Chronic inflammation and cancer: emerging roles of triggering receptors expressed on myeloid cells

Abstract

Inflammation is tightly regulated by a vast system that is intricately interconnected with innate immunity. Aberrations in expression or signaling, such as in innate immune receptors, can create excessive inflammation and, when chronic, often promote oncogenesis. The triggering receptor expressed on myeloid cells receptor family has been characterized as a major player in the amplification and signaling of the inflammatory response. In a number of chronic inflammatory conditions and malignancies, the triggering receptor expressed on myeloid cells has been implicated in disease severity and progression. In this article, the current understanding of triggering receptor expressed on myeloid cells function in pre-malignant, malignant and chronic inflammatory conditions is critically reviewed. The potential for therapeutic application is also discussed.

Keywords: TREM-1; TREM-2; chronic inflammation; colorectal cancer; hepatocellular carcinoma; inflammatory bowel disease; leukemia; neoplastic disease; non small cell lung cancer; triggering receptor expressed on myeloid cells.

Figure 1. TREM expression in various tissue types

TREM-1 is generally expressed in some monocyte/macrophage subtypes as well as neutrophils. In particular, alveolar macrophages have highly specific TREM-1 expression. TREM-2 regulates the development and function of dendritic cells (DCs), microglia and osteoclasts. Only a small fraction of the resident mucosal myelocyte population in the gut expresses TREM-1.

Figure 2. A generalized model of the possible roles of TREM in tumorigenesis

Upregulation of TREM on local myelocytes as well as recruitment of TREM-expressing myelocytes will amplify the ongoing chronic inflammatory state, promoting metaplasia and oncogenesis. The tumor microenvironment could cause further upregulation of TREM in local myelocytes as well as additional recruitment of TREM-expressing macrophages, increasing the tumor-associated macrophage (TAM) population. TREM-1 is thought to be associated with metastatic ability. TAMs have been associated with pro-tumor effects including promotion of angiogenesis, matrix remodeling, immunosuppression, and tumor cell proliferation.