title: Restoration of PTEN activity decreases metastases in an orthotopic model of colon cancer.
abstract: BACKGROUND
  Mutational loss of tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) is associated with malignant progression in many cancers, including colorectal cancer (CRC). PTEN is involved in negatively regulating the phosphatidylinositol 3-kinase/AKT oncogenic signaling pathway and has been implicated in the metastatic colonization process. Few in vivo models are available to study CRC metastasis. The purpose of this study was to determine the effect of restoring PTEN activity on metastases in an orthotopic murine model.
  
  
  METHODS
  Green fluorescent protein labeled TENN, a highly metastatic human colon cancer cell line with mutational loss of PTEN gene and TENN clones (with restoration of PTEN gene) tumors were orthotopically implanted onto the colons of BALB/c nude mice and allowed to develop primary and metastatic tumors. Seven weeks post-implantation, mice were euthanized and organs extracted for examination.
  
  
  RESULTS
  Both TENN and TENN clone cell lines demonstrated 100% primary invasion. However, compared with the parental TENN cells, which demonstrated 62% metastases to both lungs and liver, TENN clone cells showed an approximately 50% reduction in metastasis, with only 31.6% liver metastasis and no metastasis to the lungs (P = 0.02).
  
  
  CONCLUSIONS
  Our study shows that reactivation of PTEN tumor suppressor pathway leads to a 50% reduction in CRC metastasis without affecting primary tumor formation. Importantly, PTEN restoration also changed the organotropic homing from liver and lung metastasis to liver metastasis only. This in vivo study demonstrates that PTEN might act specifically as a metastasis suppressor and, thus, efforts to target the phosphatidylinositol 3-kinase/PTEN pathway are legitimate.
authors.affiliation: Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Melanie
authors.initials: M
authors.lastname: Ongchin
authors.forename: Guanghua
authors.initials: G
authors.lastname: Wan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sharratt
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brattain
authors.forename: Ashwani
authors.initials: A
authors.lastname: Rajput
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D015994:Incidence; D008113:Liver Neoplasms / Q000453:epidemiology* / Q000556:secondary*; D008175:Lung Neoplasms / Q000453:epidemiology* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase
keywords: Colorectal cancer; Metastases; PI3Kinase; PTEN