Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

الملخص EN

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.