title: Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow.
abstract: Annexin 2 (ANXA2) plays a critical role in hematopoietic stem cell (HSC) localization to the marrow niche. In part, ANXA2 supports HSCs by serving as an anchor for stromal-derived factor-1 (CXCL12/SDF-1). Recently, it was demonstrated that prostate cancer cells, like HSCs, use ANXA2 to establish metastases in marrow. The present study determined the capacity of ANXA2 expression by bone marrow stromal cells (BMSC) to facilitate tumor recruitment and growth through ANXA2-CXCL12 interactions. Significantly more CXCL12 was expressed by BMSC(Anxa2) (+/+) than by BMSC(Anxa2) (-/-) resulting in more prostate cancer cells migrating and binding to BMSC(Anxa2) (+/+) than BMSC(Anxa2) (-/-), and these activities were reduced when CXCL12 interactions were blocked. To further confirm that BMSC signaling through ANXA2-CXCL12 plays a critical role in tumor growth, immunocompromised SCID mice were subcutaneously implanted with human prostate cancer cells mixed with BMSC(Anxa2) (+/+) or BMSC(Anxa2) (-/-). Significantly larger tumors grew in the mice when the tumors were established with BMSC(Anxa2) (+/+) compared with the tumors established with BMSC(Anxa2) (-/-). In addition, fewer prostate cancer cells underwent apoptosis when cocultured with BMSC(Anxa2) (+/+) compared with BMSC(Anxa2) (-/-), and similar results were obtained in tumors grown in vivo. Finally, significantly more vascular structures were observed in the tumors established with the BMSC(Anxa2) (+/+) compared with the tumors established with BMSC(Anxa2) (-/-). Thus, ANXA2-CXCL12 interactions play a crucial role in the recruitment, growth, and survival of prostate cancer cells in the marrow.
  
  
  CONCLUSIONS
  The tumor microenvironment interaction between ANXA2-CXCL12 is critical for metastatic phenotypes and may impact chemotherapeutic potential.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Eunsohl
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Samantha
authors.initials: S
authors.lastname: McGee
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Berry
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yumoto
authors.affiliation: Department of Urology and Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Urology and Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan. rtaich@umich.edu.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000096:biosynthesis / Q000235:genetics*; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D017306:Annexin A2; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse