For Claudia & other tumeric devotees: new federal grant for food related cancer research!

For my work I have to check the Federal Register daily to see what new federal grants were announced that day. I saw this one yesterday and saved it because it is a federal grant for research related to FOOD and CANCER. It's long & boring, & none of us are eligible to apply, but you'll be interested in the cancer-fighting FOODS your tax dollars are helping to pay to research!

Department of Health and Human Services
Enhancing Tumoricidal Activity of Natural Killer (NK) Cells by Dietary Components for Cancer Prevention (R01)

Purpose
This NCI-sponsored Funding Opportunity Announcement (FOA) promotes research to characterize the significance of dietary components in regulating the tumoricidal activity of natural killer (NK) cells for cancer prevention. Specifically, this FOA encourages studies that can establish the physiological significance of dietary components in modulating the tumoricidal activity of NK cells. Research projects that are appropriate to this FOA should focus on defining the minimum quantity and duration of exposure to specific dietary components to modulate tumoricidal activity of NK cells for cancer prevention and the underlying mechanism(s) accounting for this response.

The growth and spread of cancer depend not only on the biological characteristics of the tumor per se but also on the host responses. NK cells represent one significant venue for influencing tumor growth and metastasis. NK cells are large granular lymphocytes without B or T cell characteristics; these cells are highly effective killers of both tumor cells and virally infected cells without the need for prior sensitization or recognition of a specific antigen. An important characteristic of cancer is that the disease can overcome the surveillance of the immune system. One possible explanation for this resistance (to immune surveillance) arises from the ability of tumor cells to inactivate the tumoricidal activity of hosts NK cells, thereby evading this first-line immune defense mechanism. Furthermore, inappropriate changes in microenvironment caused by treatment with various drugs, such as interferons (IFNs), and Interleukin-2 (IL-2) that can up-regulate NK cell activity, result in their attacking both self and non-self cells. Thus, it is extremely important to understand the early stage(s) of tumor-host interactions, and redirect these events from a pro-tumor to an anti-tumor state. Diet may represent a subtle approach to regulating NK cells without losing their self-tolerance mechanism.

Several lines of preliminary evidence suggest that a number of bioactive food components can induce tumor cell death, possibly by enhancing NK cell activity. For example, extracts of the Maitake- (Grifola frondosa) and Brazilian sun- mushrooms (Agaricus Blazei) can enhance the cytolytic activity of NK cells in tumor-bearing mice. Likewise, dietary supplementation with 250 mg vitamin E/day (for 2 weeks) can enhance NK cell cytolytic activity in advanced colorectal cancer patients. In addition, the supplementation of vitamin E (administered at 100 mg/day for 8 weeks) restored NK cell activity in a 16 month-old boy with Shwachman-Diamond syndrome that is classically associated with a persistent reduction in NK cytolytic activity. However, these preliminary findings and rare cases are only suggestive of the involvement of dietary components in regulation of the tumoricidal activity of NK cells. The precise role(s) by which these and other dietary components influence NK cells, such as modulation of receptor-ligand interactions and/or the release of cytokines and lytic enzymes, remains largely unknown.

Interaction of bioactive food components with NK cell receptors and their ligands.
Both experimental and clinical data indicate an important role for NK cells in early neoplastic development, possibly by either responding to specific ligands generated by cancer cells, or to various types of extracellular or cell-associated proteinases. NK cells are known to exert their activity through a diverse repertoire of activating (e.g., NKG2 receptor family) and inhibitory (e.g., killer immunoglobulin-like receptor [KIR] family) receptors that recognize specific ligands on the surface of target cells. Many of the KIRs recognize major histocompatibility (MHC) class I molecules, which in humans are human leukocyte antigen (HLA) class I molecules. The KIRs provide protection for cells that express normal levels of MHC class1 molecules on their surface. In general, the co-ligation of activating and inhibitory receptors results in a net negative (i.e., no cytotoxicity) reaction. In contrast, the down-regulation of MHC class I in cancer, together with expression of specific ligands for activating receptors such as MICA, MICB, or UL16-binding proteins, enhances the sensitivity of target cells to NK cell-mediated cytotoxicity.

There is some evidence to suggest that certain dietary components may modulate the NK cell activity in response to antigen stimuli. For example, when C57BL/6J mice were maintained for eight weeks on Selenium (Se)-deficient (~0.02 ppm), Se-normal (~0.20 ppm), or Se-supplemented (~2.00 ppm) diets, lymphocyte activity was differentially modulated; lymphocytes isolated from animals maintained on the Se-supplemented diets had an enhanced ability to destroy tumor cells compared with lymphocytes from animals that were maintained on either a normal or Se-deficient diet. While these studies support the general concept that specific dietary components can modify tumoricidal activity of NK cells, the evidence largely remains indirect. Therefore, the underlying mechanisms deserve additional study in order to develop and optimize future intervention strategies.

Influence of bioactive food components on cytokine release from NK cells.
Circulating NK cells are mature, as opposed to dendritic cells, which only mature during inflammation or infection. During early onset inflammation, immature dendritic cells secrete a variety of cytokines including tumor necrosis factor alpha (TNF-a), IL-2, and IL-12. These cytokines can induce a rapid expression of IFN-gamma and subsequently enhance the intrinsic cytolytic activity of NK cells. However, the response is complex since a T-Helper 2 (TH2) cytokine such as IL-4, which is generally viewed as an antagonist of IFN-gamma expression (in T cells), can induce signal transducer and activator of transcription 6 (STAT6)-dependent IFN-gamma secretion by NK cells. While some evidence suggests that specific bioactive food components (such as those derived from fermentable fibers and mushrooms) can modulate the release of various cytokines, it remains unclear whether these changes accompany a proportional alteration in the NK cell activity. NK cells, which can lyse tumor cells, provide antigenic cellular debris for mature dendritic cells to present to T cells; in later stages, NK cells terminate the process by lysing the dendritic cells and halting their ability for antigen presentation.

Dietary modulation of release of lytic granules from NK cells.
The lysosomal release of cytotoxic granules from NK cells, including two membrane-perturbing proteins such as perforin and granulysin, and a family of serine proteases (also known as granzymes), constitutes the main pathway for the immune system-mediated elimination of tumor cells. A number of studies indicate that dietary habits, including caloric restriction and alcohol consumption, may influence the cytolytic activity of NK cells by down-regulating the release, activity, and expression of perforin and granular proteases. Nevertheless, these observations need to be further characterized in mechanistic studies to establish a link between dietary modulation and cancer prevention.

Models for examining dietary components on NK tumoricidal activity.
NK cells, once activated, initiate the tumoricidal process through the release of both lytic granules and serine proteases (granzymes) or tumor-suppressive cytokines such as IFN-gamma, to mediate transformed cell death. Support for these findings comes from the inability of cytotoxic T lymphocytes (CTLs) to kill their target cells in either perforin-null or ashen mice that possess impaired granule pathway. Recently, genetically modified mouse cancer models have been extensively used for analyzing the occurrence of molecular events during the tumoricidal process. Analogous studies have also been conducted in humans with diseases caused by defects in tumor cell killing. Since a number of dietary components may influence NK cell tumoricidal activity, it would be prudent to use various models to establish the physiological significance of dietary components as either cancer protectants or modulators of cancer risk.

An example of the usefulness of the defined mouse model systems comes from studies using a recombination activating gene 2-deficient (RAG-2 -/-) mice. These mice fail to produce mature lymphocytes, which are critical for generating active forms of perforin and IFN-gamma. Consequently, RAG-2 -/- mice are highly susceptible to spontaneous development of adenocarcinomas in colon and lungs. Tumor growth in these genetically engineered mice was shown to be suppressed in response to dietary supplementation with Brazilian sun-mushrooms (Agaricus Blazei). A. blazei is an edible mushroom with anticancer activity native to Brazil; oral intake of A. blazei can enhance NK cell activation through IL-12-mediated IFN-gamma production.

Another mouse model includes deficiencies in STAT1 gene that is critical for the function of IFN-gamma. Double knockout animals of STAT1 -/- and RAG-2 -/- not only exhibit early onset of malignancy in colon and lung, but also demonstrate an exaggerated incidence of mammary cancers. In addition, mice with deficiencies in a subunit of IFN receptor expression (IFNAR -/-) were successfully used to demonstrate that endogenous Type 1 IFN is critical for controlling NK cell-mediated anti-tumor responses. These findings suggest that both IFN-gamma and perforin are critical in regulating some solid tumors. Therefore, the use of these models for determining the influence of bioactive food components on NK cell activity warrants further studies, given the literature evidence that several food items can modulate cancer risk, especially in cancers of the colon, lung, prostate, and mammary tissue.

Research topics that are relevant to this FOA include, but are not limited to, the following examples:
* Define if the exposure to varying quantities of mushroom-derived ß-glucans and vitamin E corresponds to changes in an activation (e.g. NKG2D) or inhibition (e.g. KIRs) of NK cell receptors and accompanies proportional change(s) in the removal of transformed cells
* Evaluate if NK cells from MHC1-deficient mice and humans respond differently to specific bioactive food components and thus examine the importance of MHC1 in target recognition for pre-neoplastic lesions
* Evaluate the response to garlic extracts on secretion of specific cytokines (such as TNF-a, IL-6, IL-10, and IL-13), and its relationship to tumoricidal activity of NK cells following exposure to pathogens
* Evaluate the influence of time and duration of exposure to dietary phytic acids on the release of lytic enzymes (such as granulysin or perforin) from NK cells derived from cancer cells
* Examine if dietary curcumin can influence interactions between NK and regulatory T cells, and whether these interactions can partially reverse tumor exosome-mediated inhibition of NK cell activation in vivo
* Compare the redistribution of tumoricidal NK cells from bone marrow to blood as a function of the type and quantity of dietary lipids consumed.

NCCAM’s research interests relevant to this FOA include, but are not limited to, the following examples:
* Elucidate the contribution of NK cell activation to anti-tumor activity of Angelica sinensis polysaccharides
* Elucidate the mechanism by which Astragalus membranaceus extracts potentiate NK cell anti-tumor activity
* Characterize the ginseng components that mediate NK cell activation and their mechanisms of action
* Elucidate the role of histocompatibility antigens in NK cell activation by mistletoe extracts
* Determine the ability of fruit- or medicinal herb-derived tannins to induce human tumor-targeted NK cell activity

http://grants.nih.gov/grants/guide/pa-files/PA-11-160.html