A number of commercially-obtained derivatives of the mushroom Trametes Versicolor (Tv) have been shown to activate the immune system in rodent models. These derivatives contain high levels of beta-glucans, which interact with a number of immune-related cell types. Subsequent industry-sponsored research into the mechanism of these products has resulted in a dearth of research into the parental whole product that contains a number of potentially immunopotentiating constituents including ergosterol-like compounds. At this juncture, the potential for synergistic action between the beta-glucan polysaccharides and the non-glucan constituents have not been investigated. Furthermore, the direct connection between quantity of TV crude extract consumption, induction of an immune response, and tumor regression/amelioration of treatment side effects remains to be explored. We hypothesize that beta-glucan polysaccharides in Tv represent a major constituent that, when consumed orally in a murine tumor system, upregulate the immune system causing tumor regression and amelioration of therapy-induced side effects. Furthermore, we theorize that non-glucan constituents can have an additive or even synergistic effect on the stimulation of the immune response. We propose to test our hypothesis and accomplish the objective of this application by pursuing the following specific aims: 1) Determine optimal dose and schedule of complex Tv extract to induce an immune response in tumor-bearing mice treated with radiation. We will examine tumor regression and amelioration of effects of radiation on normal tissue as secondary endpoints and correlate these results with immune activity and serum beta-glucan levels; 2) Determine absorption and biodistribution of orally consumed complex Tv extract in experimental prostate and breast cancer. We expect to find that non-glucan constituents may affect the bioavailability of beta-glucan in the murine model; 3) Determine the necessity of an intact immune system for complex Tv extract to influence tumor regression and amelioration of normal tissue damage after radiotherapy. In particular, we will examine the effect of deficiencies in complement receptor 3 (CR3), the primary pathway for beta-glucan induced immune stimulation, will affect Tv-induction of an immune response, tumor regression, and inhibition of radiation damage in normal tissue. This proposal is a key component of the DCRC acting as the translational component for the other studies and will contribute towards its overall goal to determine the efficacy of Tv containing beta-glucans to induce an immune response in the setting of cancer. We expect that data derived from this project will aid in deducing the mechanisms by which Tv extracts induce an immune response and lead to the incorporation of complex Tv extracts into the treatment of cancer.
