Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow

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.

Implications: The tumor microenvironment interaction between ANXA2-CXCL12 is critical for metastatic phenotypes and may impact chemotherapeutic potential.