分析中检索到的存档数据揭示了肿瘤坏死和相关低氧途径信号传导的蛋白质组学相关性。使用 Ingenuity Pathway Analysis（IPA）进行的生物医学分析显示了低氧途径的比较验证，如GBM中的形态蛋白质组学所示，既与神经母细胞瘤中的低氧诱导基因相关，也与胚胎发生相关的网络相关。此外，使用输入到IPA和Path Designer中的UNIPROT标识符，验证了已知对低氧途径的各种成分具有活性的治疗药物（通过GBM中的形态蛋白质组学分析确定）。这些疗法也与神经母细胞瘤和胚胎发生中的低氧特征相关联。
应用形态蛋白质组学来确定GBM中适应性低氧途径的存在，与生物医学分析一致，证明了与神经母细胞瘤和胚胎发生中的低氧特征存在一致的相互作用，为肿瘤发生重现胚胎发生这一概念提供了证据。这种方法还验证了一种针对低氧途径的新的组合治疗策略，该策略旨在预防肿瘤适应性、放化疗耐药性和复发性疾病。
