Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer

Abstract

Experimental and epidemiological studies indicate a strong link between chronic inflammation and tumor progression. Human colorectal cancer (CRC), a major cause of cancer-related death in Western countries, represents a paradigm for this link. Key features of cancer-related inflammation in CRC are the activation of transcription factors (e.g. NF-κB, STAT3), the expression of inflammatory cytokines and chemokines (e.g. TNFα, IL-6, CCL2, CXCL8) as well as a prominent leukocyte infiltrate. While considerable evidence indicates that the presence of lymphocytes of adaptive immunity may positively influence patient survival and clinical outcome in CRC, the role of tumor-associated macrophages (TAM) and of other lymphoid populations (e.g. Th17, Treg) is still unclear. In this review we will summarize the different and controversial effects that TAM play in CRC-related inflammation and progression of disease. The characterization of the most relevant inflammatory pathways in CRC is instrumental for the identification of new target molecules that could lead to improved diagnosis and treatment.

Fig. 1

TAM-derived IL-6 promotes tumor cell survival and proliferation. IL-6 binds both its membrane-bound and soluble-form receptor, leading to the dimerization of gp130 expressed by tumor cells and the activation of the JAK tyrosine kinase, which phosphorylates STAT3. Translocation of STAT3 into the nucleus induces gene transcription. In colorectal cancer, STAT3 induces the expression of genes important for the proliferation (cyclin D and PCNA) and the suppression of apoptosis (Bcl-X_L, Bcl-2 and Mcl-1) strongly promoting neoplastic cell cycle-progression

Fig. 2

M2-macrophage polarization in the tumor microenvironment. Blood monocytes recruited by chemoattractants secreted by tumor cells (CCL2, CCL5, VEGF, M-CSF) differentiate in the tumor microenvironment. Tumor-derived IL-6, IL-10, TGF-β and PGE₂ promote the polarization into M2-like macrophages with pro-tumor functions. By producing growth factors (e.g. EGF, FGF, VEGF, IL-6) and matrix-degrading enzymes (MMPs), TAM favour the neo-angiogenesis switch, tumor cell proliferation and invasion of surrounding tissues. By secreting chemokines (e.g CCL17, CCL18 and CCL22) TAM recruit naïve and Th2 lymphocytes, ineffective in mounting a protective anti-tumor immune response

Fig. 3

TAM-regulate immune network in colorectal cancer. The role of TAM in colorectal cancer is controversial as both anti-tumor and pro-tumor effects have been reported. TAM accumulation at the tumor margin has been most frequently associated with longer patient survival. Although not formally demonstrated, TAM at invasive margin are likely to be less susceptible to the suppressive tumor microenvironment and may produce cytotoxic molecules (ROS, NO and TNF-α). TAM secrete key factors that affect lymphocyte differentiation into Th17 cells (IL-23, IL-6, IL-1β, TGF-β) or Treg (TGF-β, IL-10). While Treg inhibit anti-tumor adaptive immune responses, they may also have beneficial effects by decreasing the production of inflammatory cytokines. The role of Th17 cells in CRC and more in general in human tumors is still an open issue