Editors' ChoiceCancer

Hypoxia-induced plasticity in cancer cell migration

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Sci. Signal.  28 Feb 2017:
Vol. 10, Issue 468, eaan0467
DOI: 10.1126/scisignal.aan0467

Hypoxia stimulates cancer cells to switch from collective migration to amoeboid migration.

As a group of polarized cells that adhere to one another, metastatic cancer cells can migrate individually or collectively. Individually migrating cells may retain their elongated shape and express genes encoding epithelial-to-mesenchymal transition (EMT) markers or adopt a rounded shape and exhibit amoeboid movement. Metastasizing tumor cells can switch between modes of migration. Lehmann et al. found that hypoxia, such as that which exists in the tumor microenvironment, induces collectively migrating cancer cells to switch from collective to amoeboid migration. Under normoxic conditions in three-dimensional (3D) culture, highly metastatic murine 4T1 mammary carcinoma cells exhibited collective migration with a small proportion of the cells leaving the collective to migrate individually. Under hypoxic conditions, a higher proportion of these cells left the collective in a manner that depended on hypoxia-inducible factor 1 (HIF-1). Hypoxia also stimulated invasion of nonmetastatic human UT-SCC-38 head and neck squamous carcinoma cells in 3D culture. Most of the cells that disseminated from 4T1 collectives exhibited a rounded amoeboid morphology. Treating 4T1 cultures with the HIF-1 activator dimethyloxalylglycine (DMOG) promoted the dissemination of rounded cells and stimulated the accumulation of the EMT marker Twist in the nuclei of these cells. Overexpressing Twist in 4T1 cells induced an increase in the numbers of rounded disseminated cells under normoxic conditions, and knocking down Twist reduced the DMOG-induced dissemination of single cells under normoxic conditions. Treating 4T1 cells with DMOG before injecting them into mice increased the number and size of lung metastases. In clinical samples of head and neck squamous carcinoma, the abundance of HIF-1 and a HIF-1–regulated target positively correlated with metastasis. These results demonstrate that induction of EMT markers is not limited to mesenchymal migration and that hypoxia stimulates not only classical EMT (mesenchymal migration) but also amoeboid migration.

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