title: Epithelial-specific loss of PTEN results in colorectal juvenile polyp formation and invasive cancer.
abstract: Cowden syndrome (CS) is a rare autosomal dominant cancer-prone disorder caused by germ-line mutation of the phosphatase and tensin homolog mutated on chromosome 10 (PTEN) tumor-suppressor gene. Affected patients commonly develop juvenile polyps, and show an elevated risk of developing colorectal cancers. The etiology of these peculiar polyps remains unclear, although previous work has suggested somatic PTEN alterations in the stroma of juvenile polyps. After a long latency period, we find epithelial-specific PTEN deletion to cause formation of juvenile polyps in the colorectum without stromal PTEN loss. More important, we find that these lesions closely recapitulate all of the characteristic histopathological features of juvenile polyps seen in patients with CS, including stromal alterations and dysplastic transformation to colorectal carcinoma. The stromal alterations we identify after epithelial-specific PTEN loss suggest that PTEN may be involved in altered epithelial-mesenchymal cross talk, which, in turn, predisposes to colorectal neoplasia and polyposis. Our transgenic model is the first to recapitulate colorectal juvenile polyposis in patients with CS. We conclude that stromal PTEN loss is not a prerequisite for the formation of juvenile polyps, and that colorectal juvenile polyps in CS are bona fide neoplastic precursor lesions.
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Marsh Durban
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Davies
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Folkert H
authors.initials: FH
authors.lastname: Morsink
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom. Electronic address: clarkear@cardiff.ac.uk.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D044483:Intestinal Polyposis / Q000151:congenital / Q000235:genetics / Q000473:pathology; D007417:Intestinal Polyps / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse