A MOUSE MODEL OF INFLAMMATION PROMOTED LUNG CARCINOGENESIS

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Chemical carcinogenesis models in mouse have been central to elucidating the stages of tumor evolution, namely initiation, promotion, and progression. One commonly used model in the mouse lung, involves initiation of tumorigenesis with the PAH, 3-MCA. 3-MCA initiates tumorigenesis through mutational activation of the proto-oncogene K-Ras.  Subsequent promotion and progression of tumorigenesis can be accelerated by chronic administration of non-carcinogenic lung inflammatory agents, such as the chemical butylated hydroxytoluene (BHT) (50-52).  BHT undergoes metabolism by lung specific P450s to a very reactive BHT-quinone methide, which subsequently forms adducts with cellular proteins and creates an environment of chronic tissue damage and compensatory epithelial cell proliferation. This includes type I cell necrosis followed by type II cell hyperplasia and differentiation to replace lost type I cells (53-55). Repeated delivery of BHT causes massive inflammatory cell infiltration in the alveolar spaces of inflammation susceptible BALB/cByJ (BALB) strain mice.  Importantly, if BHT is administered weekly for 6 weeks after an initial single dose of MCA, the result is a 10-fold enhancement in observed lung tumors (54, 55).  It is important to note that there is strong genetic control of these inflammatory and tumor responses, as different inbred mouse strains differ in the degree of inflammation and degree of tumor promotion caused by BHT.  C57BL/6J (B6) strain mice exhibit low levels of BHT-induced inflammation and are also resistant to tumor promotion by BHT, while strains such as A/J and BALB are considered susceptible. BHT elicits similar injury as other lung irritants, such as ozone, crystalline silica, hyperoxia, and vanadium pentoxide (50).  Several genetic susceptibility mapping studies have identified genetic loci for susceptibility to inflammation that are common to different lung inflammatory agents, suggesting they operate by similar mechanisms.  Interestingly, many of these loci overlap known lung cancer susceptibility loci, suggesting common mechanisms of action between lung injury/inflammation and carcinogenesis (56).

Recent studies have demonstrated that neutrophils play a seminal pro-tumorigenic role in mediating tumor promotion by BHT (57). When compared to tumor promotion in control IgG-treated BALB mice, antibody-mediated depletion of neutrophils in BALB/cByJ mice, reduced tumor multiplicity by 71%.  BHT induces both neutrophil numbers and levels of the neutrophil chemokine KC in the airways of susceptible BALB/cByJ mice.   Furthermore, data from this study suggests that KC expression by lung tissue-resident CD11c+ cells may play an important role in susceptibility to pulmonary carcinogenesis by maintaining high levels of neutrophil trafficking into the lung.  This is consistent with other studies showing similar kinetics of KC and neutrophil levels, caused by V₂O₅, another tumor promoter of MCA tumorigenesis (58). The requirement for neutrophils in this model is consistent with enhanced neutrophil and KC levels observed in bronchoalveolar carcinoma patients with poor outcome (59). These data indicate that neutrophils and their effector functions are potential targets for prevention and therapy.