G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models

Abstract

Recent studies suggest that tumor-associated CD11b + Gr1 + myeloid cells contribute to refractoriness to antiangiogenic therapy with an anti-VEGF-A antibody. However, the mechanisms of peripheral mobilization and tumor-homing of CD11b + Gr1 + cells are unclear. Here, we show that, compared with other cytokines [granulocyte-macrophage colony stimulating factor (GM-CSF), stromal derived factor 1α, and placenta growth factor], G-CSF and the G-CSF-induced Bv8 protein have preferential expression in refractory tumors. Treatment of refractory tumors with the combination of anti-VEGF and anti-G-CSF (or anti-Bv8) reduced tumor growth compared with anti-VEGF-A monotherapy. Anti-G-CSF treatment dramatically suppressed circulating or tumor-associated CD11b + Gr1 + cells, reduced Bv8 levels, and affected the tumor vasculature. Conversely, G-CSF delivery to animals bearing anti-VEGF sensitive tumors resulted in reduced responsiveness to anti-VEGF-A treatment through induction of Bv8-dependent angiogenesis. We conclude that, at least in the models examined, G-CSF expression by tumor or stromal cells is a determinant of refractoriness to anti-VEGF-A treatment.

Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response

“…16 While this finding may be specific to the respective tumor entity, 27 it might also relate to the lower frequency of TEMs (as compared to intermediate monocytes) and hence detection limit in circulation. Since it was previously demonstrated in mouse models that pro-angiogenic, myeloid cell populations could confer resistance to anti-VEGF cancer therapy by providing substitute growth factors, 28,29 it was feasible to hypothesize that bevacizumab treatment might alter TEM frequency to compensate for the loss in VEGF activity. However, TEM (as well as intermediate monocyte) frequency remained unchanged in mCRC patients upon the addition of anti-VEGF treatment to chemotherapy.…”

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

“…However, their number is increased in the peripheral blood, possibly by the action of G-CSF produced from primary tumors. 34 These cells are shown to make direct contact with CD8 1 T cells and render them unresponsive to antigen stimulation by abolishing CD8 and TCR through the production of NO and ROS. 35 IFN-c and LPS were shown to sustain Gr-1 1 CD11b 1 -cell expansion.…”

A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells

“…Previous studies have identified two cytokines, granulocyte and macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) as important contributors in the expansion of MDSCs [18,28,29]. To determine the functional relationship of CCL5 with these myeloid colony-stimulating factors, we compared the colony-forming activity of WT and KO bone marrow Figure 6A, treatment with GM-CSF elicited a higher number of colonies from KO bone marrow cells than from WT bone marrow cells, particularly at lower concentrations.…”