Successful chemoprevention of lung cancer requires delineation of those events regulating tumor formation. Mice develop lung tumors with molecular characteristics and histogenesis similar to human pulmonary adenocarcinoma, thus providing a useful model. The only reversible stage in lung tumor progression is promotion, where benign lesions can be induced to revert to silent, non-dividing, mutated cells. We study mechanisms underlying lung tumor promotion by separating induction of the Kras protooncogene mutation that initiates tumorigenesis from application of an agent that promotes tumor development but cannot initiate it, namely, butylated hydroxytoluene (BHT). Reactive metabolites of BHT cause compensatory hyperplasia and inflammation in lungs; we have provided evidence that inflammation plays a major role in promotion. In the next funding period, we will determine how inflammation encourages lung tumor growth.
Three Aims are proposed.
In Aim I, we will identify genes regulating susceptibility to both the promotion and inflammation induced by BHT using refined linkage analysis with two sets of recombinant inbred (RI) mouse strains that are sensitive and resistant to these actions of BHT, the CXB and AXB, BXA RI strains. Adoptive transfer of bone marrow between sensitive and resistant strains will determine whether these susceptibility genes act through macrophages.
In Aim II, possible effects of BHT on allele-specific expression of Kras will be determined; we will learn if BHT enhances tumor growth in mice with an inherited Kras mutation. Also we will modulate the proliferative and inflammatory status in lungs using partial pneumonectomy as a proliferative stimulus along with application of pro-inflammatory drugs or by the use of transgenic mice that over-express pro-inflammatory mediators.
In Aim llI, we examine the cell signaling distal to Kras that involves ERK phosphorylation and prostaglandin production in bronchiolar Clara and alveolar type 2 cells isolated from promotion sensitive and resistant mice. We will also examine Cx43 and CD44 as downstream markers of prostaglandin actions on cells. These studies should lead to insights for developing novel diagnostic, preventive, and therapeutic strategies.
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