The diverse roles of the TNF axis in cancer progression and metastasis

Abstract

Metastasis is a multi-step process that ultimately depends on the ability of disseminating cancer cells to establish favorable communications with their microenvironment. The tumor microenvironment consists of multiple and continuously changing cellular and molecular components. One of the factors regulating the tumor microenvironment is TNF-α, a pleiotropic cytokine that plays key roles in apoptosis, angiogenesis, inflammation and immunity. TNF-α can have both pro- and anti-tumoral effects and these are transmitted via two major receptors, the 55 kDa TNFR1 and the 75 kDa TNFR2 that have distinct, as well as overlapping functions. TNFR1 is ubiquitously expressed while the expression of TNFR2 is more restricted, mainly to immune cells. While TNFR1 can transmit pro-apoptotic or pro-survival signals through a complex network of downstream mediators, the role of TNFR2 is less well understood. One of its main functions is to act as a survival factor and moderate the pro-apoptotic effects of TNFR1, particularly in immune cells. In this review, we summarize the evidence for the involvement of the TNF system in the progression of the metastatic process from its contribution to the early steps of tumor cell invasion to its role in the colonization of distant sites, particularly the liver. We show how the TNF receptors each contribute to these processes by regulating and shaping the tumor microenvironment. Current evidence and concepts on the potential use of TNF targeting agents for cancer prevention and therapy are discussed.

Keywords: TNF-α; TNFR; immune cells; liver; metastasis.

Figure 1. TNFR signaling pathways

Following TNF stimulation, TNFR1 sequentially recruits TNFR-associated death domain (TRADD), FAS-associated death domain (FADD) and caspase-8 leading to Caspase-3 activation and apoptosis. Both receptors can also recruit TNFR-associated factor 2 (TRAF2), MAP/ERK kinase kinase 1 (MEKK1) and MAPK kinase 7 (MKK7) leading to activation of the JNK pathway and the transcription factor AP-1. Recruitment of receptor-interacting protein (RIP) via TRAF2 leads to activation of p38 MAPK via MKK3. RIP recruitment can also lead to NF-κB activation via the inhibitor of NF-κB kinase (IKK) complex. These three pathways ultimately lead to inflammation and survival. (Adapted from Aggarwal, B. B. 2003, Nat. Rev. Immunol., 3, 745–756, with permission from Macmillan Publishers Ltd.).

Figure 2. The immune microenvironment of metastases

Shown is a schematic representation of the complex immune microenvironment of metastatic tumor cells in secondary sites such as the liver. The type of immune cells recruited and the cytokines produced determine tumor cell fate. The tumor cells must successfully extravasate from the blood vessels into the liver/secondary organ via interaction with vascular cell adhesion molecules or via interaction with neutrophils. At this stage tumor cells can be subject to direct cytotoxic effects mediated by cytokines such as IFN-γ, TNF-α, and perforin. Regulatory cells such as Tregs and MDSCs can block T cell-mediated cytotoxicity, allowing tumor cell growth. Growth factors such as IGF-I, PDGF and EGF and cytokines such as IL-6 within the liver microenvironment can increase tumor invasiveness and proliferation and promote tumor expansion.