A Dialogue between the Hypoxia-Inducible Factor and the Tumor Microenvironment

The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel “anti-microenvironment” directed therapies

Proteomic Analysis of Protein Expression Changes in a Model of Gliomagenesis

Loss of p53 function is a common event in a variety of human cancers including tumors of glial origin. Using an in vitro mouse model of malignant astrocyte transformation, three cleavable isotope coded affinity tag (cICAT) experiments were performed comparing cultured wild-type astrocytes and two p53(-/-) astrocyte cultures before and after malignant transformation. We identified and quantitated an average of 1366 proteins per experiment and demonstrated that the protein quantitation ratios in each individual cICAT experiment correlated well to ratios determined in the other two studies. These data were further supported by microarray analysis which also correlated to changes in protein expression. The results showed significant changes in protein expression in association with malignant transformation. Proteins overexpressed in malignant astrocytes were typically involved in ribosome biogenesis/protein synthesis and DNA replication, while underexpressed proteins were generally associated with the regulation of cell cycle checkpoint control, tumor suppression, and apoptosis. Among the significantly up-regulated proteins and transcripts in malignant mouse astrocytes were members of the minichromosome maintenance (MCM) family. Western blot analysis verified increased expression of MCM proteins in malignant human astrocytoma cell lines, which had not previously been described. These results demonstrate the usefulness of the cICAT approach for comparing differences in protein expression profiles between normal and malignant cells