title: ALCAM/CD166 is a TGF-β-responsive marker and functional regulator of prostate cancer metastasis to bone.
abstract: The dissemination of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer requires improved molecular understanding of the process as well as markers indicative of molecular progression. Through biochemical analyses and loss-of-function in vivo studies, we demonstrate that the cell adhesion molecule, activated leukocyte cell adhesion molecule (ALCAM), is actively shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGF-β. Not only is this posttranslational modification of ALCAM a marker of prostate cancer progression, the molecule is also required for effective metastasis to bone. Biochemical analysis of prostate cancer cell lines reveals that ALCAM expression and shedding is elevated in response to TGF-β signaling. Both in vitro and in vivo shedding is mediated by ADAM17. Longitudinal analysis of circulating ALCAM in tumor-bearing mice revealed that shedding of tumor, but not host-derived ALCAM is elevated during growth of the cancer. Gene-specific knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished both skeletal dissemination and tumor growth in bone. The reduced growth of ALCAM knockdown cells corresponded to an increase in apoptosis (caspase-3) and decreased proliferation (Ki67). Together, these data demonstrate that the ALCAM is both a functional regulator as well as marker of prostate cancer progression.
authors.affiliation: Authors' Affiliations: Departments of Pathology, Microbiology and Immunology, Cancer Biology, and Urologic Surgery, Division of Cancer Biostatistics, Vanderbilt University; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt Center for Bone Biology; and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Hansen
authors.forename: Shanna A
authors.initials: SA
authors.lastname: Arnold
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Trenis D
authors.initials: TD
authors.lastname: Palmer
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ketova
authors.forename: Alyssa
authors.initials: A
authors.lastname: Merkel
authors.forename: Michael
authors.initials: M
authors.lastname: Pickup
authors.forename: Susan
authors.initials: S
authors.lastname: Samaras
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.forename: Julie A
authors.initials: JA
authors.lastname: Sterling
authors.forename: Andries
authors.initials: A
authors.lastname: Zijlstra
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001842:Bone and Bones / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D060833:Cellular Microenvironment / Q000235:genetics; D018450:Disease Progression; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D053148:Caspase 3; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D016212:Transforming Growth Factor beta; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse