title: Milk fat globule EGF-8 promotes melanoma progression through coordinated Akt and twist signaling in the tumor microenvironment.
abstract: The pathogenesis of malignant melanoma involves the interplay of tumor cells with normal host elements, but the underlying mechanisms are incompletely understood. Here, we show that milk fat globule EGF-8 (MFG-E8), a secreted protein expressed at high levels in the vertical growth phase of melanoma, promotes disease progression through coordinated alpha(v)beta(3) integrin signaling in the tumor microenvironment. In a murine model of melanoma, MFG-E8 enhanced tumorigenicity and metastatic capacity through Akt-dependent and Twist-dependent pathways. MFG-E8 augmented melanoma cell resistance to apoptosis, triggered an epithelial-to-mesenchymal transition (EMT), and stimulated invasion and immune suppression. In human melanoma cells, MFG-E8 knockdown attenuated Akt and Twist signaling and thereby compromised tumor cell survival, EMT, and invasive ability. MFG-E8-deficient human melanoma cells also showed increased sensitivity to small molecule inhibitors of insulin-like growth factor I receptor and c-Met. Together, these findings delineate pleiotropic roles for MFG-E8 in the tumor microenvironment and raise the possibility that systemic MFG-E8 blockade might prove therapeutic for melanoma patients.
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
authors.forename: Yukoh
authors.initials: Y
authors.lastname: Nakazaki
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carrasco
authors.forename: Dobrin
authors.initials: D
authors.lastname: Draganov
authors.forename: Nicholas
authors.initials: N
authors.lastname: Souders
authors.forename: Matthew
authors.initials: M
authors.lastname: Johnson
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers; D018450:Disease Progression; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008894:Milk Proteins; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D017931:DNA Primers; C098942:MFGE8 protein, human; D008894:Milk Proteins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D051057:Proto-Oncogene Proteins c-akt