For more than 50 years, scientists have known that significant differences exist between the metabolic processes of normal and cancerous cells. These processes encompass the complex set of chemical reactions that control everything from converting food into usable energy to manufacturing cellular components for growth and reproduction. But the causes and consequences of these metabolic differences remain largely unknown -- and the possibilities for exploiting these differences as potential targets for new therapies have been largely untapped.
The altered metabolism of cancer cells allows them to grow rapidly and proliferate, leading to the development of aggressive tumors often able to spread, or metastasize, to other areas of the body. But when subjected to stressful conditions, such as oxygen- and nutrient-deprivation in the center of a tumor or an onslaught of chemotherapeutic agents, these cells are able to stop proliferating and cannibalize portions of themselves.
To determine whether specific genes play a role in autophagy in proliferating and quiescent cells, scientists reduce the activity of these genes and then determines the amount of autophagy within the cell. To assess autophagy levels in one previous experiment, researchers exposed the cells to a fluorescently labeled antibody that recognizes a protein present on autophagosomes, the structures that cells form to perform autophagy. Areas within the cell where autophagy was taking place glowed green when observed under a fluorescent microscope.
(Photo Credit: Sarah Pfau)
"This ingenious property allows these cancer cells to tolerate enormous amounts of stress," said Eileen White, associate director for basic science at CINJ, who also is a professor of molecular biology and biochemistry at Rutgers University. "If they're starving or stressed, they eat themselves and hunker down until the stress is removed. Then, as soon as the stress is gone, they grow back, often killing the patient. If we can understand this process and exploit it for cancer therapy, we may develop new ways to kill the cancer cells without killing the normal cells."
Autophagy is believed to confer stress resistance to cells by providing energy and disposing of old or damaged cell parts that might otherwise prove harmful to the cell over time, and it is not unique to cancer cells: Coller studies a metabolic state known as cellular quiescence in fibroblast cells. Fibroblasts are found in connective tissue, which includes cartilage and the cellular matrix known as stroma that provides support to body structures, such as organs, glands and also tumors.
Akin to dormant cancer cells, quiescent fibroblasts take a break from the normal cell growth cycle, but maintain the ability to re-enter the cycle in the future. Like dormant cancer cells, quiescent fibroblasts often engage in autophagy.
Cancer researchers now recognize that a full understanding of how a tumor behaves in response to stress requires knowledge about the metabolism of the cancerous cells and the stromal cells in the tumor, which often constitute a large percentage of the tumor itself, as well as an awareness of how the metabolism of cancerous and noncancerous cells affect one another.
The interdisciplinary team is seeking to define the metabolic networks in stromal and tumor cells, identify the metabolic adaptations that take place as cells transition between different metabolic states, and demonstrate how these changes alter tumor-stromal interaction. The team also is supported by grants from CINJ and the New Jersey Commission on Cancer Research.
The research effort makes use of wide-ranging scientific techniques, including DNA microarray analyses to identify the gene expression changes that underlie metabolic alterations and state-of-the-art methods to identify altered metabolic states by quantifying the concentrations of metabolites -- compounds generated during biological processes that provide chemical clues into which metabolic processes are taking place -- and watching how they change over time.
The project complements clinical trials investigating ways to modulate autophagy in cancer cells, some of which are already under way at CINJ. One study is assessing whether adding hydroxycholoroquine, an anti-malaria drug known to have autophagy-blocking activity, to standard therapy for recurrent colon cancer will increase the number of cancers that go into remission or boost the length of remission.
"The ultimate test will be to take all of our findings and use that information to develop novel approaches for eradicating cancer," White said. "If we can prevent tumor cells from utilizing this altered metabolic state then that should be the Achilles' heel of tumors."
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