- Author: Kathy Keatley Garvey
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, was inducted along with 13 other Fellows on Nov. 14 during the annual Fellowship meeting. He joins the ranks of more than 500 Academy Fellows, a governing group of distinguished scientists and other leaders who have made notable contributions to scientific research, education, and communication.
“We're proud to announce 2023's distinguished pool of new Fellows—each of their contributions to science and society represent major advancements in their respective fields,” said Academy Dean of Science and Research Collections Shannon Bennett. “Our Fellows body is a group of future thinkers and innovators whose leadership inspires the next generation of scientists, science educators, story-tellers and change-makers. We look forward to forging a future with our new Fellows that advances the Academy's mission to regenerate the natural world through science, learning, and collaborative partnerships.”
Hammock, a member of the UC Davis faculty since 1980, was nominated by colleagues James R. Carey, UC Davis distinguished professor, and Robert E. Page Jr., UC Davis distinguished emeritus professor and emeritus provost of Arizona State University. The CAS Board of Trustees selects the Fellows.
Hammock discovered that regulating degradation of insect hormone mediators is as important as biosynthesis in development. He applied this toward the development of green chemical and the first recombinant viral pesticide. He asked if the same systems of metabolism of chemical mediators could be important in other species, notably man, resulting in the discovery of a new group of human chemical mediators. By inhibiting a key enzyme in this pathway, beneficial natural mediators increased there by showing benefit in treating multiple diseases including arthritis, cancer, Alzheimer's with the resulting drug candidates currently in human trials to treat pain.
Hammock co-discovered a human enzyme termed Soluble Epoxide Hydrolase (sEH), a key regulatory enzyme involved in the metabolism of fatty acids. It regulates a new class of natural chemical mediators, which in turn regulates inflammation, blood pressure and pain. Hammock and his lab have been involved in enzyme research for more than 50 years.
Hammock founded the Davis-based pharmaceutical company, EicOsis LLC, formed in 2011 to develop an orally active non-addictive drug for inflammatory and neuropathic pain. The former chief executive officer, he now serves on the board of directors.
He is a fellow of the National Academy of Inventors and the National Academy of Sciences., and the Entomological Society of America. He is the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. At UC Davis he received the Distinguished Teaching Award and the Faculty Research Lectureship. In 2020, he received a Lifetime Achievement Award from UC Davis Chancellor Gary May.
Hammock has authored or co-authored more than 1,400 peer-reviewed publications and holds more than 95 patents in agriculture, environmental science and medicinal chemistry.
Hammock is known for his expertise in chemistry, toxicology, biochemistry and entomology. Early in his career, he founded the field of environmental immunoassay, using antibodies and biosensors to monitor food and environmental safety, and human exposure to pesticides. His groundbreaking research in insect physiology, toxicology led to his development of the first recombinant virus for insect control.
A native of Little Rock, Ark., Hammock received his bachelor's degree in entomology (with minors in zoology and chemistry) magna cum laude from Louisiana State University, Baton Rouge, in 1969. He received his doctorate in entomology-toxicology from UC Berkeley in 1973. Hammock served as a public health medical officer with the U.S. Army Academy of Health Science, San Antonio, and as a postdoctoral fellow at the Rockefeller Foundation, Department of Biology, Northwestern University, Evanston, Ill.
In the Army, he served as a medical officer at Fort Sam, Houston, and what he saw--severely burned people in terrible pain--made a lasting impression on him and steered him toward helping humankind.
2023 Fellows. Among the new CAS Fellows is Beth Rose Middleton Manning, professor of Native American Studies and designated emphasis chair at UC Davis who also was supported by the NIEHS Superfund Program. She focuses on environmental policy, cultural site protection, and climate adaptation with Native nations and communities.
Other new Academy Fellows:
Peter Alagona, PhD
Professor, Environmental Studies
University of California, Santa Barbara
Nicole Ardoin, PhD
Associate Professor, Social Sciences and Emmett Family Faculty Scholar
Stanford University
Junko Habu, PhD
Professor of Anthropology
University of California, Berkeley
Vanessa Handley, PhD
Director of Conservation Science and Global Conservation Consortium for Cycads Chair
University of California, Berkeley
Terry Jones, PhD
Professor of Anthropology
California Polytechnic State University
Marjorie Matocq, PhD
Foundation Professor, Department of Natural Resources and Environmental Science
University of Nevada, Reno
Derrick Rossi, PhD
CEO, Convelo Therapeutic
CEO, New York Stem Cell Foundation
Partner, Castle Rock Entertainment
Harvard University
Robert Bullard, PhD
Distinguished Professor of Urban Planning and Environmental Policy and Director of the
Bullard Center for Climate and Environmental Justice
Texas Southern University
Franck Marchis, PhD
Senior Planetary Astronomer
SETI Institute
Melissa Nelson, PhD
Professor of American Indian Studies
Arizona State University
Daniel Pauly, PhD
Professor of Fisheries
University of British Columbia
Aomawa Shields, PhD
Clare Boothe Luce Associate Professor of Physics and Astronomy
University of California, Irvine
The list of UC Davis Department of Entomology and Nematology faculty or former faculty who are Fellows:
UC Davis distinguished professors James R. Carey, Walter Leal (now with College of Biological Sciences) and Frank Zalom; distinguished professor emeritus Robert E Page Jr. (chair emeritus of the Department of Entomology and provost emeritus of Arizona State University; Professors Phil Ward and Neal Williams; and department affiliate Catherine Tauber (formerly of Cornell)
The late Robbin Thorp (1933-2019), UC Davis distinguished emeritus professor, and Maurice Tauber (1931-2014, a UC Davis visiting professor/scientist and formerly of Cornell) also were CAS Fellows.
See more information about the CAS Fellows here.
- Author: Kathy Keatley Garvey
Every year some 10,000 burn victims in the United States undergo an acute inflammatory reaction and die of burn-related infections, according to the Centers for Disease Control and Prevention.
Now a newly published study by a research team from the laboratory of distinguished professor Bruce Hammock, University of California, Davis, and the Department of Surgery, University of Cincinnati College of Medicine (UC CoM), has identified a key regulatory mechanism in inflammation that may lead to new targets for resolving that inflammation—and the inflammation of patients with sepsis, cancer and COVID.
In research published in the current edition of Proceedings of the Natural Academy of Sciences, the scientists announced that they have discovered a pathway that regulates the immune response after infection or injury, such as burns. Dysregulation of this pathway could differentiate those who are at risk of fatal sepsis or help identify targets to resolve this unregulated inflammation.
“We are very excited about the findings in this paper and the far-reaching impacts it could have on understanding a key regulatory step in the immune response,” said co-lead author and researcher Cindy McReynolds of the Hammock lab and director of research at EicOsis, a Davis-based company founded by Hammock. Hammock, the corresponding author of the publication, has been involved in enzyme research for more than 50 years.
“Our previous work identified that these same lipid mediators were up-regulated in severe COVID infections, and we are now finding that these compounds play a role in modulating the immune response so that the body is unable to fight infection or respond properly to trauma without leading to a potentially fatal overreaction,” said McReynolds, who holds a doctorate in pharmacology and toxicology from UC Davis.
“The immunological disbalance we see in many cases of severe burn injury, trauma and sepsis pose a huge clinical challenge as we lack the understanding of how to diagnose and treat it,” said co-lead author Dr. Christian Bergmann, formerly with UC CoM's Department of Surgery and now headquartered in Germany with the University of Ulm's Department of Trauma Surgery, Hand, Plastic and Reconstructive Surgery. “With this work, we reveal an important mechanism how immune cells are functionally disabled by sEH-derived metabolites of linoleic acid.”
“The natural compounds we are studying in this paper are metabolites of linoleic acid (LA), an essential fatty acid the body needs in very small amounts to survive and is only available through the diet,” McReynolds explained. “At lower concentrations, these metabolites are necessary for regulating thermogenesis and heart health but promote inflammation at higher concentrations. LA is more stable and much cheaper than longer chain polyunsaturated fatty acids, so heavily processed foods have higher LA content to increase shelf-life. Additionally, agricultural practices, such as feeding animals corn-based diets, have increased LA in meats and dairy products.”
The research, titled "sEH-Derived Metabolites of Linoleic Acid Drive Pathologic Inflammation while Impairing Key Innate Immune Cell Function in Burn Injury,” is co-authored by Debin Wan, formerly of the Hammock lab and now a scientist at Escape Bio, San Francisco; Nalin Singh of the Hammock lab; and three UC CoM researchers: Charles Caldwell, professor and director, Division of Research, Department of Surgery; Dorothy Supp, adjunct professor in the Department of Surgery and a scientific staff member at Shriners Children's Ohio; and Holly Goetzman, principal research assistant in the Caldwell lab.
“Chronic pain is an enormous emotional and economic burden for more than 100 million people in the United States alone,” said co-author Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. "The extreme and poorly treated pain that I observed as a medical officer working in a burn clinic in the Army, is a major driver for me to translate laboratory research to help patients with severe pain and at risk from sepsis." Another major influence: his mother served 15 years as a nurse in a children's hospital burn center, caring for hundreds of patients.
Hammock founded EicOsis in December 2011 to advance novel, safe and effective oral treatments for patients suffering from pain and inflammation. The LLC is developing a new class of oral non-narcotic analgesics based on inhibition of the soluble epoxide hydrolase enzyme. Human clinical trials are underway to test the drug candidate, EC5026, a first-in-class, small molecule that potently inhibits sEH. The sEH inhibitors have already shown to be effective for inflammatory and neuropathic pain in animals, with no apparent adverse or addictive reactions.
Several grants supported the research: Dr. Bergmann received a grant from Deutsche Forschungsgemeinschaft (German Research Foundation) and a National Institutes of Health (NIH) grant from the National Institute of General Medical Sciences (NIGMS); Supp, a grant from the Shriners Hospitals for Children; and Hammock, a RIVER (Revolutionizing Innovative Visionary, Environmental Health) grant from the NIH's National Institute of Environmental Health (NIEHS), and an NIH/NIEHS Superfund Program grant. Hammock has directed the UC Davis Superfund Program for nearly four decades.
Resources:
- PNAS paper
- UC Davis distinguished professor Bruce Hammock, bdhammock@ucdavis.edu
- Author: Kathy Keatley Garvey
“We show that both activities of soluble epoxide hydrolase enzyme (sEH), the center of 50 years work in the Hammock laboratory, and a second integrated phosphatase activity, discovered by us 20 years ago in the same protein, have complementary biological action in vivo, with implications in cardiac biology,” said biochemist and co-author Christophe Morisseau of the Hammock lab who researches the biology and pharmaceutical applications of epoxide hydrolase inhibition in diabetes, pulmonary and cardiovascular diseases.
The research paper, titled “CRISPR/Cas9-mediated Inactivation of the Phosphatase Activity of Soluble Epoxide 1 Hydrolase Prevents Obesity and Cardiac Ischemic Injury,” involved recombinant animal models.
The abstract reads: “Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown. This study aimed to assess in vivo the physiological role of sEH-P.”
“Such di catalytic activities of separate enzymes jointed during the evolutionary process have been said a Rosetta stone for understanding cell biology,” said co-author Hammock, a UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. For the past 50 years, the Hammock lab has been studying sEH inhibitors, leading to drugs that target such diseases as diabetes, hypertension (heart disease), Alzheimer's disease, and cancer. Co-discovered by Hammock and Sarjeet Gill, now a UC Davis distinguished professor at UC Riverside, sEH is a key regulatory enzyme involved in the metabolism of fatty acids.
The work of the UC Davis-French team collaboration may have implications in major diseases of the circulatory system, including atherosclerosis, coronary artery disease, stroke, and hypertension. Research shows that patients with diabetes, obesity, dyslipidemia, cancer, fibrosis, and sepsis have a significant increase in the risk and incidence of cardiovascular disease.
Bellien, a professor in the Department of Pharmacology who holds a doctorate in pharmacology from the Rouen University School of Pharmacy, heads a research group on endothelial protection within INSERM U1096. The endothelium is a thin membrane that lines the inside of the heart and blood vessels. Bellien and his team study the role of endothelial lipid mediators in the pathophysiology of cardiovascular diseases, and notably to study new approaches to treat vascular and valvular calcification. They have been collaborating with the UC Davis team since 2014.
- Author: Kathy Keatley Garvey
“This model is one of our nation's oldest linear index typewriters,” said Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Center. “It has no keyboard. It has a rail-type system with the characters spread out in a straight line--and not in alphabetical order, either. This is confusing compared to the modern-day QWERTY keyboard design, yet this instrument saved my grandfather's career.”
It's a 132-year-old “Odell's Type Writer,” patented in 1889 by inventor Levi Judson Odell (1855 - 1919), and the prized possession of his grandfather, Judge William Thomas Hammock (1866-1950) of Little Rock, Ark.
Not only did it save Judge Hammock's career, but Judge Hammock and his “type writer” inspired the development of Professor Hammock's 42-year career at UC Davis, which includes founding director of the UC Davis Superfund Research Program (SRP), funded by the National Institute of Environmental Health Sciences (NIEHS) since 1987. To date, the Hammock-directed program has brought in more than $90 million in grants to the UC Davis campus.
And fortunately, the 4-inch-thick, 986-page grant renewal that the Hammock team submitted to NIEHS last year didn't involve the “back-up typewriter.”
Rival newspapers figure into the history of the Hammock-owned typewriter. “It all began when The Arkansas Democrat ran an article showing a 70-year-old typewriter,” the UC Davis professor related. “In response to this, The Arkansas Gazette, then the oldest paper west of the Mississippi—it was established in 1819--published an article on an even older Odell typewriter—the one owned by my grandfather.”
Strong Arm. “I have that newspaper clipping from 1915 that shows my Aunt Maude Hammock using the typewriter in my grandfather's law office,” Hammock said. “She was secretary to her dad—my grandfather--and had an exceptionally strong arm to make it work – rather like Popeye the Sailor. In the photo, my grandfather is seated at his desk.” The newspapers merged in 1991 to become The Arkansas Democrat-Gazette.
“The oral history of the typewriter is that William Thomas Hammock was living in the country town of Quitman, Ark., in 1893 and had just passed the bar," the UC Davis professor related. "Being a new attorney with no business and lots of spare time, he jumped at a $150 contract to make a copy of the county's handwritten laws and regulations. Not being an experienced lawyer, he failed to read the fine print. The county wanted not one, but 10 handwritten copies. This was impossible on his budget.”
“Then he heard about something called a ‘type writer.' He boarded a train to Chicago, where the Odell type writer company had just relocated from Wisconsin, checked out the machine, and bought it for about $15. This invention permitted him to use carbons and he only needed to type the documents twice, with multiple carbons.”
Husky as a Blacksmith. "The number of carbon copies that can be made with the Odell is limited only by the strength of the operator's right arm," according to The Arkansas Gazette article. "Mr. Hammock took setting up exercises each morning and made 10 copies at a time. After a couple of months, he was as husky as a blacksmith and had earned $150. Mr. Hammock became quite proficient in handling the machine. He could pound out a line of legal phraseology much quicker than his forebears could chisel out a love message on stone or parchment, though the physical effort was about the same."
Valued at $2000. Today the $15 typewriter is valued at more than $2000. Brass-plated with its inventor's name and cradled in its original wooden case in a corner of the Hammock office, the machine draws such comments from visitors as “My, it is beautiful!” and “Is that REALLY a typewriter?”
“Yes,” he tells them, and then explains, to their amazement, how it works: “You slide the bar along the rail until the pointer meets the letter you want. Then you press down a lever very hard, depressing the entire rail.”
The UC Davis professor marvels at how far office machine technology has advanced: from the first primitive typographical contraption (1713) to the first linear index typewriter (1881) to the modern-day dual-screened computer that occupies his desk.
“Just as this new technology of the Odell type writer saved my grandad's career as a lawyer, this adapted word processor on the rather ‘Dr. Who-ish' PDP computer changed my career at UC Davis when we received that NIEHS grant in 1987 to establish the UC Davis Superfund Research Program. It's now the longest running Superfund Program in the country.”
What SRP Does. The UC Davis SRP conducts and translates research on hazardous substances in the environment and their impact on human health. It also cross-trains scientists in multiple physical and biological sciences to address the complexity of the toxic waste issue in the nation. Its goals: to acquire a better understanding of the human and ecological risks of hazardous substances; and to advance the development of new technologies for the cleanup of contaminated sites.
The Hammock-directed program encompasses five projects and six cores, spread throughout most of the colleges, and involving more than 12 departments, eight labs and 35 personnel, as well as several dozen undergraduate and graduate students and collaborators. In addition to the grant funding, the SRP receives supplemental funding for multiple training, equity and outreach projects. The 2021-22 budget? A little over $2.6 million.
“We have addressed multiple problems in California ranging from the clean-up of the Mare Island Naval Shipyard through the MTBE (methyl tertiary-butyl ether) groundwater crisis to now helping the Yurok Nation in Northern California deal with environmental contamination,” Hammock said. “To compete for centers, program projects and training grants, we need not only good science but also the administrative infrastructure to put together proposals.”
The NIEHS website points out that the cornerstone of SRP “is the university-based, multiproject center grant program. Since 1987, SRP has funded research at 35 universities across the United States, and currently funds 249 research and engagement projects at 23 universities with 142 collaborations at 120 institutions.”
Recalling his initial application for the federal grant, Hammock commented that “the opportunity for a large interdisciplinary grant with a very short time line arose from NIEHS. Applicants had to put together engineers, soil chemists, toxicologists, medical doctors and veterinarians in an integrated project on a short time line.”
Never Could Have Pulled This Off. “We never could have pulled this off without the technology of a word processor,” Hammock said, adding, “or without a wonderful department staff. Having the administrative staff, in this case Dee Dee Kitterman and the word processing technology of the PDP, made the difference. The renewal that went in this year was 986 pages! It makes you appreciate the collaborative nature of the science at Davis, the quality of the science, and particularly the administrative structure that supports it. We would not compete without the modern-day equivalents of the Odell Type Writer and the professionals who make our equipment sing.”
“Administrative staff are crucial,” Hammock said. “They should be appreciated all year around, not just on a single day (Administrative Professionals Day is April 27). And to think that in the past, our administrative professionals—then known as secretaries faced these challenges— with such formidable equipment as Odell's Type Writer—and won.”
- Author: Kathy Keatley Garvey
Researchers from Harvard Medical School and the University of California, Davis, blocked the progression of cancer growth caused by environmental carcinogens and food contaminants by resolving an eicosanoid/cytokine storm triggered by cell debris.
The research, from the laboratories of physician-researcher Dipak Panigrahy of Harvard Medical School and UC Davis distinguished professor Bruce Hammock, is published in the current edition of the Proceedings of the National Academy of Sciences.
“We advanced the hypothesis that cell debris from chemotherapy, resection of tumors and even immunotherapy can make these therapies a double-edged sword stimulating cancer growth and metastasis while treating it,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
In their paper, “Resolution of Eicosanoid/Cytokine Storm Prevents Carcinogen and Inflammation-Initiated Hepatocellular Cancer Progression,” the scientists covered the potent environmental carcinogen and food contaminant aflatoxin. Aflatoxins are toxins produced by certain fungi that are found in such agricultural crops as corn, peanuts, cottonseed, and nuts.
“Not only is this fungal metabolite genotoxic but it is also a tumor promoter,” said Hammock, defining a genotoxic agent as “a chemical that damages cellular DNA, resulting in mutations or cancer.”
Lead authors Anna Fishbein of Harvard University, a recently enrolled medical student in the Georgetown University School of Medicine, and Weicang Wang, a postdoctoral scholar in the Hammock lab, said aflatoxin exerts some of its cancer-promoting effects by generating cell debris which activate a pathway leading to eicosanoid and cytokine storms. These two classes of natural chemical mediators, they explained, control many of our defenses against pathogens, but when out of control, these storms lead to growth and metastasis of liver cancer.
“We demonstrated that debris generated by aflatoxin B1accelerates tumor dormancy escape in liver cancer models by stimulating a macrophage-derived eicosanoid and cytokine storm of pro-inflammatory mediators,” said Fishbein. “Thus, targeting a single inflammatory mediator or eicosanoid pathway is unlikely to prevent carcinogen-induced tumor progression.”
The researchers showed that the inhibition of the soluble epoxide hydrolase (sEH) pathway or the combined inhibition sEH and cyclooxygenase-2 (COX-2) pathways prevented the carcinogen debris-induced storm of both cytokines and lipid mediators by macrophages--specialized detect-and-destroy cells.
In animal models, the dual COX-2/sEH inhibitor PTUPB prevented the onset of debris-stimulated liver cancer. The dual inhibition of COX-2/sEH pathways may be “a novel approach” to control cancer of the liver, the researchers said.
“We also showed that carcinogen-generated debris stimulates an endoplasmic reticulum (ER) stress response which may promote HCC progression. Importantly, PTUPB prevents the ER stress response,” Wang added. “We created a novel model of debris-stimulated liver cancer designed to study new strategies for the prevention and treatment of carcinogen-induced cancers with tremendous potential to translate to the clinic.”
From a nutritional standpoint, aflatoxin is a common food contaminant, Wang said. “But good agricultural practice and post-harvest technology keep the levels very low. However, in much of the world, aflatoxin levels are so high that many crops are discarded. In other cases, these contaminated grain and nut crops enter the human food chain, where they cause acute toxicity, severe anemia and of course later lead to cancer.”
UC Davis co-author and nutritional scientist Yuxin Wang (who is the wife of Weicang Wang) said that “finding a way to modulate the events that lead to the eicosanoid storm would have a major effect on children's health in many developing countries.”
Fishbein and Allison Gartung of the Panigrahy lab not only used the soluble epoxide hydrolase inhibitors from the Hammock lab but also used some prototype drugs synthesized by chemist Sung Hee Hwang of the UC Davis School of Veterinary Medicine “which proved to be even better,” Hammock said.
“These compounds are a synthetic combination of cyclooxygenase inhibitors like celebrex with epoxide hydrolase inhibitors,” Hammock said. “Since epoxide hydrolase inhibitors stabilize the endoplasmic reticulium stress response and transcriptionally down regulate inflammatory cyclooxygenase we expected them to synergize with cyclooxygenase inhibitors. We were surprised and pleased with the dramatic interaction of these inhibitors when combined in the same molecule in reducing the cytokine and eicosanoid production by in response to cell debris.”
“The observations from Harvard show that by inhibiting soluble epoxide hydrolase, we can block the activation of these inflammatory cascades leading to tumor promotion, growth and metastasis,” Hammock said. “We have a compound in human clinical trials that inhibits sEH, which should be clinically available in a few years. In addition. we have found natural inhibitors of the epoxide hydrolase in a variety of plants, including crop plants. This may allow us to reduce the cancer risk and block the gastrointestional erosion and bleeding caused by dietary aflatoxin using natural means.”
Other members of the 15-member team are UC Davis researchers Jun Yang, Yuxin Wang and Sung Hee Hwang; Harvard researchers Haixia Yang, Victoria Hallisey, Jianjun Deng, Sanne Verheul, Allison Gartung, Diane Bielenberg and Mark Kiernan (now of Bristol-Myers Squibb); and Sui Huang, Institute for Systems Biology, Seattle. Hammock and Panigrahy are the corresponding authors.
The research drew strong financial support as the Panigrahy's laboratory is generously supported by the Credit Unions Kids at Heart Team, the CJ Buckley Pediatric Brain Tumor Fund, and the Joe Andruzzi Foundation; and Hammock's UC Davis grants from the National Institute of Environmental Health (NIEHS) Superfund Research Program, and the NIEHS RIVER Award (Revolutionizing Innovative, Visionary, Environmental Health Research).
Hammock, a member of the UC Davis faculty since 1980, has directed the UC Davis Superfund Research Program for nearly four decades. It supports scores of pre- and postdoctoral scholars in interdisciplinary research in five different colleges and graduate groups on campus. Last year Hammock received a $6 million, eight-year “Outstanding Investigator” federal grant for his innovative and visionary environmental health research: The award is part of the Revolutionizing Innovative, Visionary Environmental Health Research (RIVER) Program of NIEHS.
The abstract:
“Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an ‘eicosanoid and cytokine storm.' AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cyto- kine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.”