Oncogenesis recapitulates embryogenesis via the hypoxia pathway: morphoproteomics and biomedical analytics provide proof of concept and therapeutic options

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.