ALCAM/CD166 Is a TGF-β―Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-03, Vol.74 (5), p.1404-1415
• Main Authors: HANSEN, Amanda G, ARNOLD, Shanna A, HAYWARD, Simon W, STERLING, Julie A, ZIJLSTRA, Andries, MING JIANG, PALMER, Trenis D, KETOVA, Tatiana, MERKEL, Alyssa, PICKUP, Michael, SAMARAS, Susan, SHYR, Yu, MOSES, Harold L
• Format: Article
• Language: English
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAM17 Protein; Antigens, CD - genetics; Antigens, CD - metabolism; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Bone and Bones - pathology; Caspase 3 - genetics; Caspase 3 - metabolism; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Cell Survival - genetics; Cellular Microenvironment - genetics; Disease Progression; Fetal Proteins - genetics; Fetal Proteins - metabolism; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-1296

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.