Review
Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis

https://doi.org/10.1016/S1383-5742(03)00033-4Get rights and content

Abstract

Carcinomas arising from epithelial cells represent the most prevalent malignancies in humans, and metastasis is the major cause for the death of carcinoma patients. The breakdown of epithelial cell homeostasis leading to aggressive cancer progression has been correlated with the loss of epithelial characteristics and the acquisition of a migratory phenotype. This phenomenon, referred to as epithelial to mesenchymal transition (EMT), is considered as a crucial event in late stage tumorigenesis. Here we summarize the multitude of EMT models derived from different tissues, and review the diversity of molecular mechanisms contributing to the plasticity of epithelial cells. In particular, the synergism between activation of Ras, provided by the aberrant stimulation of receptor tyrosine kinases, and transforming growth factor (TGF)-β signaling plays a pivotal role in inducing EMT of various epithelial cell types. Cytokines such as TGF-β and extracellular matrix molecules are thought to fundamentally contribute to the microenvironmental interaction between stromal and malignant cells, and provide the basis for a broad repertoire of epithelial differentiation. Investigations of EMT tumor models, which represent in vitro correlates to local invasion and metastasis in vivo, facilitate the identification of diagnostic markers for a more accurate and faithful clinical and pathological assessment of epithelial tumors. In addition, the analysis of molecular mechanisms involved in EMT might yield novel therapeutic targets for the specific treatment of aggressive carcinomas.

Introduction

Tumorigenesis associated with metastasis formation accounts for 90% of cancer deaths, and represents one of the prime causes of human mortality [1]. In general, cancer arises from the stepwise accumulation of genetic changes and the progressive alterations in gene expression, disengaging cells from homeostatic constraints that normally keep the tissue balance in the healthy adult. Several defined events have been described as common to cancer cells including self-sufficiency in proliferation signals, insensitivity to growth inhibitory signals, evasion from cell death, limitless replicative potential, aberrant angiogenesis, as well as tissue invasion and metastasis [2], [3]. Importantly, tumor cell invasion is representative for aggressive cancer cells and is most frequently observed in epithelial tumors (carcinomas). Tumor-borne vascular connection and the acquisition of a migratory behavior of tumor cells is a prerequisite for the release of cells from organized tissue structures and invasion to more distal locations. The initial phase of tumor cell evasion from well-structured assemblies requires a phenotypical conversion which is referred to as epithelial to mesenchymal (fibroblastoid) transition (EMT; [4], [5], [6], [7]). This process is reminiscent of early stages of embryonic development but has also been described to be crucial in transient pathological situations such as wound healing and inflammation [8], [9], [10]. In these physiological events, cytokine and growth factor signals trigger competent cells to invade distal sites of interactions for providing specific and temporary functions. Similarly, a variety of pro-inflammatory cytokines, which display EMT-inducing abilities in vitro, have been reported to act as mitogens and motogens for epithelial cells and their mesenchymal derivatives [7], [11]. Thus, several EMT-related changes in cell motility during tumorigenesis reflect common physiological events. However, tumorigenesis-associated EMT includes additional critical features, which drastically increase the malignancy of the cells towards local tumor infiltration and metastasis. Since EMT-specific events in developmental processes and in malignancy have been compared and excellently reviewed [4], [5], [7], [10], we summarize several aspects of epithelial cell plasticity from well-characterized EMT models and discuss the molecular mechanisms underlying invasiveness of carcinoma cells. The data raised in cellular EMT models are further put into the context of recent advances in molecular cancer research.

Section snippets

EMT models derived from various tissues

In general, EMT represents phenotypical alterations which allow epithelial cells to acquire motile features. During embryonic development, such events are tightly regulated in a spatial and temporal fashion in order to ensure proper homing and reversion of cells to a non-motile phenotype after migration into a destined location [12]. In contrast, cancer cells undergoing EMT have lost specific target recognition, and are usually equipped with self-sufficient autocrine loops of growth signals,

Molecular mechanisms and crosstalks of signaling pathways in EMT

Loss of cell–cell adhesion and cytoskeletal rearrangements are basically raised as hallmarks of EMT and are used to assess progression of this process. The ability of cells to dissociate from epithelial entities are due to the disruption of intercellular adhesion. At initial stages of EMT, junctional protein complexes including tight junctions, adherens junctions, desmosomes and gap junctions are remodeled and functionally disintegrated (reviewed in [5], [8]). The re-organization of adherens

Microenvironmental interactions

A variety of studies showed a dramatic influence of the tumor surrounding environment on the behavior of (pre)-cancerous cells which is even able to control neoplastic transformation (reviewed in [8], [46]). The dissociation of epithelial cells from each other and from cell substratum is intimately associated with substantial remodeling of the ECM composition. Also the ECM significantly modulates epithelial development and cell plasticity both by functional and physical constraints. ECM

Relevance of cellular EMT models

The molecular aspects on epithelial–mesenchymal interactions along with the differentiation repertoire of epithelial cells raise the question whether EMT can be monitored by histological analysis. Noteworthy, the pathological evaluation of cancerous tissues depends mainly on two different standardized descriptions with the aim to identify the origin of primary tumors, and to provide diagnostic predictions and prognosis in combination with clinical records. These methods include (i) the tumor

Concluding remarks and future prospectives

Tumorigenesis is a multi-step process allowing cells to escape from regulatory loops involved in the maintenance of tissue balance at early stages, which finally leads to the adoption of an aggressive invasive phenotype causing colonization at later stages. The plasticity of epithelial cells as represented by EMT models at least partially recapitulates late stage carcinoma progression in vitro, thus providing important cellular models to investigate the manifold aspects of this lethal

Acknowledgements

The authors apologize to those investigators whose experimental work has only been cited indirectly because of space limitations. The work in the authors laboratories was supported by grants from the “Herzfeld Family Foundation” to WM, and from the “Fonds zur Förderung der wissenschaftlichen Forschung”, Austria to WM (P15435), and to RF and HB (SFB006).

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