Zheng Cui, MD PhD
Cancer Biology; Institute for Regenerative Medicine; Molecular Genetics & Genomics (Cancer); Molecular Medicine Graduate Program
1) Innate immunity against cancer in mice and humans
Why don’t most humans get cancer despite big body mass, long lifespan and even some intentional exposures to known carcinogens (such as cigarette smoking)? The answer may come from a single male BALB/c mouse that unexpectedly survived challenges of highly lethal cancer cells in 1999. The survival of this mouse was very surprising since no other mouse of any strain had ever survived this type of cancer. Even more surprising was that about 40% of offspring of this male mouse also survived many different cancer challenges, meaning that this cancer resistance is a genetic trait. This trait has now been passed on to more than 2000 offspring in more than 15 generations and in several different mouse strains.
In the last several years, intense study has revealed additional surprises. 1) Although the inheritance pattern of this trait is simple, the genetics is not conventional. There was no conventional linkage found so far between the trait and a fixed location on any chromosome, suggesting a possibility for a jumping gene or a “paramutation”-like element. 2) The cancer resistance is entirely mediated by the leukocytes of innate immunity that are able to sort out cancer cells for specific killing without harming normal cells. The cancer resistant mice are healthy and long-lived. 3) The mice can resist a wide array of cancer cells and endogenous malignancies. 4) Transfer of leukocytes with this high level of cancer-killing activity (CKA) from these cancer-resistant mice cures the most aggressive advanced cancers in other mice without any side effect.
Most surprisingly, a similar activity of killing cancer cells was discovered in the granulocytes and monocytes of some healthy people.
Additional studies also indicate that CKA is highly dynamic in human populations. CKA is affected profoundly by individual genetic make-ups, by different seasons, by different ages and by emotional stresses. More importantly, low CKA has a significant association with cancer patients in comparison to healthy people. It seems reasonable to believe that cancers can be treated by transferring granulocytes, an abundant white cell fraction that contains the most CKA, from cancer-resistant human donors to cancer patients. This new therapeutic concept is significantly different from the conventional immunotherapies based on the attempts to revive cancer patients' own adaptive immunity to fight their own cancers. Now, a new clinical trial is being planned at Wake Forest University to test this novel cancer therapy, termed "Leukocyte Infusion Therapy" or LIFT. This clinical trial has met all regulatory requirements including approval by the Wake Forest School of Medicine's Institutional Review Board (IRB) and been granted an IND (Investigational New Drug) status by the Food and Drug Administration (FDA).
Representative publications on this topic:
Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W, Kim J, Simpson AJ, Old LJ, Cui Z. Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7753-8.
Cui Z, Willingham MC, Hicks AM, Alexander-Miller MA, Howard TD, Hawkins GA, Miller MS, Weir HM, Du W, DeLong CJ. Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6682-7.
2) Lipidomics and Metabolipidomics
Lipids and lipid metabolism are perhaps the most important aspects associated with human health and human nutrition. Fat content varies greatly from individual to individual and may have an intimate association with many human diseases, such as diabetes, heart and coronary diseases and cancer. Yet, lipid analyses had traditionally been a less developed area of research in comparison to other fields due to a lack of powerful analytical technologies at the molecular level. The advent of tandem mass spectrometry technology (MS/MS) has brought a new dawn to the world of lipid analysis with unprecedented sensitivity, resolution and ease of use. One of our research interests is to continue our efforts in using MS/MS to find new ways for lipid analysis and lipid profiling. We also developed several new ways of analyzing lipid metabolism using stable isotope labeling of lipid metabolites in combination with MS/MS. We also have particular interests in phospholipids and gangliosides and their associated human diseases.
Representative publications on this topic:
Bleijerveld OB, Houweling M, Thomas MJ, Cui Z. Metabolipidomics: profiling metabolism of glycerophospholipid species by stable isotopic precursors and tandem mass spectrometry. Anal Biochem. 2006 May 1; 352(1): 1-14.
DeLong CJ, Hicks AM, Cui Z.Disruption of choline methyl group donation for phosphatidylethanolamine methylation in hepatocarcinoma cells. J Biol Chem. 2002 May 10; 277(19): 17217-25.
DeLong CJ, Shen YJ, Thomas MJ, Cui Z. Molecular distinction of phosphatidylcholine synthesis between the CDP-choline pathway and phosphatidylethanolamine methylation pathway. J Biol Chem. 1999 Oct 15; 274(42): 29683-8.
Link to Coy C. Carpenter Library Publication Database