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 under way 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 University 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.
Click here to read more about the cancer-resistant mouse studies.
Stehle JR Jr, Weeks ME, Lin K, Willingham MC, Hicks AM, Timms JF, Cui Z. Mass spectrometry identification of circulating alpha-1-B glycoprotein, increased in aged female C57BL/6 mice. Biochim Biophys Acta. 7 Jan; 1770(1):79-86.
Hicks AM, Willingham MC, Du W, Pang CS, Old LJ, Cui Z. Effector mechanisms of the anti-cancer immune responses of macrophages in SR/CR mice. Cancer Immun. 2006 Oct 31;6:11.
Hicks AM, DeLong CJ, Thomas MJ, Samuel M, Cui Z. Unique molecular signatures of glycerophospholipid species in different rat tissues analyzed by tandem mass spectrometry. Biochim Biophys Acta. 2006 Sep;1761(9):1022-9.
Hicks AM, Riedlinger G, Willingham MC, Alexander-Miller MA, Von Kap-Herr C, Pettenati MJ, Sanders AM, Weir HM, Du W, Kim J, Simpson AJG, Old LG, 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.
Stehle JR Jr, Willingham MC, Lin K, Cui Z. A nonterminal method for frequent collection of mouse circulating proteins by peritoneal lavage. Anal Biochem. 2006 Feb 1;349(1):162-4.
Shen YJ, Delong CJ, Terce F, Kute T, Willingham MC, Pettenati MJ, Cui Z. Polyploid Formation via Chromosome Duplication Induced by CTP:Phosphocholine Cytidylyltransferase Deficiency and Bcl-2 Overexpression: Identification of Two Novel Endogenous Factors. J Histochem Cytochem. 2005 Jun;53(6):725-33.
Tsui ZC, Chen QR, Thomas MJ, Samuel M, Cui Z. A method for profiling gangliosides in animal tissues using electrospray ionization-tandem mass spectrometry. Anal Biochem. 2005 Jun 15;341(2):251-8.
Cui Z, Willingham MC. Halo naevus: a visible immunosurveillance response against neoplasia in humans? Lancet Oncol. 2004 Jul;5(7):397-8.
Cui Z, Willingham MC. The effect of aging on cellular immunity against cancer in SR/CR mice. Cancer Immunol Immunother. 2004 Jun;53(6):473-8.
Zhang H, Links PH, Ngsee JK, Tran K, Cui Z, Ko KW, Yao Z. Localization of low density lipoprotein receptor-related protein 1 to caveolae in 3T3-L1 adipocytes in response to insulin treatment. J Biol Chem. 2004 Jan 16; 279(3): 2221-30.
Cui Z. The winding road to the discovery of the SR/CR mice. Cancer Immun. 2003 Oct 16;3:14.
Cui Z, Willingham MC, Hicks AM, Alexander-Miller MA, Howard T, Hawkins G, Miller MS, Weir HM, Du W, DeLong CJ. Spontaneous regression of advanced cancer: Identification and characterization of a genetically-determined, age-dependent trait in mice. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6682-6687. A printable version of the article is available here; the free Adobe® Reader® is required to download this file.
Cui Z and Houweling M. Phosphatidylcholine and cell death. Biochim Biophys Acta. 2002 Dec 30;1585(2-3):87-96. Review.
Tran K, Thorne-Tjomsland G, DeLong CJ, Cui Z, Shan J, Burton L, Jamieson JC, Yao Z. Intracellular assembly of very low density lipoproteins containing apolipoprotein B100 in rat hepatoma McA-RH7777 cells. J Biol Chem. 2002 Aug 23;277(34):31187-200.
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, Baker PR, Samuel M, Cui Z, Thomas MJ. Molecular species composition of rat liver phospholipids by ESI-MS/MS: the effect of chromatography. J Lipid Res. 2001 Dec;42(12):1959-68.
Tran K, Wang Y, DeLong CJ, Cui Z, Yao Z. The assembly of very low density lipoproteins in rat hepatoma McA-RH7777 cells is inhibited by phospholipase A2 antagonists. J Biol Chem. 2000 Aug 11;275(32):25023-30.
DeLong CJ, Qin L, Cui Z. Nuclear localization of enzymatically active green fluorescent protein-CTP:phosphocholine cytidylyltransferase alpha fusion protein is independent of cell cycle conditions and cell types. J Biol Chem. 2000 Oct 13;275(41):32325-30.
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.
Lehner R, Cui Z, Vance DE. Subcellullar localization, developmental expression and characterization of a liver triacylglycerol hydrolase. Biochem J. 1999 Mar 15;338 ( Pt 3):761-8.
Tessitore L, Dianzani I, Cui Z, Vance DE. Diminished expression of phosphatidylethanolamine N-methyltransferase 2 during hepatocarcinogenesis. Biochem J. 1999 Jan 1;337 ( Pt 1):23-7.
Vance DE, Cui Z, Houweling M, Wlkey CJ, Tessitore L. Phosphatidylethanolamine N-methyltransferase: an unexpected regulator of hepatocyte cell division. In: Choline, Phospholipids, Health and Diseases (Szuhai B and Zeisel S, eds.) AORS Press, Champaign, IL: 1998, 23-29.
Stone SJ, Cui Z, Vance JE. Cloning and expression of mouse liver phosphatidylserine synthase-1 cDNA. Overexpression in rat hepatoma cells inhibits the CDP-ethanolamine pathway for phosphatidylethanolamine biosynthesis. J Biol Chem. 1998 Mar 27;273(13):7293-302.