Low-Oxygen Microenvironments Program Cancer Cells Resist Chemotherapy

The hypoxic microenvironment of primary tumors signals the tumor to pre-program disseminated tumor cells (DTCs) to become dormant, allowing them to evade chemotherapy, a recent study found.

Hypoxia is a hallmark of solid tumors that induces stress responses, quiescence programs, and resistance to chemotherapy and radiation.

In a study published in Nature Cell Biology, investigators used biosensors and advanced imaging technology to develop a device that manipulates the microenvironments of primary tumors.

The devices were loaded with drugs that induced hypoxia, and then implanted into the tumors to create controlled hypoxic and non-hypoxic niches, according to the study. The modified microenvironments in the tumors allowed the investigators to isolate the cancer cells to determine how they behaved when moved from the primary tumor to the lungs.

The DTCs were tracked with genetically encoded biosensors to determine which cells were exposed to low-oxygen, which were dormant, and how they reacted to therapy, according to the study.

“This approach and the hypoxia biosensor and nano- and imaging technology innovations developed by SUNY Polytechnic Institute and the Integrated Imaging Program at Einstein allowed linking primary tumor microenvironments to fate of DTCs in a way that was never before attempted and at single cell resolution allowing definitive tests of mechanism,” said co-corresponding senior investigator John Condeelis, PhD, in a press release.

The results of the study showed DTCs from hypoxic regions were still able to metastasize, and were more likely to become dormant compared with cells from tumors with high-oxygen levels. The findings indicate that the hypoxic regions could rapidly spread and grow DTCs, and send large proportions of the cells into dormancy.

“This research is an important step to further explore the biology of these dormant cells and design therapies that specifically address this biology,” said senior investigator Julio A. Aguirre-Ghiso, PhD.

According to the authors, low-oxygen tumor microenvironments may indicate a poor prognosis because it activates aggressive characteristics in tumor cells, and allows dormant cancer cells to evade chemotherapy.

The findings suggest the use of a marker test to predict which patients might be more prone to carrying more dormant, drug-resistant cancer cells.

“This research highlights the signals in the primary tumor that instruct disseminated cancer cells to become dormant,” Aguirre-Ghiso said. “Dormant cells must be targeted to address the whole spectrum of disease and attacking the cancer. 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.”