Oxygen-starved cancer cells programmed to evade therapy after spreading

By manipulating the environment surrounding cells in primary tumors, scientists have discovered for the first time the conditions that program migrating cancer cells to become dormant and hide from chemotherapy after spreading.

A paper on this discovery, led by Mount Sinai School of Medicine in New York, is published in the journal Nature Cell Biology.

The researchers suggest that the work could lead to new drugs and therapies that transform the treatment of metastatic cancers, most of which cannot be cured with current approaches.

Most deaths to cancer are due to metastasis - a disease stage that begins when cancer cells escape primary tumors, migrate through the blood or lymph system, and establish secondary tumors in other parts of the body.

The secondary, or metastatic, tumor is the same form of cancer as the primary tumor.

When metastatic cells are examined, they have features matching those of the primary cancer and not of the tissue that the secondary tumor has formed in.

Finding ways to stop cancer cells acquiring the ability to migrate, or establish and grow secondary tumors, could save many lives.

Dormant cells that 'hide' from chemotherapy

Hypoxia, a condition in which cells are starved of oxygen, is a known hallmark of solid tumors that triggers stress responses and induces resistance to chemotherapy and radiotherapy.

Fast facts about cancer

  • Cancer is a leading cause of disease and deaths worldwide
  • In 2012, there were 8.2 million cancer-related deaths and around 14 million new cases
  • The amount of new cases is expected to rise by approximately 70 percent over the next 20 years.

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Until now, however, it has not been clear how hypoxia in primary tumors influences what happens to cancer cells that migrate to new sites, and how this affects the prognosis of the disease.

The new study suggests that hypoxic microenvironments in primary tumors give rise to dormant disseminated tumor cells (DTCs) that "hide" from therapy and may be a cause of disease relapse and poor outcomes.

Senior author Julio A. Aguirre-Ghiso, Ph.D., a professor of medicine, hematology, and medical oncology at Mount Sinai, says: "This research highlights the signals in the primary tumor that instruct disseminated cancer cells to become dormant."

"Dormant cells must be targeted to address the whole spectrum of the disease and attacking the cancer," he adds.

With the help of biosensors, nanotechnology, and advanced imaging, the team implanted drugs that create hypoxic and non-hypoxic niches in breast tumors in mice and observed the effect on cells.

Biomarkers for treatment-resistant dormant cells

The researchers were able to isolate the cancer cells one by one and find out how they behaved when they traveled from the primary tumor to the lungs.

Genetically encoded biosensors allowed them to determine which cells were dormant, which ones were exposed to low oxygen, and their reactions to therapy.

They discovered that hypoxic tumor microenvironments not only produce DTCs that rapidly grow and spread, but also send a large proportion of them into a dormant state that makes them better able to evade chemotherapy.

The study suggests, therefore, that the poor prognoses associated with hypoxic tumors may arise not only because they produce more aggressive cancer cells, but also because they program many of them to enter a dormant state where they can hide from chemotherapy.

Researchers also found genes in the primary tumor that correlated with the behavior of dormant, treatment-resistant cells in the secondary tumors.

They suggest that these genes could form the basis of a biomarker to predict which patients are likely to have more of the dormant, resistant cells.

Prof. Aguirre-Ghiso describes the study as "an important step to further explore the biology of these dormant cells and design therapies that specifically address this biology," and he concludes:

"We hope this research may lead to the use of dormancy markers in primary tumors to assess the prevalence of disseminated cancer cells in secondary organs and thus tailor treatments to eliminate these dormant and therapy evading cancer cells."

Learn how cancer cells' ability to break free and spread arises from a 'broken switch'.

    Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments, Georg Fluegen et al., Nature Cell Biology, doi:10.1038/ncb3465, published online 23 January 2017, abstract.

    Mount Sinai Hospital / Mount Sinai School of Medicine news release, accessed 27 January 2017 via EurekAlert.

    Additional source: WHO, Cancer: Key facts, accessed 27 January 2017.

    Additional source: NIH: National Cancer Institute, Metastatic cancer, accessed 27 January 2017.