EMT and inflammation: inseparable actors of cancer progression

Abstract

Tumors can be depicted as wounds that never heal, and are infiltrated by a large array of inflammatory and immune cells. Tumor-associated chronic inflammation is a hallmark of cancer that fosters progression to a metastatic stage, as has been extensively reviewed lately. Indeed, inflammatory cells persisting in the tumor establish a cross-talk with tumor cells that may result in a phenotype switch into tumor-supporting cells. This has been particularly well described for macrophages and is referred to as tumor-associated 'M2' polarization. Epithelial-to-mesenchymal transition (EMT), the embryonic program that loosens cell-cell adherence complexes and endows cells with enhanced migratory and invasive properties, can be co-opted by cancer cells during metastatic progression. Cancer cells that have undergone EMT are more aggressive, displaying increased invasiveness, stem-like features, and resistance to apoptosis. EMT programs can also stimulate the production of proinflammatory factors by cancer cells. Conversely, inflammation is a potent inducer of EMT in tumors. Therefore, the two phenomena may sustain each other, in an alliance for metastasis. This is the focus of this review, where the interconnections between EMT programs and cellular and molecular actors of inflammation are described. We also recapitulate data linking the EMT/inflammation axis to metastasis.

Keywords: cancer; chemokines; cytokines; epithelial-to-mesenchymal transition; inflammation; metastasis.

Figure 1

Schematic representation of the soluble factor‐mediated interactions between cancer cells undergoing EMT‐like changes and innate immune cells. RTK, receptor tyrosine kinase; GPCR, G‐protein‐coupled receptor; TAM, tumor‐associated macrophages; MDSCs, myeloid‐derived suppressor cells; Th1/Tc, T helper one cell/cytotoxic T cell. The pink Pacman‐shaped symbol represents some metalloproteinase degrading the extracellular matrix.

Figure 2

Overview of major signaling cascades leading to EMT program activation and inflammatory target gene activation in cancer cells.