Annexin 2-CXCL12 Interactions Regulate Metastatic Cell Targeting and Growth in the Bone Marrow

作者：Jung Younghun; Wang Jingcheng; Lee Eunsohl; Mcgee Samantha; Berry Janice E; Yumoto Kenji; Dai Jinlu; Keller Evan T; Shiozawa Yusuke; Taichman Russell S^*

来源：Molecular Cancer Research, 2015, 13(1): 197-207.

DOI：10.1158/1541-7786.MCR-14-0118

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 BMSCAnxa2-/- than by BMSCAnxa2-/- resulting in more prostate cancer cells migrating and binding to BMSCAnxa2-/- than BMSCAnxa2-/-, 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 BMSCAnxa2-/- or BMSCAnxa2-/-. Significantly larger tumors grew in the mice when the tumors were established with BMSCAnxa2-/- compared with the tumors established with BMSCAnxa2-/-. In addition, fewer prostate cancer cells underwent apoptosis when cocultured with BMSCAnxa2-/- compared with BMSCAnxa2-/-, and similar results were obtained in tumors grown in vivo. Finally, significantly more vascular structures were observed in the tumors established with the BMSCAnxa2-/- compared with the tumors established with BMSCAnxa2-/-. Thus, ANXA2-CXCL12 interactions play a crucial role in the recruitment, growth, and survival of prostate cancer cells in the marrow.

• 出版日期2015-1