Oxygen-Deprived Tumor Environment Linked to Cancer Metastasis

The stiffness of a tumor and hypoxia was found to cause breast cancer progression in laboratory cultures during a recent study.

Hypoxia is a condition where the body, or a region of the body, is deprived of adequate oxygen supply at the tissue level. Tumors are hypoxic, which means they grow so large and dense that they exclude blood vessels, resulting in a lack of oxygen in their cores.

What role these characteristics play in the development of cancer remains unknown, but findings from a study published in Cancer Research moved researchers closer to answering this question.

“Our study suggest that to combat cancer, we should be developing treatments that target the stiff, hypoxic regions of tumors,” said lead study author Celeste Nelson. “We were surprised to see just how important these 2 properties in the tumor microenvironment — stiffness and hypoxia – were for regulating cancer stem cells.”

These specific cells that are triggered by hypoxia and stiffness are cancer stem cells. They represent only a small proportion of the total tumor cells; however, researchers believe they may play a key role in the disease spreading.

Regular stem cells help form an embryo, or aid in repairing muscles, while cancer stem cells generate new malignant cells. Furthermore, in addition to the spread of cancer cells, only 10 to 100 leftover cancer stem cells are needed to regenerate a tumor after it has been removed.

For the study, researchers used cultures of human breast cancer cells and mouse mammary cancer cells, and found an association between the protein integrin-linked kinase and the development of cancer stem cells. Integrin-lined kinase normally assists cells with an array of important cellular tasks; however in dense, oxygen-deprived tumors the proteins function goes awry.

While in the lab, researchers created a variety of mouse and human breast cancer cultures that reflect different tissue conditions. The results of the study showed that stiff hypoxic cultures promoted cancer stem cells. However, when the integrin-linked kinase proteins were eliminated from the cultures, they found that the cancer stem cells stopped forming.

When researchers forced abnormal levels of the protein in the samples that contained less hypoxic or softer tissue, they found that cancer stem cells formed. Additionally, researchers were able to confirm a significant association between tumor stiffness, integrin-linked kinase, and cancer stem cell presence in the human breast cancer cultures.

“We could see tumor cells expressing cancer stem cell markers and integrin-linked kinase located at regions with high collagen, which is used to estimate stiffness in a tumor,” said researcher Mei-Fong Pang.

The findings suggest that stiffness and hypoxia environments cause integrin-kinase to behave abnormally, triggering cancer stem cell formation, according to the study.

The authors noted that, although it is likely that there are other features in tumors that causes the formation of cancer stem cells, the results indicate that stiffness and hypoxia, as well as their effects on integrin-linked kinase, are 2 of the most prominent ones. Meaning that the results could be used to help better understand some type of cancers, as well as for developing treatments for those characterized by solid tumors.

“These findings may lead to the identification of a new therapeutic target to halt cancer progression and metastasis,” said Ren Xu, an associate professor who is familiar with the study but played no role in it. “Given the crucial function of integrin-linked kinase in hypoxia and stiff-induced cancer progression, it is now critical to define the molecular mechanisms by which integrin-linked kinase expression is regulated under these conditions.”

Next, the team of researchers plan to investigate the specific molecular pathways that promote cancer stem cell formation in the presence of stiff, hypoxia, and integrin-linked kinase.

“If we can make the tumor softer or reduce hypoxia we could potentially have a way to treat breast cancer and maybe other cancers as well,” Nelson said.