Promotion of Tumor Invasion by Tumor-Associated Macrophages: The Role of CSF-1-Activated Phosphatidylinositol 3 Kinase and Src Family Kinase Motility Signaling

Abstract

Macrophages interact with cells in every organ to facilitate tissue development, function and repair. However, the close interaction between macrophages and parenchymal cells can be subverted in disease, particularly cancer. Motility is an essential capacity for macrophages to be able to carry out their various roles. In cancers, the macrophage's interstitial migratory ability is frequently co-opted by tumor cells to enable escape from the primary tumor and metastatic spread. Macrophage accumulation within and movement through a tumor is often stimulated by tumor cell production of the mononuclear phagocytic growth factor, colony-stimulating factor-1 (CSF-1). CSF-1 also regulates macrophage survival, proliferation and differentiation, and its many effects are transduced by its receptor, the CSF-1R, via phosphotyrosine motif-activated signals. Mutational analysis of CSF-1R signaling indicates that the major mediators of CSF-1-induced motility are phosphatidyl-inositol-3 kinase (PI3K) and one or more Src family kinase (SFK), which activate signals to adhesion, actin polymerization, polarization and, ultimately, migration and invasion in macrophages. The macrophage transcriptome, including that of the motility machinery, is very complex and highly responsive to the environment, with selective expression of proteins and splice variants rarely found in other cell types. Thus, their unique motility machinery can be specifically targeted to block macrophage migration, and thereby, inhibit tumor invasion and metastasis.

Keywords: Src family kinases; colony-stimulating factor-1; macrophage motility; paracrine interaction; phosphatidyl-inositol-3-kinase.

Figure 1

Colony-stimulating factor-1 (CSF-1) induces macrophage precursors to mature into adherent, motile baseline macrophages (M0). M0 macrophages are then activated into pro-inflammatory macrophages by IFNγ and LPS or anti-inflammatory, pro-tumoral macrophages by IL-4 or IL-13. Definitions: LPS, lipopolysaccharide; IFNγ, interferon-γ; IL, interleukin.

Figure 2

Contribution by tumor-associated macrophages (TAM) to tumor progression with an emphasis on tumor invasion and metastasis. TAMs secrete epidermal growth factor (EGF) and tumour cells secrete CSF-1 to induce a paracrine loop-driven co-migration and invasion of both cell types towards blood vessels.

Figure 3

Schematic of the colony-stimulating factor-1 receptor (CSF-1R) and downstream motility signaling. Upon binding of CSF-1, the CSF-1R homo-dimerizes and autophosphorylates up to eight tyrosine residues. Both the pY721 and pY974 motifs have been shown to be important for motility signaling. pY721 directly stimulates macrophage motility through activation of PI3K p110δ, leading to activation of downstream signalling involving the Rho GTPases (Rac, Rho and Cdc42), Akt and PDK1. pY974, which has been demonstrated to bind the E3 ubiquitin ligase, c-Cbl, also indirectly affects motility signalling through regulation of expression of Src family kinases (SFK). Hck, and possibly other SFKs, directly regulate CSF-1-induced motility, likely through integrin-mediated activation of adhesion and actin polymerization.