Given the importance of environmental factors in colorectal cancer (CRC), it is widely held that the incidence of this disease can be significantly reduced through dietary alterations, supplementation or therapeutic administration of chemoprotective agents, or by preventing exposure to initiating or tumor promoting chemical exposures. The list of currently popular chemoprotective agents includes naturally occurring dietary compounds such as indole-3- carbinol, chrysin and curcumin, as well as therapeutic agents like Sulindac and other NSAIDs. Interestingly, many proposed chemopreventative agents are known agonists of the aryl hydrocarbon receptor (AHR). We hypothesize that the AHR plays an important, yet complex, role in how environmental factors influence CRC in human populations. There are a number of data gaps that must be addressed before recommendations for increasing exposure to AHR agonists can be made with confidence. First, we must understand how AHR activation and AHR deletion in experimental animals lead to both increases and decreases in cancers at various sites. Second, we must understand whether AHR activation is an important step in the mode of action of known chemopreventative agents. If receptor agonism is mechanistically linked to chemoprevention, how do we modulate doses so we do not mimic the pro-carcinogenic effects of dioxins? If it is not mechanistically related to chemoprevention, can we modify structures of the chemopreventative agents to minimize this off-target AHR effect? We propose that the bifunctional role of the AHR in CRC can be explained using recombinant mouse models. We hypothesize that the pro- and anti-carcinogenic activity of the AHR depends upon the cell type in which the receptor is expressed and activated, as well as the degree to which the receptor is activated in that cell type. In addition, we propose that activation of the AHR in colonic mucosal epithelial cells leads to an altered lymphocyte response within the colon and that it us through this AHR-dependent lymphocyte biology that anti-carcinogenic activity is produced. To test these ideas, we offer the following specific aims:
Aim 1. Use cell specific deletion to define cell autonomy of AHR signaling and susceptibility to CRC.
Aim 2. Use models of conditional activation of AHR to determine tissue autonomy and test the rheostat model of AHR signaling and susceptibility to CRC.
Aim 3. Clarify the underlying mechanism of AHR-mediated tumor suppression in the CRC model. Through these aims, we propose the development of novel animal models that will almost certainly provide a significant step forward in our understanding of how environmental and dietary chemicals influence diseases such as CRC at barrier organs. Prior to this work, a thorough characterization of AHR's role in anti- carcinogenesis has never been carefully performed, making these experiments essential, timely and novel.
Chemicals that activate the aryl hydrocarbon receptor (AHR) are currently being used as chemopreventives for a number of cancers. This is problematic as AHR activation in experimental animals can both increase and decrease risk for cancers at various sites. Therefore, the goals of this proposal can be broadly defined as: First, to better understand whether AHR activation is an important step in the mode of action of known chemopreventive agents. Secondly, to determine how to modulate doses of AHR agonists so that too much action does not mimic the cancer causing side effects. Finally, to better understand the signaling events mediated by AHR agonists that are required for chemoprevention in an attempt to identify new agents that bypass the potential negative effects of AHR activation.
|Megna, Bryant W; Carney, Patrick R; Depke, Mitchell G et al. (2017) The aryl hydrocarbon receptor as an antitumor target of synthetic curcuminoids in colorectal cancer. J Surg Res 213:16-24|
|Díaz-Díaz, Carol J; Ronnekleiv-Kelly, Sean M; Nukaya, Manabu et al. (2016) The Aryl Hydrocarbon Receptor is a Repressor of Inflammation-associated Colorectal Tumorigenesis in Mouse. Ann Surg 264:429-36|
|Ronnekleiv-Kelly, Sean M; Nukaya, Manabu; Díaz-Díaz, Carol J et al. (2016) Aryl hydrocarbon receptor-dependent apoptotic cell death induced by the flavonoid chrysin in human colorectal cancer cells. Cancer Lett 370:91-9|
|Megna, Bryant W; Carney, Patrick R; Nukaya, Manabu et al. (2016) Indole-3-carbinol induces tumor cell death: function follows form. J Surg Res 204:47-54|