Cancer stem cells: the lessons from pre‐cancerous stem cells

Abstract

How a cancer is initiated and established remains elusive despite all the advances in decades of cancer research. Recently the cancer stem cell (CSC) hypothesis has been revived, challenging the long-standing model of ‘clonal evolution’ for cancer development and implicating the dawning of a potential cure for cancer [1]. The recent identification of pre-cancerous stem cells (pCSCs) in cancer, an early stage of CSC development, however, implicates that the clonal evolution is not contradictory to the CSC hypothesis but is rather an aspect of the process of CSC development [2]. The discovery of pCSC has revealed and will continue to reveal the volatile properties of CSC with respect to their phenotype, differentiation and tumourigenic capacity during initiation and progression. Both pCSC and CSC might also serve as precursors of tumour stromal components such as tumour vasculogenic stem/progenitor cells (TVPCs). Thus, the CSC hypothesis covers the developing process of tumour-initiating cells (TIC) → pCSC → CSC → cancer, a cellular process that should parallel the histological process of hyperplasia/metaplasia (TIC) → pre-cancerous lesions (pCSC) → malignant lesions (CSC → cancer). The embryonic stem (ES) cell and germ line stem (GS) cell genes are subverted in pCSCs. Especially the GS cell protein piwil2 may play an important role during the development of TIC → pCSC → CSC, and this protein may be used as a common biomarker for early detection, prevention, and treatment of cancer. As cancer stem cell research is yet in its infancy, definitive conclusions regarding the role of pCSC cannot be made at this time. However, this review will discuss what we have learned from pCSC and how this has led to innovative ideas that may eventually have major impacts on the understanding and treatment of cancer.

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…At the initial stage of tumorigenesis, intrinsic and extrinsic factors cause intracellular genetic mutations and epigenetic alterations, resulting in generation of oncogenes that induce the production of CSCs and tumorigenesis [6]. The CSCs can be produced from precancerous stem cells [59][60][61][62][63][64], cell de-differentiation [65], or an epithelial-mesenchymal transition [66][67][68]. Malignant mesenchymal stem cells have been found in the niche of cancers [66,67], and an epithelial-mesenchymal transition may be an early key step in the initiation of TME and tumorigenesis [68].…”

“…First, CSCs actively participate in the development of the CSC niche [11]. Second, CSCs may trans-differentiate into cancer-associated stromal cells [58][59][60][61][62][65][66][67][68][69], such as cancer-associated fibroblasts and tumor endothelial cells [70,71]. The CSC-differentiated tumor endothelial cells are important in tumor neovascularization and the genesis of TME [72][73][74][75].…”

“…3). These tumor cells include precancerous stem cells [59][60][61], CSCs [62][63][64], and vasculogenic tumor cells [71][72][73][74][75].…”

“…Various growth factors promote TME formation, including AREG, BDNF, CTGF, CSF2, CSF3, EGF, FGF1, HGF, IGF1, LEF, VEGF, PDGF, SDF-1, SDF4, SCF, TCF, TF, and TGFβ1. Various cytokines increase generation of the TME, including IL-1, IL-10, IL-12, IL-15, IL-21, IL-3, IL-6, IL-7, IL-17, IL-8, interferons, and TNFs [60,62] . The C-C motif chemokines and their receptors trigger the formation of TME in cancers, including CCL2/MCP-1, CCL8/MCP-2, CCL7/ MCP-3, CCL21, CCL22, CCL25, CCR1, CCR2, CCR5, CCR9, CX3CL1, CX3CR1, CXCL10, CXCL12, CXCR3, and CXCR4.…”

“…Several options potentially may target CSCs in the TME. First, precancerous cells are reversible and may be induced to regress to normal cells, depending on the environmental cue [59][60][61]. Second, oncogenic mesenchymal stem cells could be reversed to normal epithelial cells using the approach of mesenchymalepithelial transition, because epithelial-mesenchymal transition may be reversible [65][66][67][68].…”