Hypoxic control of metastasis

“…We next assessed PRAK and HIF-1α protein expression using immunohistochemistry in a human tissue array containing 40 lung carcinoma samples with paired lymphatic metastases. Consistent with many other previous reports 6 , 34 – 36 , HIF-1α showed more intensive staining in metastatic than primary tumors (Fig. 6b and d ).…”

“…As several lines of evidence suggest that hypoxia precedes the formation of the EMT state ( Figure 2F, Figure S2I, Figure 3E ), we postulate that these environmental changes contribute to the induction and selection of an epigenetically-stable, pro-metastatic EMT state. This hypothesis aligns with prior reports associating hypoxia with genomic instability and EMT 22,86–88 , including in human lung adenocarcinoma 89 , and here our spatial-lineage data provide new evidence linking subclonal expansion as a mechanism driving hypoxia and tumor progression. In addition to our observation that human lung adenocarcinoma tumors contain spatially-defined hypoxic regions 90 ( Figure S3N-O ), hypoxia has also been shown to play critical roles in lung adenocarcinoma 91 and other cancers (e.g., glioma 92 and clear cell renal cell carcinoma 22 ); thus, further dissecting the relationships between subclonal expansions and hypoxia in these cancers may reveal opportunities for therapies spanning multiple cancer types.…”

“…In view of this decline in blood perfusion, it is not surprising that intratumour hypoxia is markedly increased under these conditions ( Figure 5). The aberrant increase in HIF-1a and its target genes, VEGF and CA9, in FSaII tumours observed in response to 15 Gy irradiation ( Figure 6) is in agreement with previous reports that high-dose irradiation induces significant upregulation of HIF-1a in various tumours [31,[35][36][37][38][39][40]43]. In the context of radiation-induced upregulation of HIF-1a, studies to date have shown that hypoxic cells in tumours are reoxygenated after irradiation and HIF-1a is activated in response to the reactive oxygens formed [36].…”