Abstract
Although Vascular Endothelial Growth Factor (VEGF)-targeted therapies have shown efficacy in the treatment of certain advanced cancers, benefits to patients have been modest, which is attributed to tumor resistance to VEGF neutralization. Recent efforts to identify new targets to inhibit tumor angiogenesis have identified Bv8 (prokineticin 2), a myeloid cell-derived protein that promotes endothelial cell growth and tumor angiogenesis, but many mechanistic aspects of the pro-tumorigenic function of Bv8 are unclear. Here we demonstrate that CD11b+, Ly6C+, Ly6G+ granulocytes are the predominant cell source of Bv8 expression in bone marrow, spleen and in tumor tissues. Using granulocyte-deficient Growth factor independence-1 (Gfi1)-null mutant mice and normal littermates, we found that EL4 lymphoma tumors grow significantly larger in the granulocyte and Bv8-deficient mutant mice in comparison to the normal mice that display abundant tumor-associated granulocytes and Bv8 expression. Conversely, Lewis lung carcinoma (LLC-1) tumors grew to a significantly greater size in the normal mice in comparison to the Gfi1-null mice, but normal granulocyte tumor infiltration was modest. Quantitative analysis of tissue vascularization showed that EL4 and LLC-1 tumors from normal and Gfi1-mutant mice are similarly vascularized. These results confirm the critical contribution of the tumor microenvironment in determining the rate of tumor progression independently of tumor angiogenesis, and reveal some of the complexities of granulocyte and Bv8 functions in modulating tumor growth.
Highlights
Angiogenesis, the process by which new vessels are formed through the sprouting of endothelial cells, is critical during development as it provides a means for supplying oxygen and nutrients to tissues with increased need [1]
The bone marrow (Figures 1A, 1B) and spleen (Figures 1C, 1D) of growth factor independence-1 (Gfi1)-null knock out mice (KO) clearly lack of CD11b+, Ly6C+, Ly6G+ granulocytes, whereas this population is normally represented in the wild-type (WT; Gfi1+/+) littermates
Consistent with the results in vitro, we found that granulocyte colony stimulatory factor (G-CSF) promotes Bv8 expression in WT bone marrow cells, whereas levels of Bv8 remained low in Gfi1-null bone marrows in spite of G-CSF administration (Figure 3B)
Summary
Angiogenesis, the process by which new vessels are formed through the sprouting of endothelial cells, is critical during development as it provides a means for supplying oxygen and nutrients to tissues with increased need [1]. The therapeutic benefits have been modest as tumors either are resistant or rapidly develop resistance to anti-VEGF treatment. To clarify the underlying reasons and improve anti-angiogenic treatment of cancer, recent efforts have focused on a more fundamental understanding of the angiogenic process in physiology and disease [3,4,5], and the discovery of biochemical signals and pathways other than those directly dependent on VEGF [1]
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