Dynamic In Vivo Imaging Reveals That Leukemia-Induced Changes in the Bone Marrow Microenvironment Alter Mechanisms of Metastasis.

Tissue microenvironments have been shown to critically regulate cancer cell survival and proliferation. Conversely, while tumor growth can induce neovascularization, the impact of other tumor-induced changes in the microenvironment are less well understood. Here we utilize a xenograft model of Nalm-6 pre-B acute lymphoblastic leukemia (ALL) in SCID mice to examine how tumor growth alters the bone marrow (BM) microenvironment. Using dynamic confocal and multiphoton in vivo imaging, we find that tumor growth dramatically down-regulates expression of the chemokine SDF-1 in the BM microvasculature in areas of leukemic proliferation. SDF-1 has been shown to play a key role in cancer cell metastasis for numerous cell types including Nalm-6, and directs initial Nalm-6 homing to specific SDF-1-positive vascular beds. In contrast, we found that Nalm-6 introduced in mice previously engrafted with leukemia home to SDF-1-negative vasculature, predominantly at the advancing tumor margin. Furthermore, inhibition of chemokine signaling by pertussis toxin pre-treatment of Nalm-6 cells demonstrates that Nalm-6 homing in engrafted mice is chemokine-independent. In summary, these findings suggest that leukemic growth profoundly alters the mechanisms underlying the metastatic process by inducing changes in the host vascular microenvironment. These changes may increase the efficiency of the metastatic process and/or the advancement of the tumor margin. Therapies directed at blocking tumor metastases, therefore, may need to be tailored according to tumor stage.