Inflammation and EMT: an alliance towards organ fibrosis and cancer progression

Abstract

Recent advances in our understanding of the molecular pathways that govern the association of inflammation with organ fibrosis and cancer point to the epithelial to mesenchymal transition (EMT) as the common link in the progression of these devastating diseases. The EMT is a crucial process in the development of different tissues in the embryo and its reactivation in the adult may be regarded as a physiological attempt to control inflammatory responses and to 'heal' damaged tissue. However, in pathological contexts such as in tumours or during the development of organ fibrosis, this healing response adopts a sinister nature, steering these diseases towards metastasis and organ failure. Importantly, the chronic inflammatory microenvironment common to fibrotic and cancer cells emerges as a decisive factor in the induction of the pathological EMT.

Figure 1. The history of EMT in cancer

1. Betty Hay coined the term ‘epithelial to mesenchymal transformation’ (Hay, 1968) and described the transient nature of this process, as well as the reversion to the epithelial character (MET, Hay, 1991). Modified from Acloque et al (2008).

2. More than 100 years ago Santiago Ramón y Cajal drew and described the morphological appearance of breast carcinoma so accurately that we can find what we believe to be the first description of EMT (see text). Drawings are adapted from figs. 53 and 48 in Ramon y Cajal (1890). Note the morphology of the cell highlighted as ‘b’.

3. At the turn of the 20th century, Hugo Apolant also clearly represented the morphology of EMT-type mouse mammary tumours (Apolant, 1906). The micrograph shows the distribution of cytokeratin 8/18 in both the epithelial and spindle cell populations in a mouse mammary tumour diagnosed as EMT-type. This picture is courtesy of Dr P. Damonte and Dr R. Cardiff, Univ. California at Davis.

Figure 2. Histological features of EMT in cancer and fibrosis

1. Immunohistochemical staining of a colorectal carcinoma for β-catenin in red and nuclear counterstaining in blue. The central area of the tumour exhibits polarized epithelial tumour cells lacking nuclear β-catenin, while cells at the invasive front undergo EMT and show nuclear β-catenin (Brabletz et al, 2001). Picture from Dr Thomas Brabletz, Univ. Freiburg (Germany).

2. Histological sections showing the halmarks of EMT in the medulla of fibrotic kidney from patients subjected to nephrectomy. Sections are stained with haematoxylin–eosin (H/E) to better appreciate cell morphology and the disappearance of the tubular structures in fibrosis, vimentin expression showing mesenchymal cells (brown, Vim) and fibrotic deposits revealed by the blue Masson–Trichome staining (M/T) (Boutet et al, 2006).

Figure 3. Inflammation, oxidative stress and hypoxia cooperate in the induction of EMT for the progression of organ fibrosis and cancer metastasis

In the fibrotic kidney or in the tumour inflammatory microenvironment TNF-α, Ang II, reactive oxygen species (ROS) and hypoxia converge in the induction of NF-κB, the main inflammatory response pathway. TGF-β is first secreted to control the inflammatory response (dotted red line) but in a chronic inflammatory environment it behaves as a fibrogenic agent and as an inducer of invasiveness. Indeed, the signals released in response to inflammation, oxidative stress ad hypoxia in the stromal or interstitial cells (TAMs, CAFs, leukocytes and myofibroblasts) induce the EMT process in renal and carcinoma cells. TGF-β, NF-κB and hypoxia play a crucial role in the activation of EMT inducers in renal or carcinoma cells. NF-κB and hypoxia also contribute to the EMT process increasing the stability of the inducers. CAFs, cancer associated fibroblasts; CNS2, component of the signalosome; HIF1-α, hypoxia factor 1α; LOX, lysyl-oxidase; TAMs, tumour-associated macrophages.