Increased, Induced Mutations in Critical Genes leads to Increased, Proliferation/Clonal Expansion of Mutant Cells (Pre-Neoplastic Lesions/Altered H

There is no direct evidence addressing AFB1 induced critical gene mutations and the subsequent induction of AHF. However, in general the progression from chemical exposure to pre-neoplastic lesions appears to include six general mechanisms: 1) decrease in the activity of the Keap1/Nrf2/ARE pathway; 2) decrease in p53 function leading to increased survival in the presence of genomic instability; 3) changes in the tumor microenvironment within cells; 4) alterations in apoptosis; 5) changes in Wnt/b-catenin signaling, and 6) gene expression changes that may be related to cancer promotion/progression (Caballero et al., 2004; Ma and He, 2012; Gross-Steinmeyer and Eaton, 2012; Liby et al., 2008; Yates and Kensler, 2007; Liby and Sporn, 2012; Ikeda et al., 2004; Harida et al., 2004; Kwak et al, 2001; Honda et al., 2011; Shelton and Jaiswal, 2013; Johnson et al., 2014; Fabregat, 2009). In addition to these six possible mechanisms, epigenetic changes in DNA methylation may occur and may be related to the progression of cancer (Zhang et al., 2003, 2006, 2012; Wu et al, 2013; Pogribney et al., 2011).

While studies have been conducted to quantitate clonal expansion and pre-neoplastic foci following exposure to AFB1, there are no studies that evaluate the quantitative relationship between cells carrying critical cancer gene mutations and clonal expansion/pre-neoplastic foci. This is primarily due to the lack of appropriate techniques. The chemoprevention data, however, indicate that the relationship between induced mutations in critical genes and AHF is likely not a linear one; additional data, such as with ACB-PCR techniques (Parsons et al., 2010), collected in a carefully designed study, could address this.

In mammals, the identification of AHF as a pre-neoplastic lesion has been recognized for many years as part of the general etiology of HCC (Beer and Pitot, 1987; Dragan et al., 1995; Goldsworthy et al., 1986; Pitot et al., 1990; Sargent et al., 1989). In rats, the presence of AHF with altered growth characteristics has been observed in a number of studies (Bannasch et al., 1985; Fischer, 1986; Fischer et al., 1987; Gil et al., 1988; Godlewski et al., 1985; Manson et al., 1984; Newberne, 1976; Nishizumi et al., 1977; Roebuck et al., 1991; Youngman and Campbell, 1992). The mechanisms involved in the formation of AHF appear to be generalizable across animals and likely apply to fish and birds as well as mammals.