Antitumor activity of targeting SRC kinases in endothelial and myeloid cell compartments of the tumor microenvironment.
OBJECTIVE
Several Src family kinase (SFK) inhibitors have entered clinical trials based on their direct effects against tumor cells. Here, we characterize the effects of targeting Src kinases on the tumor microenvironment and how these effects influence tumor growth.


METHODS
Human cancer cells grown in cell culture or in mice were treated with dasatinib, a small-molecule inhibitor of SFKs. Tumor cell, endothelial cell, and myeloid cell compartments within the tumor microenvironment were analyzed. Primary human endothelial cells and freshly isolated CD11b+/CD11c- myeloid cells from mice were treated with dasatinib in cell culture. Cellular functions and signaling pathways affected by dasatinib were evaluated.


RESULTS
Dasatinib was not cytotoxic in cell culture against the human cancer cell lines investigated here. However, dasatinib administration in human tumor-bearing mice suppressed tumor growth associated with increased tumor cell apoptosis, decreased microvessel density, and reduced intratumoral CD11b+ myeloid cells. Dasatinib directly inhibited motility and other functions of endothelial and myeloid cells, accompanied by the inhibition of phosphorylation of SFKs and downstream signaling. Tumor-infiltrating myeloid cells were identified as the major source of matrix metalloproteinase (MMP)-9 in the tumor microenvironment. Dasatinib treatment reduced MMP-9 levels in the tumor microenvironment through the simultaneous inhibition of recruitment of MMP9+ myeloid cells and MMP-9 gene expression in tumor-infiltrating myeloid cells.


CONCLUSIONS
These findings suggest that Src kinase inhibitors such as dasatinib possess a previously unrecognized anticancer mechanism of action by targeting both host-derived endothelial and myeloid cell compartments within the tumor microenvironment.
Liang
Wei
W
City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Kujawski
Maciej
M
Wu
Jun
J
Lu
Jianming
J
Herrmann
Andreas
A
Loera
Sofia
S
Yen
Yun
Y
Lee
Frank
F
Yu
Hua
H
Wen
Wei
W
Jove
Richard
R
D000818:Animals; D000069439:Dasatinib; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019061:src-Family Kinases; D000069439:Dasatinib