Chemical Mechanism of Mutation during Inflammation-Induced Carcinogenesis

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

It is a central theme of this Program Project that inflammation causes cancer. We strive to understand how it causes cancer, particularly cancers of the gastrointestinal tract, because understanding the chemical and molecular steps underlying the mechanism of neoplastic transformation provides valuable insight into the biology of end stage cancers. Moreover, this mechanistic understanding identifies steps at which intervention in terms of therapy or prevention strategies is likely to reduce disease burden in humans. Project 2 integrates with Project 1, which identifies a population of chemical mediators that in aggregate represent the drivers of the genetic changes many researchers believe underpin the conversion of normal cells into cancer cells. These mediators then promote the further genetic and non-genetic changes associated with fully developed malignant tumors. Project 2 is an effort to define the precise mechanisms by which chemical damage in the genome (Project 1) is converted into local genetic changes (point mutations) or into more global changes (strand breaks that initiate recombination) that, together, are likely to contribute to the conversion of a normal cell into a cancer cell (Project 4). Aim 1 of the current Project uses a battery of mammalian cell lines each of which is altered in a known way in a damage response (e.g., DNA repair) pathway and exposes those cells to nitric oxide, HOCI and related inflammatory agents. Unique tools to measure global DNA rearrangements are used to identify pathways critical to cellular susceptibility to, and defense against, inflammation. Together with Projects 3 and 4, the work of this Aim assorts the chemical mediators (e.g., DNA lesions) of Project 1 into categories reflecting their potential roles in tumorigenesis. Aim 2 examines each candidate chemical mediator'' one at a time and answers the following three questions: (a) Is it mutagenic and, if so, how mutagenic is it? (b) What kinds of mutation does it induce and do we see that mutational pattern in inflamed cells (Project 3) or in tissues or tumors derived from inflammation in animals (Project 4)? (c) Do cells have defenses (e.g., repair enzymes, bypass polymerases) against the chemical mediators and, if so, how do those defenses work? Aim 2 uses a unique approach to get at these issues. Specifically, candidate chemical mediators are built into the genomes of viruses or plasmids, one at a time, and the lesion is interrogated for the type, amount and genetic requirements for mutagenesis and genotoxicity of the lesion. In Aim 3, we ask about DNA damage from inflammation that occurs by reaction of inflammatory mediators (e.g., peroxynitrite, HOCI, etc.) directly with DNA. Aim 3 addresses another source of damage that has been much overlooked in the past -- damage from the nucleotide pool, which also is vulnerable to chemical modification, forming a host of species that, if incorporated into the genome by polymerases, can amplify the mutagenic and toxic potential of inflammation.