Tumor associated macrophages (TAMs) are currently thought to be critical for tumor progression. Increased expression of the urea cycle enzyme arginase 1 (Arg1) is closely correlated with TAMs. One hypothesis for Arg1's role in TAM function is that Arg1 regulates nitric oxide (NO) production by depleting L-arginine, the common substrate of nitric oxide synthases and arginases. The overall goal of this proposal is to investigate the functions of TAM Arg1, iNOS, L-arginine metabolism and free radical production in tumor development, growth and gene expression modification. Our working hypothesis is that Arg1 is an essential enzyme in solid tumor progression and its elimination from TAMs will lead to reduced tumor progression and/or the discovery of compensatory mechanisms vital to NO regulation, angiogenesis, and immune evasion by tumors. We will test the functions of Arg1, NO, and macrophage (MO) L-arginine metabolism in solid tumor models using unique genetic tools where we can manipulate MO L-arginine metabolism, specifically in TAMs, in multiple ways. The outcomes of the proposed experiments will illuminate new aspects of TAM function and immune responses in tumors. The experiments proposed will address the following aims:
Aim 1 - Determine the mechanistic aspects of Arg1-mediated regulation of NO production by TAMs through the metabolism of L-arginine, Aim 2 - Determine the requirement for Arg1 in the production of matrix metalloproteinases (MMPs) by TAMs, and Aim 3 - Determine the requirement for TAM Arg1 for solid tumor survival. Each of the aims will be achieved by implanting solid tumors into Arg1flox/flox;Tie2cre (in which MOs cannot produce Arg1) and control mice. TAMs will be isolated from the tumor and analyzed for gene expression, protein production, and control of tumor progression when they can, or cannot, produce Arg1.
TAMs are generally associated with poor prognosis in cancer, including breast, prostate, and bladder cancers. Arg1 is expressed in large amounts in most tumors, and its expression is assumed to be primarily by TAMs. The major goal of this proposal is to determine the link between Arg1 expression and TAM function, and their interrelationship with associated tumors. The information gained will lead to better treatment regimens targeting immune cells, as well as the tumor.
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