Bone marrow suppression by c-kit blockade enhances tumor growth of colorectal metastases through the action of stromal cell-derived factor-1

Background. mobilization of c-kit + hematopoietic cells (hcs) contributes to tumor vascularization. whereas survival and proliferation of hcs are regulated by binding of the stem cell factor to its receptor c-kit,migration of hcs is directed by stromal cell-derived factor (sdf)-1. therefore,targeting migration of hcs provides a promising new strategy of anti-tumor therapy. methods. balb/c mice (n = 16) were pretreated with an anti-c-kit antibody followed by implantation of ct26.wt-gfp colorectal cancer cells into dorsal skinfold chambers. animals (n = 8) additionally received a neutralizing anti-sdf-1 antibody. animals (n = 8) treated with a control antibody served as controls. investigations were performed using intravital fluorescence microscopy,immunohistochemistry,flow cytometry and western blot analysis. results. blockade of c-kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. c-kit blockade significantly increased vegf and cxcr4 expression within the growing tumors. neutralization of sdf-1 completely antagonized this anti-c-kit-associated tumor growth by suppression of tumor neovascularization,inhibition of tumor cell proliferation and reduction of muscular infiltration. conclusion. our study indicates that bone marrow suppression via anti-c-kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the sdf-1/cxcr4 pathway which is involved in hc-mediated tumor angiogenesis. copyright © 2012 kathrin rupertus et al.