TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion

Abstract

Tumour necrosis factor-alpha (TNF-alpha) is an important inflammatory factor that acts as a master switch in establishing an intricate link between inflammation and cancer. A wide variety of evidence has pointed to a critical role of TNF-alpha in tumour proliferation, migration, invasion and angiogenesis. The function of TNF-alpha as a key regulator of the tumour microenvironment is well recognised. We will emphasise the contribution of TNF-alpha and the nuclear factor-kappaB pathway on tumour cell invasion and metastasis. Understanding the mechanisms underlying inflammation-mediated metastasis will reveal new therapeutic targets for cancer prevention and treatment.

Figure 1

The downstream signalling pathways of TNF-α. The TNF-α can activate different pathways to induce apoptosis, cell survival or inflammation. Tumour necrosis factor induces the apoptosis by binding caspase-8 to FADD and promotes inflammation and survival, which is mediated through TRAF2 via JNK-dependent kinase cascade, MEKK kinase cascade and NF-κB activation by RIP.

Figure 2

An overview of the signalling pathways mediated by TNF-α in metastasis. The TNF-α induces protein stabilisation of Snail and β-catenin by inhibiting GSK-3β-mediated phosphorylation through NF-κB and Akt signalling pathways. It also induces CSN2 expression through a NF-κB-dependent pathway. Together, these signalling events contribute to EMT induction and invasion in tumour cells.