Engaging plasticity: Differentiation therapy in solid tumors

Abstract

Cancer is a systemic heterogeneous disease that can undergo several rounds of latency and activation. Tumor progression evolves by increasing diversity, adaptation to signals from the microenvironment and escape mechanisms from therapy. These dynamic processes indicate necessity for cell plasticity. Epithelial-mesenchymal transition (EMT) plays a major role in facilitating cell plasticity in solid tumors by inducing dedifferentiation and cell type transitions. These two practices, plasticity and dedifferentiation enhance tumor heterogeneity creating a key challenge in cancer treatment. In this review we will explore cancer cell plasticity and elaborate treatment modalities that aspire to overcome such dynamic processes in solid tumors. We will further discuss the therapeutic potential of utilizing enhanced cell plasticity for differentiation therapy.

Keywords: EMT; TGFb signaling; cancer cell plasticity; differentiation therapy; solid tumors; trans-differentiation.

FIGURE 1

Plasticity and diversity in a cell population. This figure symbolizes the inherent plasticity of every differentiated state and of every cell type on the vertical axis. Plasticity, induced by dynamic changes, is represented on the horizontal axis. Differentiated states are on the left where different colors are marked, and dedifferentiated and stem cell-like states are on the right where colors are light. Cell diversity includes cell identity, mutations and epigenetic landscape of cells creating cellular heterogeneity. Plasticity is triggered by external signals from the tumor microenvironment and is exhibited in the varying response of cells depending on cell state and location, thus creating a variety of phenotypic changes.

FIGURE 2

Representation of structural and cellular changes during EMT/MET. Epithelial cells (blue) exhibit apical-basal polarity and cortical actin organization. Epithelium comprises tightly packed and functionally synchronized epithelial cells connected to each other via cell-cell junctions and are anchored to the basement membrane via integrins. Upon EMT, cells lose epithelial characteristics and become dedifferentiated single cells (partial EMT—green). The full conversion gives rise to mesenchymal-like cells (purple) with front-rear polarity and actin stress fibers formation.

FIGURE 3

Differentiation treatment potential facilitated by cancer plasticity. This figure schematically illustrates the concurrency of cell plasticity and cancer survival during malignant progression with the differentiation potential. When cancer cells are responding to stress induced by the changing microenvironment during dissemination or in response to treatment application, cell plasticity and adaptability are enhanced, correlating with cell survival. The increased cell plasticity is linked to the multi-differentiation potential of the cells, proposing a therapeutic window. Figure created with BioRender.com.