Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity

Abstract

The epithelial-to-mesenchymal transition (EMT) is a critical developmental process that has recently come to the forefront of cancer biology. In breast carcinomas, acquisition of a mesenchymal-like phenotype that is reminiscent of an EMT, termed oncogenic EMT, is associated with pro-metastatic properties, including increased motility, invasion, anoikis resistance, immunosuppression and cancer stem cell characteristics. This oncogenic EMT is a consequence of cellular plasticity, which allows for interconversion between epithelial and mesenchymal-like states, and is thought to enable tumor cells not only to escape from the primary tumor, but also to colonize a secondary site. Indeed, the plasticity of cancer cells may explain the range of pro-metastatic traits conferred by oncogenic EMT, such as the recently described link between EMT and cancer stem cells and/or therapeutic resistance. Continued research into this relationship will be critical in developing drugs that block mechanisms of breast cancer progression, ultimately improving patient outcomes.

Figure 1

Functional consequences of a type III epithelial-to-mesenchymal transition. An oncogenic epithelial-to-mesenchymal transition (EMT) in a breast carcinoma cell gives rise to a tumor cell with mesenchymal-like features. This transition can lead to the acquisition of a number of pro-metastatic features, including increased motility, invasiveness, anoikis resistance and evasion of the immune system. Recently, the acquisition of cancer stem cell-like properties has been added to this list (that is, self-renewal, multipotency, therapeutic resistance), resulting in significant cross-talk between the EMT and cancer stem cell fields.

Figure 2

Epithelial-to-mesenchymal transition may contribute to metastasis through multiple mechanisms. (a) Carcinoma cells that undergo an oncogenic epithelial-to-mesenchymal transition (EMT) may cooperate with epithelial tumor cells to stimulate metastasis. In this example, mesenchymal-like tumor cells, arising from an exogenously induced oncogenic EMT, are required to enable the parental epithelial tumor cell access to the vasculature; however, once both cell types have accessed the vasculature, only the epithelial cell is able to colonize the secondary site. In this model, the tumor cells are not plastic, and exist as two distinct populations. (b) Tumor cells that are plastic can carry out both early and late stages of the metastatic cascade by utilizing the mesenchymal-like state to leave the primary tumor and enter the vasculature, while the epithelial state is needed to colonize a secondary site; a combination of strictly epithelial and mesenchymal-like cancer cells is not needed.

Figure 3

Clinical implications of the plasticity of cancer stem cells. (a) The initial tumor is composed of non-cancer stem cells (CSCs; yellow) and the rare CSCs (red). Non-CSCs within the tumor can mutate, resulting in a genetically distinct non-CSC (blue). Spontaneous conversion of this new non-CSC (blue) into a new CSC (green) provides a given tumor with genetically distinct CSCs (red and green) that can foster the outgrowth of different clonal populations. (b) Conventional therapy is known to be ineffective at eliminating CSCs, which allow tumor cells to eventually repopulate (left); however, targeting solely CSCs will leave the bulk of the tumor intact (middle). A remaining tumor cell could then convert into a CSC, allowing for tumor recurrence and metastasis. Combination therapies targeting both CSCs and non-CSCs are likely needed to better prevent tumor recurrence and metastasis (right).