title: Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma.
abstract: Esophageal adenocarcinoma (EAC) is often diagnosed at an advanced stage, thus understanding the molecular basis for EAC invasion and metastasis is critical. Here we report that SPP1/OPN was highly overexpressed in primary EACs and intracellularly localized to tumor cells. We further demonstrate that all known OPN isoforms (OPNa, b, c, 4 and 5) were frequently co-overexpressed in primary EACs. Distinct pro-invasion and dissemination phenotypes of isoform-specific OPNb and OPNc stable transfectants were observed. Expression of OPNb significantly enhanced cell migration and adhesion to laminin. In contrast, OPNc cells showed significantly decreased cell migration yet increased cell detachment. Enhanced invasion, both in vitro and in vivo, was observed for OPNb- but not OPNc-expressing cells. Inhibition of RGD integrins, one family of OPN receptors, attenuated OPNb cell migration, abrogated OPNb cell adhesion and significantly reduced OPNb cell clonogenic survival but did not affect OPNc phenotypes, indicating that OPNb but not OPNc acts through integrin-dependent signaling. Differential expression of vimentin, E-cadherin and β-catenin in OPN stable cells may account for the variation in cell adhesion and detachment between these isoforms. We conclude that while all OPN isoforms are frequently co-overexpressed in primary EACs, isoforms OPNb and OPNc enhance invasion and dissemination through collective yet distinct mechanisms.
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jules
authors.initials: J
authors.lastname: Lin
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Myers
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Zhuwen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Nancarrow
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Daysha
authors.initials: D
authors.lastname: Ferrer-Torres
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Handlogten
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kimmy
authors.initials: K
authors.lastname: Leverenz
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wang
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Orringer
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Rishindra M
authors.initials: RM
authors.lastname: Reddy
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chang
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.affiliation: Section of Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015994:Incidence; D009361:Neoplasm Invasiveness; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D015820:Cadherins; D020033:Protein Isoforms; C506895:SPP1 protein, human; D014746:Vimentin; D053495:Osteopontin
keywords: OPN/SPP1 isoforms; co-overexpression; collective function; esophageal adenocarcinoma