Abstract
The microenvironment of solid tumors is dynamic and frequently contains pockets of low oxygen levels (hypoxia) surrounded by oxygenated tissue. Indeed, a compromised vasculature is a hallmark of the tumor microenvironment, creating both spatial gradients and temporal variability in oxygen availability. Notably, hypoxia associates with increased metastasis and poor survival in patients. Therefore, to aid therapeutic decisions and better understand hypoxia’s role in cancer progression, it is critical to identify endogenous biomarkers of hypoxia to spatially phenotype oncogenic lesions in human tissue, whether precancerous, benign, or malignant. Here, we characterize the glucose transporter GLUT3/SLC2A3 as a biomarker of hypoxic prostate epithelial cells and prostate tumors. Transcriptomic analyses of non-tumorigenic, immortalized prostate epithelial cells revealed a highly significant increase in GLUT3 expression under hypoxia. Additionally, GLUT3 protein increased 2.4-fold in cultured hypoxic prostate cell lines and was upregulated within hypoxic regions of xenograft tumors, including two patient-derived xenografts (PDX). Finally, GLUT3 out-performs other established hypoxia markers; GLUT3 staining in PDX specimens detects 2.6–8.3 times more tumor area compared to a mixture of GLUT1 and CA9 antibodies. Therefore, given the heterogeneous nature of tumors, we propose adding GLUT3 to immunostaining panels when trying to detect hypoxic regions in prostate samples.
Highlights
Oxygen consumption rates are high in tumors due to the proliferative nature of cancer cells and to the presence of infiltrating immune cells
Hypoxia induces the expression of approximately 1% of the genome and, there appears to be some common upregulated genes, the transcriptional response can vary dramatically in different cell types [51,54]
Considering the high degree of identity between the GLUT3 and GLUT14 genes, it is likely that GLUT3 transcripts were signature for localized prostate cancer [70]
Summary
Oxygen consumption rates are high in tumors due to the proliferative nature of cancer cells and to the presence of infiltrating immune cells. Uncontrolled proliferation of cancer cells causes tumors to outgrow their blood (and, oxygen) supply, leading to regions with low oxygen levels, known as hypoxia [1]. Cells exposed to acute hypoxia (low intracellular oxygen levels that last minutes to hours) or chronic hypoxia (lasting hours to days) exhibit dramatic changes in gene expression due to the stabilization of hypoxia-inducible factors (HIF), HIF-1α and HIF-2α These HIF transcription factors are master-regulators of the hypoxia response, accounting for the bulk of transcriptional changes in hypoxia [11,12]. Hypoxia and activation of the HIF-1α/2α gene networks participate in numerous cancerous behaviors including cell immortalization, most aspects of the metastatic cascade, vascularization, and suppression of the immune response [11,13–17]. Low oxygen levels are associated with resistance to chemotherapy and radiotherapy, as well as poor patient survival [18–21]
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