Oxygen’s role in cancer spread

Cancer cells need oxygen to survive, as do most other life forms, but scientists had never tracked their search for oxygen in their early growth stages until now — a step toward a deeper understanding of one way cancer spreads that could help treat the disease.

In a paper published online by the Proceedings of the National Academy of Sciences, bioengineers from Johns Hopkins University and the University of Pennsylvania report results of their work showing 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.

Oxygen-front.svg“If you think about therapeutic targets, you could target this process specifically,” said Sharon Gerecht, professor in Johns Hopkins University’s Whiting School of Engineering’s Department of Chemical and Biomolecular Engineering and a lead author of the study. She acknowledged that clinical application is a long way off, but said these results reached after three years of study in her laboratory 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. (Gerecht is an associate director of Johns Hopkins Institute for NanoBioTechnology.)

Sarcoma is a cancer that affects connective tissue, including bones, muscles, tendons, cartilage, nerves, fat and some blood vessels.  The study focused specifically on soft tissue sarcoma that does not affect bones, a type diagnosed in some 13,000 patients a year in the United States. Roughly a quarter to half of those patients develop recurring and spreading, or metastasizing, cancer.

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.

Gerecht and her seven co-authors – four affiliated with Johns Hopkins, three with Penn – tracked thousands of early stage cancer cells taken from mice as they moved through a mockup of bodily tissue made of clear gel in a petri dish.  The hydrogel – a water-based material with the consistency of gelatin – replicates the environment surrounding cancer cells in human tissue.

Kyung Min Park, 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 concentrations, or “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 low-oxygen or “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, Gerecht said.

“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. 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.

The research was supported by the National Cancer Institute (grants CA153952 and CA158301), the American Heart Association (61675), the National Science Foundation (1054415) and Johns Hopkins University’s President’s Frontier Award.

Story by Arthur Hirsch: ahirsch6@jhu.edu

Gerecht nets American Heart Association grant

Sharon Gerecht, associate professor in the Department of Chemical and Biomolecular Engineering and affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology, has received the prestigious American Heart Association Established Investigator Award.

sharongerecht_cropThe AHA awarded only four such grants this year, funding designed to support mid-career of investigators who show unusual promise and accomplishments in the study of “cardiovascular or cerebrovascular science.”

Gerecht’s research focuses on engineering platforms, specifically hydrogels, that are designed to coax stem cells to develop into the building blocks of blood vessels. The hope is that these approaches could be used to help repair circulatory systems that have been damaged by heart disease, diabetes, and other illnesses.

Additionally, Gerecht leads a research project in the Johns Hopkins Physical Science-Oncology Center where she is studying the effects of low oxygen (hypoxia) on the tumor growth and blood vessel formation. The AHA funding will support her work on regulating hypoxia in hydrogels for vascular regeneration. The award is worth approximately $400,000 over five years.

Learn more about the Gerecht lab here.

For all press inquiries regarding INBT, its faculty and programs, contact INBT’s science writer Mary Spiro, mspiro@jhu.edu or 410-516-4802.

 

EOC leader Gregg Semenza wins Canada Gairdner Award

Gregg Semenza

Gregg Semenza, associate director of Johns Hopkins Engineering in Oncology Center (EOC), has been named among seven 2010 winners of Canada’s international prize for medical research–the Canada Gairdner Award. The award is among the most prestigious for medical research and comes with a $100,000 cash prize.

The Canada Gairdner Award recognized Semenza for his work on how cells respond to oxygen availability in the body. He was the first to identify and describe hypoxia-inducible factor-1 (HIF-1), which switches genes on or off in response to oxygen levels.

Semenza leads a research project related to this topic for EOC with Sharon Gerecht, an assistant professor of chemical and biomolecular engineering. Their work focuses on analyzing the makeup and physical properties of the extracellular matrix, the three-dimensional scaffold in which cells live.

“Normal cells live in a flexible scaffold, but cancer cells create a rigid scaffold that they climb through to invade normal tissue,” Semenza said. “We will study how this change occurs and how it is affected by the amount of oxygen to which cancer cells are exposed. Our studies have shown that cancer cells are deprived of oxygen, which incites them to more aggressively invade the surrounding normal tissues where oxygen is more plentiful. Hypoxia-inducible factor 1 controls the responses of cancer cells to low oxygen, and we have recently identified drugs that block the action of HIF-1 and inhibit tumor growth in experimental cancer models.”

Semenza is the C. Michael Armstrong Professor in Medicine and founding director of the Vascular Biology program at  Johns Hopkins Institute for Cell Engineering at the School of Medicine. He also is a member of the McKusick-Nathans Institute of Genetic Medicine, is an affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology, and has ties to the Department of Biological Chemistry and the Sidney Kimmel Comprehensive Cancer Center, both at the Johns Hopkins School of Medicine.

The Johns Hopkins Engineering in Oncology Center, launched October 2009, is one of 12 funded by the National Cancer Institute to bring a new cadre of theoretical physicists, mathematicians, chemists and engineers to the study of cancer. During the five-year initiative, the NCI’s Physical Sciences-Oncology Centers (PS-OC) will take new, nontraditional approaches to cancer research by studying the physical laws and principles of cancer; evolution and evolutionary theory of cancer; information coding, decoding, transfer and translation in cancer; and ways to deconvolute cancer’s complexity.

Read more about Gregg Semenza winning the Canada Gairdner Award in the Johns Hopkins Gazette story by Audrey Huang here.

Johns Hopkins Engineering in Oncology Center