Scientists from Johns Hopkins University and the University of Pennsylvania reported on work that showed how sarcoma cells in mice pursue a path toward greater concentrations of oxygen, almost as if they were following a widening trail of breadcrumbs. That path is suggested to lead the cells to blood vessels, through which the cells can spread to other parts of the body.
“If you think about therapeutic targets, you could target this process specifically,” said Sharon Gerecht, Ph.D., professor in Johns Hopkins University's Whiting School of Engineering's department of chemical and biomolecular engineering and a lead author of the study (“Intratumoral Oxygen Gradients Mediate Sarcoma Cell Invasion”) that appeared in PNAS. She acknowledged that clinical application is a long way off, but said these results provide clues about a key part of the life cycle of soft-tissue sarcomas and also a proven way to test cancer treatments in the lab.
Cancers of all sorts are known to thrive with little oxygen, and researchers have looked at the role of low oxygen conditions in tumor development. Less well understood is how cancer cells respond to varying oxygen concentrations in their early stages. That was the focus of this research.
Dr. Gerecht and her team tracked thousands of early-stage cancer cells taken from mice as these cells moved through a mockup of bodily tissue made of clear gel in a petri dish. The hydrogel replicates the environment surrounding cancer cells in human tissue.
Kyung Min Park, Ph.D., then a postdoctoral researcher in the Johns Hopkins lab, developed the hydrogel–cancer cell system, and Daniel Lewis, a Johns Hopkins graduate student, analyzed cellular migration and responses to rising oxygen gradients. For this experiment, the hydrogels contained increasing concentrations of oxygen from the bottom of the hydrogel to the upper layer. That allowed researchers to track how cancer cells respond to different levels of oxygen, both within a tumor and within body tissues.
Analysis of sarcoma tumors in mice, for instance, shows that the largest tumors have a large area of very low oxygen at the center. Smaller tumors have varying oxygen concentrations throughout. The researchers' first step was to show that cancer cells migrate more in hypoxic hydrogels as compared with hydrogels containing as much oxygen as the surrounding atmosphere. They then looked at the direction of the cell movement.
In the hydrogel, which mimics the oxygen concentrations in smaller tumors, cells were found to move from areas of lower oxygen to higher. Researchers also found that the medication minoxidil, widely used to treat hair loss and known by its trade name Rogaine, stopped the movement of cancer cells through the hydrogel.
Cancer cells are known to modify their environment to make it easier for them to move through it, but this study takes that understanding a step further, noted Dr. Gerecht.
“We did not know it was the oxygen” that effectively directs the movement, she said. “It's suggesting oxygen gradient affects early stages of the metastasis process.”
The study also demonstrates the three-dimensional hydrogel model as an effective tool for testing cancer treatments in a laboratory, the authors wrote. Dr. Gerecht said a human patient's cancer cells could be placed into the hydrogel just as the mouse cells were, allowing clinicians to see how they respond before treatments are given to patients.