Our lab is interested in both the effects of various diets on cancer (CA) incidence and in determining who is at risk of developing CA so we can prevent it by adopting life style changes. In regard to the first goal, since tumour cells are more dependent on blood glucose than normal cells for their growth, we have been testing low carbohydrate (CHO) diets on mice and found they reduce the incidence, growth rate and metastasis of primary tumours. Related to this, we have been studying ways to alter the properties of the immune cells within tumours to enhance their ability to kill the CA cells. Because many tumours secrete factors that subvert the ability of tumour-infiltrating immune cells to kill CA cells, we have been examining the effects of different immune modulating agents and found that low levels of non-steroidal anti-inflammatory drugs like Celebrex, in conjunction with our low CHO diets, dramatically reduce the growth rate of tumours.
In regard to the second goal, there is growing evidence that low levels of chronic inflammation (CI), i.e., below those manifesting in obvious disease, coupled with a poor immune response to viral infections increase the incidence of many human CAs. Thus the identification of individuals with low but detectable levels of CI and a poor anti-viral response would be of great value in indentifying high-risk people. As well, recent research has shown that what we eat determines the type of bacteria that reside in our gut (i.e., our gut microbiome) and these bacteria likely play an important role in determining our levels of CI. Lastly, macrophages (MФs), which are key immune cells in all our tissues, vary from person to person in their properties, from being skewed to very pro-inflammatory (M1 or killer MФs) in some people to very anti-inflammatory (M2 or healer MФs) in others, with most people being somewhere in between. Since MФs secrete many immune modulators, where on this spectrum a person’s MФs exist profoundly influences his/her level of CI and ability to fight off infections.
To explore all these areas further we have devised a series of simple tests in which very small amounts of whole human blood are both tested for markers of CI and incubated for 7 hours in the presence and absence of live bacteria and viruses to assess an individual’s immune response. As well, small fecal samples are analyzed to determine the bacterial makeup of our gut in order to relate the presence of specific bacteria with levels of CI to gain insight into which bacteria may be beneficial and which may be harmful. Ultimately, we hope to identify specific immune markers that can be used to predict an individual’s susceptibility to developing CA.
We are also interested in searching for nature-derived compounds that may be used to modulate our immune responses to prevent or treat CA and, lastly, since we have recently elucidated the factors in mouse blood that dramatically influence the skewing of MФs we would now like to determine if the same factors play a role in skewing human MФs. Identifying them would enable treatments to reduce CI and fight off infections and CA cells more effectively.
Elisia I, Nakamura H, Lam V, Hofs E, Cederberg R, Cait J, Hughes MR, Lee L, Jia W, Adomat HH, Guns ES, McNagny KM, Samudio I & Krystal G. DMSO represses inflammatory cytokine production from human blood cells and reduces autoimmune arthritis. PLoS One 11: e0152538 2016. View Abstract
Ho VW, Hofs E, Elisia I, Lam V, Hsu BE, Lai J, Luk B, Samudio I & Krystal G. All trans retinoic acid, transforming growth factor b and prostaglandin E2 in mouse plasma synergize with basophil-secreted Interleukin-4 to M2 polarize murine macrophages. PLoS One 11: e0168072, 2016. View Abstract
Krystal G. The effects of protein and carbohydrates on cancer. Integrative Med 14: 52-58, 2016.
Samudio I, Rezvani K, Shaim H, Hofs E, Ngom M, Bu L, Liu G, Lee JT, Imren S, Lam V, Poon GF, Ghaedi M, Takei F, Humphries K, Jia W & Krystal G. UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells. Blood 127: 2575-2586, 2016. View Abstract
Ho VW, Hamilton MJ, Dang N-HT, Hsu BE, Adomat HH, Guns ES, Weljie A, Samudio I, Bennewith KL & Krystal G. A low carbohydrate, high protein diet combined with celecoxib markedly reduces metastasis. Carcinogenesis 35: 2291-2299, 2014. View Abstract
Hamilton MJ, Banath J, Lam V, LePard NE, Krystal G & Bennewith KL. Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice. Cancer Immunol Immunother 61: 643-654, 2012. View Abstract
Ruschmann J, Antignano F, Lam V, Kim C, Essak M, Zhang A, Lin AH, Mali RS, Kapur R & Krystal G. The role of SHIP in the development of activation of mouse mucosal and connective tissue mast cells. J Immunol 188: 3839-3850, 2012. View Abstract
Hamilton MJ, Ho VW, Kuroda E, Ruschmann J, Antignano F, Lam V & Krystal G. The role of SHIP in cancer. Exp Hematol 39: 2-13, 2011. View Abstract
Antignano F, Hamilton M, Patterson S, Ho V, Cohen C, Levings MK & Krystal G. SHIP-deficient dendritic cells, unlike wild type dendritic cells, suppress T cell proliferation via a nitric oxide-independent mechanism. PLoS One 6:e21893, 2011. View Abstract
Kuroda E, Antignano F, Ho VW, Hughes MR, Ruschmann J, Lam V, Kawakami T, Kerr WG, McNagny KM, Sly LM & Krystal G. SHIP represses Th2 skewing by inhibiting IL-4 production from basophils. J Immunol 186: 323-332, 2011. View Abstract
Ho VW, Leung K, Hsu A, Luk B, Lai J, Shen SY, Minchinton AI, Waterhouse D, Bally MB, Lin W, Nelson BH, Sly LM & Krystal G. A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Cancer Res 71: 1184-1193, 2011. View Abstract
Antignano F, Ibaraki M, Kim C, Ruschmann J, Zhang A, Helgason CD & Krystal G. SHIP is required for dendritic cell maturation. J Immunol 184: 2805-2813, 2010. (Recommended by the Faculty of 1000 Biology). View Abstract
Ruschmann J, Ho V, Antignano F, Kuroda E, Lam V, Ibaraki M, Synder K, Kim C, Flavell RA, Kawakami T, Sly L, Turhan AG & Krystal G. Tyrosine phosphorylation of SHIP promotes its proteasomal degradation. Exp Hematol 38: 393-402, 2010. View Abstract
Kuroda E, Ho V, Antignano F, Hamilton M, Ruschmann J, Rauh MJ, Antov A, Flavell RA, Sly LM & Krystal G. SHIP represses the generation of IL-3-induced M2 macrophages by inhibiting IL-4 production from basophils. J Immunol 183: 3652-3660, 2009. View Abstract
Sly LM, Hamilton MJ, Kuroda E, Ho VW, Antignano FL, Omeis SL, van Netten-Thomas CJ, Wong D, Brugger HK, Williams O, Feldman ME, Houseman BT, Fiedler D, Shokat KM & Krystal G. SHIP prevents lipopolysaccharide from triggering an anti-viral response in mice. Blood 113: 2945-2954, 2009. View Abstract
Sly LM, Kalesnikoff J, Lam V, Wong D, Song C, Omeis S, Chan K, Lee CWK, Siraganian RP, Rivera J & Krystal G. IgE-induced mast cell survival requires the prolonged generation of reactive oxygen species . J Immunol 181: 3850-3860, 2008. View Abstract
Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, Kim J, Demirjian L, Qasimi P, Ruschmann J, Cao LP, Ma K, Chung SW, Duronio V, Andersen RJ, Krystal G, & Mui AL. Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 110 (6): 1942-9, 2007. View Abstract
Sly LM, Ho V, Antignano F, Ruschmann J, Hamilton M, Lam V, Rauh MJ, & Krystal G. The role of SHIP in macrophages. Front Biosci 12: 2836-48, 2007. View Abstract
Rauh MJ, Ho V, Pereira C, Sham A, Sly LM, Lam V, Huxham L, Minchinton AI, Mui A, & Krystal G. SHIP represses the generation of alternatively activated macrophages. Immunity 23 (4): 361-74, 2005. View Abstract
Sly LM, Rauh MJ, Kalesnikoff J, Song CH, & Krystal G. LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 21 (2): 227-39, 2004. View Abstract
Takeshita S, Namba N, Zhao JJ, Jiang Y, Genant HK, Silva MJ, Brodt MD, Helgason CD, Kalesnikoff J, Rauh MJ, Humphries RK, Krystal G, Teitelbaum SL, & Ross FP. SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat Med 8 (9): 943-9, 2002. View Abstract
Kalesnikoff J, Huber M, Lam V, Damen JE, Zhang J, Siraganian RP, & Krystal G. Monomeric IgE stimulates signaling pathways in mast cells that lead to cytokine production and cell survival. Immunity 14 (6): 801-11, 2001. View Abstract