Revisiting Cancer Stem Cells as the Origin of Cancer-Associated Cells in the Tumor Microenvironment: A Hypothetical View from the Potential of iPSCs.

Amira Osman,Masaharu Seno,Akimasa Seno,Ghmkin Hassan,Xiaoying Fu,Said M Afify

doi:10.3390/cancers12040879

Abstract

The tumor microenvironment (TME) has an essential role in tumor initiation and development. Tumor cells are considered to actively create their microenvironment during tumorigenesis and tumor development. The TME contains multiple types of stromal cells, cancer-associated fibroblasts (CAFs), Tumor endothelial cells (TECs), tumor-associated adipocytes (TAAs), tumor-associated macrophages (TAMs) and others. These cells work together and with the extracellular matrix (ECM) and many other factors to coordinately contribute to tumor growth and maintenance. Although the types and functions of TME cells are well understood, the origin of these cells is still obscure. Many scientists have tried to demonstrate the origin of these cells. Some researchers postulated that TME cells originated from surrounding normal tissues, and others demonstrated that the origin is cancer cells. Recent evidence demonstrates that cancer stem cells (CSCs) have differentiation abilities to generate the original lineage cells for promoting tumor growth and metastasis. The differentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity. Using induced pluripotent stem cells (iPSCs), our group postulates that CSCs could be one of the key sources of CAFs, TECs, TAAs, and TAMs as well as the descendants, which support the self-renewal potential of the cells and exhibit heterogeneity. In this review, we summarize TME components, their interactions within the TME and their insight into cancer therapy. Especially, we focus on the TME cells and their possible origin and also discuss the multi-lineage differentiation potentials of CSCs exploiting iPSCs to create a society of cells in cancer tissues including TME.

Highlights

Cancer stem cells (CSCs), identified as cancer-originating cells, are responsible for the maintenance and development of malignant tumors being defined by the potentials of self-renewal, differentiation, and tumorigenicity
We summarize tumor microenvironment (TME) components discussing the origin of TME cells and the ability of CSCs to differentiate into tumor stromal cells, cancer-associated fibroblasts (CAFs), Tumor endothelial cells (TECs), tumor-associated adipocytes (TAAs), and tumor-associated macrophages (TAMs) providing the progenies, Cancers 2020, 12, x which establish a society in tumor tissue
Our group proved that CSCs converted from induced pluripotent stem cells (iPSCs) could be the source of the CAFs which provide for tumor maintenance and persistence

Summary

Introduction

Cancer stem cells (CSCs), identified as cancer-originating cells, are responsible for the maintenance and development of malignant tumors being defined by the potentials of self-renewal, differentiation, and tumorigenicity. Another study supports that Osteopontin induces mesenchymal stem cells in the tumor microenvironment (TME) to differentiate into cancer-associated fibroblasts (CAFs), which promotes cancer development and can be stimulated to release periostin in the metastatic microenvironment [6,7]. Our group succeeded in designing a model of CSCs derived from induced pluripotent stem cells (iPSCs), which were reprogrammed from normal cells, in the conditioned medium from a variety of mouse and human cancer cell lines These obtained CSCs exhibited a capacity of self-renewal, differentiation, and malignancy in vivo. We summarize TME components discussing the origin of TME cells and the ability of CSCs to differentiate into tumor stromal cells, CAFs, TECs, TAAs, and TAMs providing the progenies, Cancers 2020, 12, x which establish a society in tumor tissue.

Differentiation of CSC Population in the TME

Limitations

Findings

Conclusions