Differentiation and transdifferentiation potentials of cancer stem cells

Abstract

Tumor cells actively contribute to constructing their own microenvironment during tumorigenesis and tumor progression. The tumor microenvironment contains multiple types of stromal cells that work together with the extracellular matrix and local and systemic factors to coordinately contribute to tumor initiation and progression. Tumor cells and their stromal compartments acquire many genetic and/or epigenetic alternations to facilitate tumor growth and metastasis. The cancer stem cell (CSC) concept has been widely applied to interpreting tumor initiation, growth, metastasis, dormancy and relapse. CSCs have differentiation abilities to generate the original lineage cells that are similar to their normal stem cell counterparts. Interestingly, recent evidence demonstrates that CSCs also have the potential to transdifferentiate into vascular endothelial cells and pericytes, indicating that CSCs can transdifferentiate into other lineage cells for promoting tumor growth and metastasis in some tissue contexts instead of only recruiting stromal cells from local or distant tissues. Although the transdifferentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity, many aspects of CSC transdifferentiation remain elusive. In this review, we summarize the multi-lineage differentiation and transdifferentiation potentials of CSCs as well as discuss their potential contributions to tumor heterogeneity and tumor microenvironment in tumor progression.

Keywords: cancer stem cell; differentiation; stromal cells; transdifferentiation; tumor microenvironment.

Figure 1. A schematic illustration showing the different types of cells involved in tumor progression

Tumors are very complicated neoplasms that not only consist of cancer stem cells (CSCs) and non-stem cancer cells, they also have numerous types of stromal cells, including cancer-associated fibroblasts (CAFs), endothelial cells, pericytes, tumor-associated macrophages (TAMs), mesenchymal stem cells (MSCs), MSC-derived cells and other stromal cells.

Figure 2. Glioblastoma stem cells (GSCs) have the potential to give rise to endothelial cells and pericytes

A. With the induction of activated Notch signaling, GSCs transdifferentiate into endothelial-cell progenitors, which further differentiate into endothelial cells by VEGF induction. GSCs also have potential to generate pericytes. When induced by TGF-β, GSCs, which are recruited by endothelial cells via SDF-1/CXCR4 chemokine signaling, can transdifferentiate into pericytes. B. GSC-derived pericytes and GSC-derived endothelial cells, together with normal pericytes and endothelial cells, contribute to tumor vessel function and tumor development.

Figure 3. Differentiation and transdifferentiation potentials of cancer stem cells (CSCs)

CSCs can differentiate into the non-stem original cell lineages from which the tumor arose as well as have potential to transdifferentiate into other cell lineages, such as endothelial cells, pericytes, cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), adipocytes, osteocytes, chondrocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and neurons in specific tissue contexts. However, there is insufficient direct evidence supporting the transdifferentiation of CSCs into most of other cell lineages.