General aspects of colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the main causes of death. Cancer is initiated by several DNA damages, affecting proto-oncogenes, tumour suppressor genes, and DNA repairing genes. The molecular origins of CRC are chromosome instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). A brief description of types of CRC cancer is presented, including sporadic CRC, hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndromes, familiar adenomatous polyposis (FAP), MYH-associated polyposis (MAP), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). Some signalling systems for CRC are also described, including Wnt-β-catenin pathway, tyrosine kinase receptors pathway, TGF-β pathway, and Hedgehog pathway. Finally, this paper describes also some CRC treatments.

Figure 1

Classical theory of carcinogenesis. Cancer is generated by a three-step process: initiation, promotion, and progression. Several mutations are needed to develop a cancer.

Figure 2

Cell cycle and its control. G₀ stands for gap 0, G₁ for gap 1, S for synthesis, G₂ for gap 2, and M for mitosis. Cell cycle includes interface (G₁, S, and G₂), and M (including prophase, metaphase, anaphase, and telophase). Nondividing cells (G₀ or resting phase) are not considered to be in the cell cycle. Cytokinesis follows mitosis. Checkpoint G₁/S decides if cells go to rest (G₀) or to S. Checkpoint G₂/M decides if cells can begin mitosis. Checkpoint M occurs in metaphase of mitosis and it is in charge of biorientation.

Figure 3

Canonical Wnt-β-catenin pathway. Wnt signaling pathway is shown in the “OFF” (left hand side) and “ON” (right hand side) states. In the absence of a Wnt signal, the destruction complex phosphorylates and ubiquinates β-catenin, being therefore destroyed by the proteasome. In the presence of a Wnt signal, as the dishevelled protein (Dsh) recruits the Axin2 and inhibits GSK-3, β-catenin is not phosphorylated and therefore not destroyed. It can translocate to the nucleus and activate transcriptions genes (adapted from [72]).

Figure 4

Tyrosine kinase receptors pathway. Tyrosine kinase receptors include the following dimmers receptors: EGFR, epidermal growth factor receptor (also known as HER2 or ErbB2); HER, human epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor. IGFR, insulin growth factor receptor, is also a tyrosine kinase receptor. When a growth factor binds to the receptor, a cascade of phosphorylations is initiated, which finishes with activation of transcription genes (adapted from [73]).

Figure 5

Transforming growth factor-β (TGF-β) pathway. TGF-β receptor is a dimer formed by TβRII (with a binding site for TGF-β) and TβRI (with a glycine/serine rich domain). The complete receptor is autophosphorylated and recruits and phosphorylates a gene regulatory protein called SMAD (adapted from [74]).

Figure 6

Hedgehog pathway. In absence of Hedgehog (Hh), PTCH1 binds to SMO, whereas in presence of Hh, the complex Hh-PTCH1 internalizes and releases SMO. Free SMO activates a family of transcription factors, including GLI (adapted from [75]).