title: Portrait of the PI3K/AKT pathway in colorectal cancer.
abstract: PI3K/AKT signaling leads to reduced apoptosis, stimulates cell growth and increases proliferation. Under normal conditions, PI3K/AKT activation is tightly controlled and dependent on both extracellular growth signals and the availability of amino acids and glucose. Genetic aberrations leading to PI3K/AKT hyper-activation are observed at considerable frequency in all major nodes in most tumors. In colorectal cancer the most commonly observed pathway changes are IGF2 overexpression, PIK3CA mutations and PTEN mutations and deletions. Combined, these alterations are found in about 40% of large bowel tumors. In addition, but not mutually exclusive to these, KRAS mutations are observed at a similar frequency. There are however additional, less frequent and more poorly understood events that may also push the PI3K/AKT pathway into overdrive and thus promote malignant growth. Here we discuss aberrations of components at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational level where perturbations may drive excessive PI3K/AKT signaling. Integrating multiple molecular levels will advance our understanding of this cancer critical circuit and more importantly, improve our ability to pharmacologically target the pathway in view of clonal development, tumor heterogeneity and drug resistance mechanisms. In this review, we revisit the PI3K/AKT pathway cancer susceptibility syndromes, summarize the known aberrations at the different regulatory levels and the prognostic and predictive values of these alterations in colorectal cancer.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Stine Aske
authors.initials: SA
authors.lastname: Danielsen
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Peter Wold
authors.initials: PW
authors.lastname: Eide
authors.affiliation: K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway.
authors.forename: Arild
authors.initials: A
authors.lastname: Nesbakken
authors.affiliation: K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway.
authors.forename: Tormod
authors.initials: T
authors.lastname: Guren
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Edward
authors.initials: E
authors.lastname: Leithe
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. Electronic address: rlothe@rr-research.no.
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic / Q000502:physiology; D015894:Genome, Human; D006801:Humans; D035683:MicroRNAs / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D020543:Proteome / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D020543:Proteome; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Colorectal cancer; Copy number variation; Gene expression; MicroRNA; Mutation; PI3K/AKT pathway