title: FOXC2 augments tumor propagation and metastasis in osteosarcoma.
abstract: Osteosarcoma is a highly malignant tumor that contains a small subpopulation of tumor-propagating cells (also known as tumor-initiating cells) characterized by drug resistance and high metastatic potential. The molecular mechanism by which tumor-propagating cells promote tumor growth is poorly understood. Here, we report that the transcription factor forkhead box C2 (FOXC2) is frequently expressed in human osteosarcomas and is important in maintaining osteosarcoma cells in a stem-like state. In osteosarcoma cell lines, we show that anoikis conditions stimulate FOXC2 expression. Downregulation of FOXC2 decreases anchorage-independent growth and invasion in vitro and lung metastasis in vivo, while overexpression of FOXC2 increases tumor propagation in vivo. In osteosarcoma cell lines, we demonstrate that high levels of FOXC2 are associated with and required for the expression of osteosarcoma tumor-propagating cell markers. In FOXC2 knockdown cell lines, we show that CXCR4, a downstream target of FOXC2, can restore osteosarcoma cell invasiveness and metastasis to the lung.
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Maricel C
authors.initials: MC
authors.lastname: Gozo
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Dongyu
authors.initials: D
authors.lastname: Jia
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Paul-Joseph
authors.initials: PJ
authors.lastname: Aspuria
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Dong-Joo
authors.initials: DJ
authors.lastname: Cheon
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Walts
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
mesh_terms: D000818:Animals; D023102:Anoikis; D001859:Bone Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C527276:CXCR4 protein, human; D051858:Forkhead Transcription Factors; D019718:Receptors, CXCR4; C082078:mesenchyme fork head 1 protein
keywords: anoikis; forkhead box C2; invasion; metastasis; osteosarcoma