anoikis

Anoikis is a form of programmed cell death (apoptosis) that is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix (ECM).

Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival.

When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.

Anoikis in metastasis

The mechanism by which invading tumor cells survive the anoikis process remains largely unknown. Recent findings suggest that the protein TrkB, best known for its role in the nervous system, might be involved together with its ligand, brain-derived neurotrophic factor (BDNF). It seems that TrkB could make tumor cells resistant to anoikis by activating phosphatidylinositol 3-kinase (PI3K) signaling cascade.

In squamous cell carcinoma, researchers have found that anoikis resistance can be induced through hepatocyte growth factor (HGF) activating BOTH extracellular signalling-receptor kinase (ERK) and PI3K.

Using a novel high-throughput screening assay, Mawji et al. showed that anisomycin can sensitize metastatic epithelial cells to anoikis and reduce circulating tumor cell implantation in vivo.

Anisomycin achieved this anti-metastatic activity in part by decreasing the abundance of the death receptor inhibiting protein FLIP. In related work, Schimmer’s team showed that FLIP levels are higher in metastatic cells than non-metastatic cells, and that reducing FLIP levels using RNAi (RNA Interference) or other small molecule inhibitors of FLIP can sensitize metastatic cells to anoikis.

Given that FLIP is an inhibitor of anoikis, and that reducing FLIP can sensitize metastatic cells to anoikis, Mawji et al. hypothesize that FLIP reduction may be a viable therapeutic strategy against cancer metastasis.