title: Mesenchymal stromal cell mutations and wound healing contribute to the etiology of desmoid tumors.
abstract: Desmoid tumors are nonmalignant neoplasms of mesenchymal origin that mainly contain fibroblast lineage cells. These tumors often occur in patients with familial adenomatous polyposis (FAP) coli who have germ line mutations in the APC gene. Given emerging data that has implicated multipotent mesencyhmal stromal cells (MSC) in the origin of mesenchymal tumors, we hypothesized that desmoid tumors may arise in patients with FAP after MSCs acquire somatic mutations during the proliferative phase of wound healing. To test this idea, we examined 16 desmoid tumors from FAP-associated and sporadic cases, finding that all 16 of 16 tumors expressed stem cell markers, whereas matching normal stromal tissues were uniformly negative. Desmoid tumors also contained a subclass of fibrocytes linked to wound healing, angiogenesis, and fibrosis. Using an MSC cell line derived from an FAP-associated desmoid tumor, we confirmed an expected loss in the expression of adenomatous polyposis coli (APC) and the transcriptional repressor BMI-1 while documenting the coexpression of markers for chondrocytes, adipocytes, and osteocytes. Together, our findings argue that desmoid tumors result from the growth of MSCs in a wound healing setting that is associated with deregulated Wnt signaling due to APC loss. The differentiation potential of these MSCs combined with expression of BMI-1, a transcriptional repressor downstream of Hedgehog and Notch signaling, suggests that desmoid tumors may respond to therapies targeting these pathways.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts MA 02115, USA.
authors.forename: Adelaide M
authors.initials: AM
authors.lastname: Carothers
authors.forename: Hira
authors.initials: H
authors.lastname: Rizvi
authors.forename: Rian M
authors.initials: RM
authors.lastname: Hasson
authors.forename: Yvonne I
authors.initials: YI
authors.lastname: Heit
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Davids
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cho
mesh_terms: D045744:Cell Line, Tumor; D018222:Desmoid Tumors / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009154:Mutation; D014945:Wound Healing
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