title: Six1 promotes colorectal cancer growth and metastasis by stimulating angiogenesis and recruiting tumor-associated macrophages.
abstract: The homeoprotein Six1 is overexpressed in many human cancers and is associated with increased tumor progression and metastasis. Recent studies have shown that Six1 is associated with poorer overall survival in advanced-stage colorectal cancer (CRC). In the current study, we explored the functional changes and molecular events associated with Six1 overexpression in a mouse model of CRC. An orthotopic model and a splenic injection metastasis model were used to investigate the role of Six1 in CRC tumor growth and metastasis using mouse colon adenocarcinoma MC38 cells overexpressing Six1. We found that overexpression of Six1 dramatically promotes CRC tumor growth and metastasis in vivo. Six1 overexpression in MC38 increased protein levels of aldehyde dehydrogenase-1 and expanded CD44+/CD166+ populations, indicating Six1 increased features of cancer stem cells. In addition, Six1 overexpression stimulated angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). Six1-overexpressing tumor cells recruited tumor-associated macrophages (TAM) by increasing the expression of macrophage-specific colony stimulating factor, chemokine (C-C motif) ligand 2/5 and VEGF, further facilitating CRC tumor growth and metastasis. Furthermore, we determined that Six1 activated mitogen-activated protein kinase (MAPK) signaling in CRC cells. In summary, our studies strongly suggest that Six1 overexpression promotes CRC growth and metastasis and remodels tumor stroma by stimulating angiogenesis and recruiting TAM. MAPK activation may be a pivotal event in Six1-associated tumor progression, which may provide opportunities for pharmacologic intervention.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Columbia, SC 29208, USA.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Peña
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pirisi
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Columbia, SC 29208, USA.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Creek
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D045325:HCT116 Cells; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C099236:SIX1 protein, human; C490947:Six1 protein, mouse; D042461:Vascular Endothelial Growth Factor A