The Chromosomal Instability Pathway in Colon Cancer Maria S. Pino, Daniel C. Chung  Gastroenterology  Volume 138, Issue 6, Pages 2059-2072 (May 2010) DOI: 10.1053/j.gastro.2009.12.065 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 Multistep genetic model of colorectal carcinogenesis. The initial step in colorectal tumorigenesis is the formation of aberrant crypt foci (ACF). Activation of the Wnt signaling pathway can occur at this stage as a result of mutations in the APC gene. Progression to larger adenomas and early carcinomas requires activating mutations of the proto-oncogene KRAS, mutations in TP53, and loss of heterozygosity at chromosome 18q. Mutational activation of PIK3CA occurs late in the adenoma–carcinoma sequence in a small proportion of colorectal cancers. Chromosomal instability is observed in benign adenomas and increases in tandem with tumor progression. Copyright © 1998 Massachusetts Medical Society. All rights reserved. Reproduced from Takayama T, Katsuki S, Takahashi Y, et al. Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med 1998;339:1277–1284. Gastroenterology 2010 138, 2059-2072DOI: (10.1053/j.gastro.2009.12.065) Copyright © 2010 AGA Institute Terms and Conditions

Figure 2 Regulation of sister chromatid separation at the metaphase–anaphase transition. In prometaphase, highly condensed chromosomes establish bipolar attachments to the mitotic spindle. Unattached or mal-orientated chromosomes generate a signal to delay the onset of anaphase until all pairs of sister chromatids are properly aligned on the metaphase plate. This signal is transduced by a relay of spindle-checkpoint proteins, including MAD1, MAD2, BUB1, BUBR1, BUB3, and CENP-E, which inhibits cell division cycle 20 (CDC20)–mediated activation of an E3 ubiquitin ligase, the APC/C. Following attachment and alignment of all the chromosomes at metaphase, the checkpoint signal is silenced and APC/C initiates the ubiquitin-dependent degradation of securin and activation of separase. Separase in turn cleaves a multiprotein complex termed cohesin, which creates physical links between sister chromatids to initiate anaphase. Gastroenterology 2010 138, 2059-2072DOI: (10.1053/j.gastro.2009.12.065) Copyright © 2010 AGA Institute Terms and Conditions

Figure 3 The Wnt signaling pathway in the “OFF” and “ON” states. In the absence of a Wnt signal, the destruction complex containing APC, glycogen synthase kinase 3β (GSK-3β), and casein kinase 1α/ε (CK1α/ε) on an axin-conductin scaffold targets the degradation of cytoplasmic β-catenin in a proteasome-dependent manner. In the nucleus, Wnt target genes are also kept silent by the repressor Groucho interacting with DNA-bound T cell factor (TCF). In the presence of a Wnt ligand, occupancy of the receptors Frizzled (Frz) and coreceptor low-density lipoprotein receptor-related protein (LRP) triggers the phosphorylation of the cytoplasmic tail of LRP by CK1 and GSK-3β as well as the disheveled (Dsh)-dependent recruitment of axin on phosphorylated LRP. Phosphorylation of β-catenin no longer occurs, and the increased cytoplasmic levels of β-catenin translocate to the nucleus, where the transcription of multiple genes is initiated through displacement of Groucho and the interaction of β-catenin with TCF/lymphoid enhancer factor (LEF) family of transcription factors. Gastroenterology 2010 138, 2059-2072DOI: (10.1053/j.gastro.2009.12.065) Copyright © 2010 AGA Institute Terms and Conditions

Figure 4 The RAS signaling pathway. Growth factors binding to their cell surface receptors activate guanine exchange factors (GEF), such as SOS (son of sevenless) that are attached by the adaptor protein GRB2 (growth-factor-receptor bound protein 2). SOS stimulates the release of bound guanosine diphosphate (GDP) from RAS, and it is exchanged for guanosine triphosphate (GTP), leading to the active RAS-GTP conformation. The guanosine triphosphatase (GTPase)-activating proteins (GAP) can bind to RAS-GTP and accelerate the conversion of RAS-GTP to RAS-GDP, which terminates signaling. Mutated RAS is constitutively active in the RAS-GTP conformation. Activated RAS regulates multiple cellular functions through effectors including the Raf–MEK–ERK pathway, phosphatidylinositol 3 kinase (PI3K), RALGDS, RALGDS-like gene (RLG), and RGL2. Gastroenterology 2010 138, 2059-2072DOI: (10.1053/j.gastro.2009.12.065) Copyright © 2010 AGA Institute Terms and Conditions

Maria S. Pino Gastroenterology 2010 138, 2059-2072DOI: (10.1053/j.gastro.2009.12.065) Copyright © 2010 AGA Institute Terms and Conditions

Daniel C. Chung Gastroenterology 2010 138, 2059-2072DOI: (10.1053/j.gastro.2009.12.065) Copyright © 2010 AGA Institute Terms and Conditions