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.

The Role of the Extracellular Matrix and Its Molecular and Cellular Regulators in Cancer Cell Plasticity

“…Monocytes are recruited to the invasive front and differentiate into macrophages in response to signals from tumor and stromal cells. An array of cytokines (IL-4, IL-10, IL-13), chemokines (CCL2, CXCL12), and growth factors (CSF-1, TGF-β, VEFG-A, PDGF, angiopoietin-2) produced at the invasive margin stimulate monocyte recruitment, differentiation and survival ( 51 – 54 ). We have previously demonstrated that the chemokine receptor CCR6 is expressed on TAMs and facilitates their migration to the cancer site in a mouse model of mammary cancer.…”

Tumor-Cell–Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

“…In brief, macrophages secrete epidermal growth factor (EGF), which interacts with its target receptor (EGFR) on the surfaces of tumor cells [123]. This binding event activates EGFR signaling, thus, leading to the secretion of colony stimulating factor 1 (CSF-1), which in turn attracts macrophages via CSF-1 receptor (CSF-1R) [123,124]. This paracrine interaction between CSF-1-secreting tumor cells and EGF-secreting macrophages drives the migration of tumor cells and the macrophages toward blood vessels.…”

Tumor‐associated macrophages (TAMs) as biomarkers for gastric cancer: A review

“…They may have an effect on the inactivation of T-cells, which crucially decreases the body's ability to resist cancer development and progression. 16 It has been shown that the patients with a large number of TAMs in cancer tissue have worse surgical outcome compared to the patients with a lower number of TAMs. TAMs also promote tumor angiogenesis, enhance metastatic spreading and contribute to invasion by producing cytokines such as IL-6, IL-17, IL-23 and inhibiting cytotoxic T lymphocyte responses.…”