The role of epithelial-mesenchymal transition programming in invasion and metastasis: a clinical perspective

Abstract

Epithelial-mesenchymal transition (EMT) is involved in normal developmental cellular processes, but it may also be co-opted by a subset of cancer cells, to enable them to invade and form metastases at distant sites. Several gene transcription factors regulate EMT, including Snail1, Snail2, Zeb1, Zeb2, and Twist; ongoing studies continue to identify and elucidate other drivers. Specific micro ribonucleic acids (RNAs) have also been found to regulate EMT, including the microRNA-200 (miR-200) family, which targets Zeb1/Zeb2. Cancer "stem cells" - with the ability to self-renew and to regenerate all the cell types within the tumor - have been found to express EMT markers, further implicating both cancer stem cells and EMT with metastasis. Microenvironmental cues, including transforming growth factor-β, can direct EMT tumor metastasis, such as by regulating miR-200 expression. In human tumors, EMT markers and regulators may be expressed in a subset of tumor cells, such as in cells at the invasive front or tumor-microenvironment interface, though certain subtypes of cancer can show widespread mesenchymal-like features. In terms of therapeutic targeting of EMT in patients, potential areas of exploration could include targeting the cancer stem cell subpopulation, as well as microRNA-based therapeutics that reintroduce miR-200. This review will examine evidence for a role of EMT in invasion and metastasis, with the focus being on studies in lung and breast cancers. We also carry out analyses of publicly-available gene expression profiling datasets in order to show how EMT-associated genes appear coordinately expressed across human tumor specimens.

Keywords: EMT; cancer stem cells; epithelial; mesenchymal transition; miR-200; tumor microenvironment.

Figure 1

EMT-associated genes appear coordinately expressed across human tumor specimens of both breast and lung cancer. Notes: Two gene expression profiling datasets are represented, (A) one being a “compendium” of published data on human breast cancers, and (B) the other being a compendium of data on human lung cancers.– Using a panel of canonical EMT markers as shown (from the review article by Lee et al4), we have “scored” each of the tumor profiles for “EMT-ness” (ie, similarity to mesenchymal cells). Yellow denotes relatively high mRNA expression; blue indicates lower mRNA expression. For each dataset, a subset of tumors appears to be relatively more mesenchymal-like as compared to the rest of the tumors. Genes represented in the breast cancer dataset are limited to those featured on the U133A array platform. Abbreviations: n, number; EMT, epithelial–mesenchymal transition; mRNA, messenger ribonucleic acid.

Figure 2

In both human breast cancer and lung cancer, lower expression of miR-200 family members is correlated with EMT marker expression. Notes: Matrix of expression correlations between individual miR-200 family members and canonical genes encoding EMT markers (the list from Lee et al, plus ZEB1 and ZEB2). Red indicates a positive correlation between microRNA and mRNA; blue indicates a negative correlation. Data are from The Cancer Genome Atlas (n = 503 human breast cancers and n = 159 human lung squamous cancers).,Abbreviations: mRNA, messenger ribonucleic acid; EMT, epithelial–mesenchymal transition.