Colon cancer develops from a combination of genetic and environmental influences. Aberrant crypt loci (ACF) represent a morphologically identifiable premalignant lesion that is associated with colon cancer pathogenesis. We and others have identified a number of alterations in tumor-related genes that may predict their outcome. We intend to fully characterize ACF in terms of their significance in the dysplasia-adenoma-carcinoma sequence. To accomplish this goal, we will examine potential genetic aberrations and expression profiles of ACF at their earliest stages of formation. We will also test how luminal factors induce their growth, focusing on bile acid (BA) composition and bacterial colonization. Finally, we will extend our recent studies on dysregulation of the ARF-p53 circuit, using pdmary epithelial tumor cells (SP-2 cells) recently established from NJ mice.
Aim 1 will determine whether genomic instability contributes to colon tumor pathogenesis in AOM-treated mice. We will use CGH and SKY to analyze colon tumors from a panel AOM sensitive strains (A,SWR, FVB/N,Balb/c). We will then use focused BAC arrays and global mutational analyses to study ACF that have been stratified by histomorphology. We will confirm altered genes by TaqMan/IHC analysis and representative known genes involved in colon tumorigenesis will be selected for analysis from regions of gain/loss and mutational alterations. Parallel gene profiling of ACF will be undertaken to determine molecular signatures that predict cancer risk in ACF stratified by tumorigenic potential. RNA from laser-captured ACF of varying morphology and predicted growth characteristics will be linear amplified and applied to high-density arrays. Finally, we will use focused BAC arrays to characterize human ACF using candidate regions identified above.
Aim 2 will establish the luminal conditions that favor ACF progression, focusing on chemical exposures, bile acids and bacterial colonization. We will test whether bile acids induce altered luminal redox status and inactivate p53 and whether ACF that form reflect these early alterations. We will also test the effects of bacterial colonization on bile acid metabolism and ACF promotion.
Aim 3 will determine the mechanism for functional inactivation of p53 that we recently reported in NJ tumors. This is the first in vivo model demonstrating loss of p53 function (DNA binding, target gene regulation) with sequence-normal cDNA. We will use our epithelial tumor cells (SP-2 cells) to study mechanisms and consequences of p53 inactivation. We will examine the responsiveness of p53 in AOM-induced colon cancer cells to p53 activators and determine the posttranslational modification status of p53. We will determine which proteins associate with p53 in the SP-2 cells and determine the influence of identified p53 modifications on p53 activity. Finally, we will evaluate the effects of BAs on p53 function both YAMC and SP-2 cells.
| Drew, David A; Mo, Allen; Grady, James J et al. (2018) Proximal Aberrant Crypt Foci Associate with Synchronous Neoplasia and Are Primed for Neoplastic Progression. Mol Cancer Res 16:486-495 |
| Hanley, Matthew P; Kadaveru, Krishna; Perret, Christine et al. (2016) Dietary Methyl Donor Depletion Suppresses Intestinal Adenoma Development. Cancer Prev Res (Phila) 9:812-820 |
| Mo, Allen; Jackson, Stephen; Varma, Kamini et al. (2016) Distinct Transcriptional Changes and Epithelial-Stromal Interactions Are Altered in Early-Stage Colon Cancer Development. Mol Cancer Res 14:795-804 |
| Anderson, Joseph C; Pleau, Devon C; Rajan, Thiruchandurai V et al. (2010) Increased frequency of serrated aberrant crypt foci among smokers. Am J Gastroenterol 105:1648-54 |
| Rosenberg, Daniel W; Giardina, Charles; Tanaka, Takuji (2009) Mouse models for the study of colon carcinogenesis. Carcinogenesis 30:183-96 |
| Spurling, Colleen C; Godman, Cassandra A; Noonan, Emily J et al. (2008) HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol Carcinog 47:137-47 |
| Godman, Cassandra A; Joshi, Rashmi; Tierney, Brendan R et al. (2008) HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling. Cancer Biol Ther 7:1570-80 |
| Flynn, Christopher; Montrose, David C; Swank, Daniel L et al. (2007) Deoxycholic acid promotes the growth of colonic aberrant crypt foci. Mol Carcinog 46:60-70 |
| Stevens, Richard G; Swede, Helen; Rosenberg, Daniel W (2007) Epidemiology of colonic aberrant crypt foci: review and analysis of existing studies. Cancer Lett 252:171-83 |
| Rosenberg, Daniel W; Yang, Shi; Pleau, Devon C et al. (2007) Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res 67:3551-4 |
Showing the most recent 10 out of 34 publications
