PNAS Profile of NAS member Angelika Amon, winner of the 2019 Vilcek Prize in Biomedical Science
Image courtesy of Samara Vise (Koch Institute for Integrative Cancer Research, Cambridge, MA.)
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Edited by Carolyn R. Bertozzi, University of California, Berkeley, CA, and approved October 8, 2008 (received for review April 24, 2008)
Abstract
Patients with cancer have circulating heterophile antibodies that agglutinate animal red cells via recognition of the mammalian cell surface sialic acid N-glycolylneuraminic acid (Neu5Gc), which was long considered an oncofetal antigen in humans. However, humans are genetically deficient in Neu5Gc production and instead metabolically accumulate Neu5Gc from dietary sources, particularly red meats and milk products. Moreover, mice with a human-like defect showed no alternate pathway for Neu5Gc synthesis and even normal humans express anti-Neu5Gc antibodies. We show here that human tumors accumulate Neu5Gc that is covalently attached to multiple classes of glycans. The paradox of human tumor Neu5Gc accumulation in the face of circulating anti-Neu5Gc antibodies was hypothesized to be due to facilitation of tumor progression by the resulting low-grade chronic inflammation. Indeed, murine tumors expressing human-like levels of Neu5Gc show accelerated growth in syngeneic mice with a human-like Neu5Gc deficiency, coincident with the induction of anti-Neu5Gc antibodies and increased infiltration of inflammatory cells. Transfer of polyclonal monospecific syngeneic mouse anti-Neu5Gc serum also enhanced growth of transplanted syngeneic tumors bearing human-like levels of Neu5Gc, with tumors showing evidence for antibody deposition, enhanced angiogenesis and chronic inflammation. These effects were suppressed by a cyclooxygenase-2 inhibitor, a drug type known to reduce human carcinoma risk. Finally, affinity-purified human anti-Neu5Gc antibodies also accelerate growth of Neu5Gc-containing tumors in Neu5Gc-deficient mice. Taken together, the data suggest that the human propensity to develop diet-related carcinomas is contributed to by local chronic inflammation, resulting from interaction of metabolically-accumulated dietary Neu5Gc with circulating anti-Neu5Gc antibodies.
Footnotes
- 1To whom correspondence should be addressed. E-mail: a1varki{at}ucsd.edu
Author contributions: M.H., V.P.-K., and A.V. designed research; M.H., V.P.-K., and N.M.V. performed research; V.P.-K. and N.M.V. contributed new reagents/analytic tools; M.H., V.P.-K., N.M.V., and A.V. analyzed data; and M.H. and A.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
- © 2008 by The National Academy of Sciences of the USA
Evidence for a human-specific mechanism for diet and antibody-mediated inflammation in carcinoma progression
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Simulations of future California climate suggest that under high CO2 conditions, by the late 21st century, increasing temperatures could lead to reduced snowpack, drier summers, and increased fire risk, independent of changes in winter precipitation.
Image courtesy of Alan H. Taylor.
Researchers report a system for obtaining information about planetary motions approximately 200 million years ago, and the system could help constrain models of Solar System evolution and provide tests of gravitational models.
Image courtesy of Paul E. Olsen.
Compared with female co-twins not exposed to a male co-twin inside the uterus, female co-twins exposed to a male co-twin had 15.2% higher probability of dropping out of high school, 8.6% lower earnings at age 32, and 5.8% fewer children, according to a study.
Image courtesy of iStock/Avril Morgan.
In the last few years, astronomers have started to get glimpses into the planet nurseries formed from newborn stars, revealing important clues as to exactly how planets form.
Image credit: Shutterstock/Neo Edmund.
More Articles of This Classification
Biological Sciences
Related Content
Cited by...
- N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils
- Loss of CMAH during Human Evolution Primed the Monocyte-Macrophage Lineage toward a More Inflammatory and Phagocytic State
- A Mouse Model for Dietary Xenosialitis: ANTIBODIES TO XENOGLYCAN CAN REDUCE FERTILITY
- A red meat-derived glycan promotes inflammation and cancer progression
- Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies
- Structural and functional characterization of NanU, a novel high-affinity sialic acid-inducible binding protein of oral and gut-dwelling Bacteroidetes species
- Emerging Principles for the Therapeutic Exploitation of Glycosylation
- Long-Term IgG Response to Porcine Neu5Gc Antigens without Transmission of PERV in Burn Patients Treated with Porcine Skin Xenografts
- Accelerated Tumor Growth Mediated by Sublytic Levels of Antibody-Induced Complement Activation Is Associated with Activation of the PI3K/AKT Survival Pathway
- Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups: MECHANISMS UNDERLYING GASTROINTESTINAL INCORPORATION OF THE NON-HUMAN SIALIC ACID XENO-AUTOANTIGEN N-GLYCOLYLNEURAMINIC ACID
- Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups: ELUCIDATING THE INTRACELLULAR FATE OF THE NON-HUMAN SIALIC ACID N-GLYCOLYLNEURAMINIC ACID
- Human Xeno-Autoantibodies against a Non-Human Sialic Acid Serve as Novel Serum Biomarkers and Immunotherapeutics in Cancer
- Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid N-glycolylneuraminic acid
- A Human-Specific Deletion in Mouse Cmah Increases Disease Severity in the mdx Model of Duchenne Muscular Dystrophy
- Uniquely human evolution of sialic acid genetics and biology
- Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition
- Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium
- Ajit Varki: On the origin of maladies