Insights into cancer metastasis from a clinicopathologic perspective: Epithelial‐Mesenchymal Transition is not a necessary step

Abstract

Epithelial-mesenchymal transition (EMT) has been implicated as the critical event initiating cancer invasion and metastasis. After disseminating through the circulation, the malignant cells have been proposed to undergo subsequent mesenchymalepithelial transition (MET) to form secondary tumors. However, strong evidence from human tumor specimens for this paradigm is lacking. In carcinomas, cancers derived from epithelial tissues, epithelial morphology and gene expression are always retained to some degree. While mesenchymal transdifferentiation may be involved in the pathogenesis of carcinosarcomas, even in these neoplasms, as well as in germ cell tumors capable of multilineage differentiation, the mesenchymal phenotype does not facilitate metastatic progression. Indeed, most cancers invade and travel through lymphatic and blood vessels via cohesive epithelial migration, rather than going through the EMT-MET sequence. EMT gene expression is also consistently associated with high histologic grade and while the transcription factors, Snail, Slug and Twist have traditionally been thought of as inducers of EMT, under certain conditions, they also mediate dedifferentiation and maintenance of the stem cell state. In various malignancies, including basal-like breast cancer and colorectal cancer, the genetically unstable, undifferentiated phenotype predicts early metastatic spread and poor prognosis. This article discusses some of the controversies surrounding differentiation and metastasis from a clinicopathologic perspective and presents evidence that the epithelial phenotype is maintained throughout the process of cancer metastasis.Metastasis is the main cause of death in cancer patients and is widely claimed to be driven by epithelial-mesenchymal transition (EMT). While the role of EMT in cancer progression has been challenged several years ago, 1 there have nevertheless been numerous studies conducted based on this underlying premise. This article reviews recent developments in the field, as well as presenting the argument that for most cancers, mesenchymal differentiation is not essential for invasion and metastasis. EMT and MetastasisDefinitions of EMT are loose. It is generally agreed that during EMT, epithelial cells show loss of cell-cell adhesion by losing E-cadherin expression, reorganization of the cytoskeleton via switching from keratin to vimentin intermediate filaments, loss of apical-basal polarity, acquisition of a fibroblast-like (i.e., spindle) cell shape and increased motility.

Loss of E-cadherin and epithelial to mesenchymal transition is not required for cell motility in tissues or for metastasis

“…13,14 Histologic grading of most tumors incorporates grade (degree of differentiation), reflected by cell morphology and tissue architecture. 5 Given the high degree of heterogeneity of cell types within tumors and the overall configuration of the tumor microenvironment, cells that are deep within the tumor as opposed to those at the invasive edge may have different gene expression signatures and invasive or metastatic potential; however, it is also possible that single cells or small groups of cells from anywhere in a tumor may …”

Distinctive properties of metastasis-initiating cells

“…In this scenario, both processes of EMT and MET would be critical for metastasis: EMT for entering dormancy, promoting survival, and drug resistance and MET as the mechanism to reactivate proliferation and self-renewal to initiate metastasis. This could also explain the pathological observation that metastases display epithelial traits rather than mesenchymal characters (Chaffer et al 2007;Korpal et al 2011;Tsai et al 2012;Chui 2013). …”

Epithelial–mesenchymal plasticity in carcinoma metastasis

“…This EMT program in tumor metastasis possesses many morphological and molecular features similar to those of the developmental EMT program. Importantly, due to the heterogeneity and constantly evolving microenvironment in human tumors, the EMT program in metastasis adapts to these conditions to allow tumor cells to successfully metastasize.While EMT has been accepted as a critical program during embryogenesis, its role in carcinoma metastasis has been under debate (Tarin et al 2005;Thomson et al 2005;Garber 2008;Ledford 2011;Chui 2013). Many cell culture and mouse tumor model studies have clearly demonstrated the importance of EMT in tumor progression.…”

“…While EMT has been accepted as a critical program during embryogenesis, its role in carcinoma metastasis has been under debate (Tarin et al 2005;Thomson et al 2005;Garber 2008;Ledford 2011;Chui 2013). Many cell culture and mouse tumor model studies have clearly demonstrated the importance of EMT in tumor progression.…”