- Author: Kathy Keatley Garvey
Earlier research by the Judah Folkman laboratory of Harvard Medical School showed that cutting off blood vessels that feed a cancerous tumor can stop its growth.
The seven-member research team—five from the Bruce Hammock laboratory of UC Davis—“characterized a novel lipid signaling molecule that can change fundamental biological processes involved in our health and disease,” said lead author and researcher Amy Rand. “We've found that a novel product derived from the metabolism of omega-6 fatty acids stimulates angiogenesis, which may contribute to enhanced tumor growth by providing tumors with oxygen and nutrients.”
“As a highly regulated process, angiogenesis is critical for wound healing and development, but many diseases result in unregulated angiogenesis, including cancer,” explained Rand, a postdoctoral fellow in the lab of Bruce Hammock, a distinguished professor who holds a joint appointment with UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “We may be able to control angiogenesis to stimulate wound healing when necessary, but also block tumor growth in patients. Diseases that rely on angiogenesis may be able to be treated in part by changes in dietary lipid exposure or by controlling levels of these metabolites through enzyme inhibitors that block their formation.”
The research, published April 10 in the Proceedings of the Natural Academy of Sciences (PNAS), explains, in part, why inhibiting the soluble epoxide hydrolase (sEH) in some systems is angiogenic whereas combining sEH inhibition with the inhibition of cyclooxygenase (COX) enzymes is dramatically antiangiogenic, which in turn may suppress tumor growth.
“There's uncertainty regarding the link between unsaturated fats and cancer, due to ongoing conflicts between scientific studies and insufficient data,” Rand said. “Because of this, there is a major gap in our understanding of how these essential dietary fats affect our health. We used tools to detect and characterize unknown metabolites from omega-6 unsaturated fats and determined their effect on angiogenesis, to address at least a small part of this uncertainty by focusing on how these fats contribute to cancer tumor growth.”
Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, said the research, titled “Cyclooxygenase-Derived Proangiogenic Metabolites of Epoxyeicosatrienoic Acids
Holds long term hope for cancer patients and those afflicted with heart, eye and other diseases. The team also included Christophe Morisseau, Bogdan Barnych, and Kin Sing Stephen Lee all of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center; Tomas Cajka of the UC Davis Genome Center; and Dipak Panigraphy of Harvard Medical School. Lee is now an assistant professor at Michigan State University.
“Pro and anti-angiogenic therapy can potentially help millions of people worldwide in various diseases such as heart, ulcers, eye and cancer as first demonstrated by Dr. Judah Folkman and his colleagues,” said Panigraphy, formerly of the Hammock lab and now with the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, and the school's Department of Pathology.
“While the COX and sEH pathways can be targeted with drugs, their interaction is poorly understood,” Panigraphy said. “These studies by Rand et al demonstrate for the first time new specific mechanisms whereby targeting the sEH pathway can be both pro- and anti-angiogenic and has the potential to help patients with devastating diseases such as in the eye and cancer where blocking angiogenesis is desired.”
Rand, who received her doctorate in chemistry from the University of Toronto, Canada, in 2013, the same year she joined Hammock's biological analytical chemistry lab, said she's “always been interested in research that combines chemistry and biology to enhance our understanding of human health.”
Future work? “We aim to understand the direct involvement of these omega-6 fatty acid metabolites with cancer tumor growth and metastasis.”
Rand last year received the $100,000 Judah Folkman Fellowship for Angiogenesis Research from the American Association for Cancer Research. She won the highly competitive international award for her proposal, “Regulation of Cancer Angiogenesis from the Metabolism of Epoxy Omega-6 Fats.” Rand joined Hammock's biological analytical chemistry lab in 2013 and was a fellow on the Oncogenic Signals and Chromosome Biology T32 Training Grant, UC Davis Department of Microbiology and Molecular Genetics.
The late Judah Folkman (1933-2008), a Harvard Medical School professor considered the father of angiogenesis research, “is best known for pioneering the concept of blocking angiogenesis (the development of blood vessels) to control cancer growth," Hammock said. "This concept has resulted in a number of anti-cancer drugs and has had a major impact on cancer treatment. Of course, blood vessel development is also critical for survival."
Folkman discovered that cutting off the blood vessels that feed the tumor can stop cancer tumor growth. His revolutionary work has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization. Inhibitors of the sEH pathway are moving toward human trials to control neuropathic pain, but if combined with nonsteroidal anti-inflammatory drugs can block tumor growth by blocking angiogenesis. So Dr. Sung Hee Hwang combined inhibitors of both pathways into one molecule which is being investigated in cancer models at the UC Davis Cancer Center by Dr. Paul Henderson and Northwestern University Medical School by Dr. Guang-yu Yang.
Hammock directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
This work was supported by NIEHS and the NIEHS Superfund Program; and two of Rand's grants: the Oncogenic Signals and Chromosome Biology T32 Training Grant, NIH/NIEHS; and her 2016 AACR Judah Folkman Fellowship for Angiogenesis Research.
- Author: Kathy Keatley Garvey
Hammock was named the recipient of the 2013 William E. M. Lands Lectureship Award in Nutritional Biochemistry at the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor. He lectured Oct. 8 on “Omega-3 Fatty Acids and Inhibitors of the Soluble Epoxide Hydrolase Block Angiogenesis, Tumor Metastasis and Tumor Growth.”
Hammock and postdoctoral researcher Guodong Zhang and their team made national news when they discovered a key mechanism by which dietary omega-3 fatty acids (fish oils) could reduce the tumor growth and spread of cancer, a disease that kills some 580,000 Americans a year.
“Bill Lands has long been one of my heroes in science,” Hammock said, “because he carried out excellent fundamental biochemistry and then applied this work to having a dramatic effect on diet and health worldwide.
Lands, a world-renowned nutritional biochemist, discovered the beneficial effects of balancing the effects of excess omega-6 fatty acids with dietary omega-3 fatty acids. One of the world's foremost authorities on fish oils and the author of the book, "Fish, Omega-3 and Human Health,” Lands is best known for his seminal studies demonstrating the benefit of reducing omega-6 and increasing dietary omega-3 lipids. He is a 1951 graduate of the University of Michigan and served on the faculty from 1955-1980.
Some of the top nutritionists in the country have lectured on the biochemical of essential nutrients at the Lands Lectureship, but this year was particularly relevant. Hammock was selected because his laboratory has shown one of the biochemical mechanisms by which omega–3 lipids reduce blood pressure, inflammation and pain.
The work was also timely in that Hammock’s laboratory, in collaboration with Kathy Ferrara at UC Davis and Dipak Panigrahy at Harvard recently demonstrated a biochemical pathway by which omega-3 fatty acids can reduce the growth and metastasis of breast and lung cancers. The work was recently published (April 3) in the Proceedings of the National Academy of Sciences (PNAS) by Hammock lab researcher Guodong Zhang, now an assistant professor in the Department of Food Science, University of Massachusetts.
The UC Davis researchers demonstrated that the omega-3 fatty acid is converted into bioactive metabolites that reduce hypertension, inflammation and pain.
While at the University of Michigan, Hammock also delivered a keynote address at the Fall Symposium on Lipid Mediators, a one-day scientific conference highlighting biomedical research involving lipid mediators. Hammock described how an omega-3 rich diet coupled with a drug candidate developed at UC Davis with researchers Bora Inceoglu and Karen Wagner can control chronic neuropathic pain such as that associated with diabetes.
“Now that the fundamental work can be translated, Alonso Guedes of the UC Davis School of Veterinary Medicine is well underway in trials of a drug to relieve pain and inflammation in horses, cats and now dogs,” Hammock said.
The omega-3 lipid project is part of the effort carried out by the UC Davis Foods For Health Institute, directed by Bruce German. The work has been in progress for a number of years in the Hammock laboratory. John Newman, former postdoctoral researcher in the Hammock lab and now an adjunct professor in nutrition, received the John Kinsella award for his Ph.D. work developing a mass spectrometry method for regulatory lipids. More recently Angela Zivokvic, former postdoctoral researcher in the Hammock lab and now associate director of scientific development and translation, has led a team using a later version of this mass spectrometry method to predict patients most likely to benefit from an increase in omega-3 dietary lipids.
“As Professor Bill Lands often says, ‘Nix the 6 (Omega-6) and eat the 3 (Omega-3,’ Hammock quipped.
Hammock directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory. He is a fellow of the Entomological Society of America, a member of the prestigious National Academy of Sciences, and the recipient of the 2001 UC Davis Faculty Research Lecture Award and the 2008 Distinguished Teaching Award for Graduate and Professional Teaching.