Stiff, oxygen-deprived tumours promote cancer spread

Hard, oxygen-poor tumours trigger a biological switch that causes cancer stem cells to invade other tissues, and could offer a promising treatment target to stop the disease from spreading, scientists have found.

Scientists from Princeton University and the Mayo Clinic Cancer Centre in the US suggests that the biological switch is critical to a tumour's ability to invade other tissue, a process called metastasis.

"Our study suggests that to combat cancer, we should be developing treatments that target the stiff, hypoxic regions of tumours," said lead author Celeste Nelson, professor at Princeton.
"We were surprised to see just how important these two properties in the tumour microenvironment - stiffness and hypoxia - were for regulating cancer stem cells," Nelson said.

The specific cells triggered by stiffness and hypoxia are called cancer stem cells. These cells represent only a small proportion of the total cells in a tumour, but researchers believe they play a key role in spreading the disease.

As normal stem cells help form an embryo, or aid in repairing muscles, cancer stem cells specialise in generating new malignant cells.

In addition to spreading cancer, just 10 to 100 leftover cancer stem cells are needed to regenerate a tumour after it has been removed.

Using cultures of human breast-cancer cells and mouse mammary-cancer cells, researchers discovered an association between a protein called integrin-linked kinase and the creation of cancer stem cells.

Normally, integrin-linked kinase assists cells with a variety of important cellular tasks. But in dense, oxygen-poor tumours, the protein's function goes awry.

Researchers created a range of human and mouse breast-cancer cultures reflecting different tissue conditions.

They showed that stiff hypoxic cultures did indeed promote cancer stem cells.
However, when they eliminated the integrin-linked kinase from those samples, they found that the cancer stem cells stopped forming.

Conversely, when they forced abnormal levels of integrin-linked kinase in samples containing softer or less hypoxic tissue, cancer stem cells formed.

They also confirmed a significant association between tumour stiffness, integrin-linked kinase and cancer stem cell presence in samples from human breast-cancer patients.

The findings suggest that stiffness and hypoxia cause integrin-linked kinase to behave abnormally, which in turn triggers cancer stem-cell formation.

There are likely other features in tumours that cause cancer stem cells to form, but the findings indicate that stiff, hypoxic conditions and their effects on integrin-linked kinase are two of the most prominent ones.The study appears in the journal Cancer Research