Unraveling the journey of cancer stem cells from origin to metastasis

Abstract

Cancer biology research over recent decades has given ample evidence for the existence of self-renewing and drug-resistant populations within heterogeneous tumors, widely recognized as cancer stem cells (CSCs). However, a lack of clear understanding about the origin, existence, maintenance, and metastatic roles of CSCs limit efforts towards the development of CSC-targeted therapy. In this review, we describe novel avenues of current CSC biology. In addition to cell fusion and horizontal gene transfer, CSCs are originated by mutations in somatic or differentiated cancer cells, resulting in de-differentiation and reprogramming. Recent studies also provided evidence for the existence of distinct or heterogeneous CSC populations within a single heterogeneous tumor. Our analysis of the literature also opens the doors for a novel hypothesis that CSC populations with specific phenotypes, metabolic profiles, and clonogenic potential metastasize to specific organs.

Keywords: Cancer stem cells; de-differentiation; metabolic reprogramming.

Fig. 1.

Overall journey of CSCs from origin to metastasis. a) Origin of CSCs. Mutations in adult stem cells (ASCs) or in differentiated somatic cells can lead to CSC origin. Dedifferentiation of somatic differentiated cell in response to various external toxic exposures can give rise to CSC phenotype. Other factors, such as metabolic reprogramming, cell fusion, and horizontal gene transfer can also induce CSCs. b) Multiple CSC populations reside within tumors. CSCs with detoxification systems such as ABCG2-mediated drug efflux mechanism and ALDH-mediated aldehyde toxic substance detoxification systems exist in various tumors. CSCs expressing cell surface markers such as CD44, CD24, and EpCAM together are also the major constituents within various heterogeneous tumors, such as pancreatic tumors. Other CSCs, which express CD133 and CXCR4, also reside within the same tumor. Intestinal tumors consist of Lgr5-expressing CSCs. c) ‘Stemness’ maintenance mechanisms. The stemness in CSCs is largely maintained by specific stemness molecules such as Wnt/β-catenin, Notch and hedgehog, along with other factors such as YAP, HIF1α, NF-kB, PPARγ, and antiapoptotic. d) Role of CSCs in metastasis. The “seed” and “soil” theory, as proposed by Stephen Paget, states that primary site tumor cells (seed) travel to a distant organ (soil), and colonize and initiate the growth of tumor. Based on this theory, it is possible that CSCs from the primary site will travel to distant organs to initiate metastatic tumors. Another hypothetical view suggests that exosomes released by CSCs in the primary site travel to target sites and form the premetastatic niche (PMN) that supports upcoming CSCs or cancer cells. Another view also suggests that distinct CSC population subtypes with subtype-specific metabolic profiles travel to different organs (organ specific metastasis).

Fig. 2.

Different modes of CSC origin. a) ‘Cell fusion’ is a process whereby two cells (one stem cell and another cancer cell) fuse together to form CSCs. b) In horizontal gene transfer, mutant fragmented DNA (from a mutant somatic cell that is undergoing apoptosis) is taken up by another somatic or cancer cell, leading to the emergence of CSCs. c) Continuous symmetric divisions in adult stem cells (ASCs) lead to mutation in these cells and give rise to CSCs. d) A metabolic shift in somatic or differentiated cells could reprogram these cells into CSCs. e) Ionizing radiation, wounding, or exposure to toxic chemicals can de-differentiate somatic cells into CSCs.

Fig. 3.

‘Stemness’ maintenance pathways in CSCs. a) Canonical Wnt/β-catenin pathway starts with binding of Wnt ligand to Frizzled receptor (Fzd) and low-density lipoprotein receptor-related protein 5/6 coreceptors (LRP5/6). This results in recruitment of Axin and dishevelled (Dvl) to the plasma membrane and leads to protection of β-catenin from degradation. Free β-catenin in the cytoplasm then translocates to the nucleus and complexes with TCF/LEF to regulate Wnt target stem cell genes. b) Hh signaling pathway is initiated by binding of hedgehog class of ligands to Patched1 (PTCH1) or Patched2 (PTCH2) receptors. The receptor-ligand binding removes Patched receptor mediated inhibition of a G-protein coupled protein, Smoothened (Smo), leading to the nuclear translocation of Gli family transcription factors (a glioma associated oncogene homolog transcription factors). c) Notch signaling is initiated when a notch ligand of a cell binds to the notch receptor of an adjacent cell. This results in release of the intracellular part of the notch, which translocates into the nucleus and acts as a transcriptional co-activator. When the Notch transcriptional co-activators bind to target gene promoter regions, this leads to the activation of its target CSC genes. d) Phosphorylation of the cytoplasmic portion of CD133 leads to the phosphorylation of AKT. Activated AKT activates the NF-kB pathway, resulting in activation of stemness genes. e) ATP-dependent mechanism of drug efflux by ABC transporters. f) HIF1α and cMyc increase glycolysis (or Warburg effect) and inhibit oxidative phosphorylation in CSCs for rapid energy production. HIF1α activates pyruvate dehydrogenase kinases (PDK1–3), which inhibit pyruvate dehydrogenase (PDH), and thus inhibits oxidative phosphorylation. c-Myc and HIF1α also activate lactate dehydrogenase A (LDHA) to favor Warburg effect (aerobic glycolysis). C-Myc also activates the GLUT-1 receptor, hexokinase, and phosphofructokinase (PFK) that favor glycolysis.

Fig. 4.

Hypothetical model showing organ-specific metastasis of CSCs. Distinct CSC populations with differential metabolic profiles (either glycolytic, oxyolytic or intermediate) reside in heterogenous tumors. The exosomes released by a specific CSC subtype population in the primary tumor site may travel to a specific distant organ to form a pre-metastatic niche (PMN), required for survival of upcoming metastatic CSC.