Abstract
Hypoxia in tumors correlates with greater risk of metastases, increased invasiveness, and resistance to systemic and radiation therapy. The evolutionary dynamics that links specific adaptations to hypoxia with these observed tumor properties have not been well investigated. While some tumor populations may experience fixed hypoxia, cyclical and stochastic transitions from normoxia to hypoxia are commonly observed in vivo. Although some phenotypic adaptations to this cyclic hypoxia are likely reversible, we hypothesize that some adaptations may become fixed through mutations promoted by hypoxia-induced genomic instability. Here we seek to identify genetic alterations and corresponding stable phenotypes that emerge following cyclic hypoxia. Although these changes may originate as adaptations to this specific environmental stress, their fixation in the tumor genome may result in their observation in tumors from regions of normoxia, a condition known as pseudohypoxia. We exposed several epithelial cell lines to 50 cycles of hypoxia-normoxia, followed by culture in normoxia over a period of several months. Molecular analyses demonstrated permanent changes in expression of several oncogenes and tumor-suppressors, including p53, E-cadherin, and Hif-1α. These changes were associated with increased resistance to multiple cytotoxins, increased survival in hypoxia and increased anchorage-independent growth. These results suggest cycles of hypoxia encountered in early cancers can select for specific and stable genotypic and phenotypic properties that persist even in normoxic conditions, which may promote tumor progression and resistance to therapy.
Highlights
As cancer cells progress, they undergo an evolutionary process during which genetic or epigenetic changes accumulate leading to progressively aggressive phenotypes
During early carcinogenesis, when neoplastic cells are confined within ducts, areas of severe hypoxia are evident in the periluminal regions
This has been inferred from immunohistochemistry (IHC) of patient tissue for the Hypoxia-Inducible Factor (HIF) clients, CA-IX (Fig. 1) and GLUT-1 (S1 Fig.) [17, 18]
Summary
They undergo an evolutionary process during which genetic or epigenetic changes accumulate leading to progressively aggressive phenotypes. Intermittent Hypoxia Selects for Increased Carcinogenesis include changes in proliferation, apoptosis resistance, and metabolism [1]. We have proposed that the emergence of these hallmarks results from selection by factors, such as hypoxia, that are altered as the microenvironment changes during carcinogenesis [2]. Tumor hypoxia is associated with radio-resistance and drug resistance [3,4,5,6]. This is relevant because drug resistance is the major cause of treatment failure for cancers and this may result from minor populations of drug resistant cells that are present within tumors prior to drug treatment [7]. We hypothesize that some of the phenotypic alterations induced by hypoxia can become hardwired so that they are expressed constitutively, even under normoxic conditions, a state known as pseudohypoxia [9, 10]
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