Distinct Types of Tumor-Initiating Cells Form Human Colon Cancer Tumors and Metastases

Abstract

Human colon cancer harbors a small subfraction of tumor-initiating cells (TICs) that is assumed to be a functionally homogeneous stem-cell-like population driving tumor maintenance and metastasis formation. We found unexpected cellular heterogeneity within the TIC compartment, which contains three types of TICs. Extensively self-renewing long-term TICs (LT-TICs) maintained tumor formation in serial xenotransplants. Tumor transient amplifying cells (T-TACs) with limited or no self-renewal capacity contributed to tumor formation only in primary mice. Rare delayed contributing TICs (DC-TICs) were exclusively active in secondary or tertiary mice. Bone marrow was identified as an important reservoir of LT-TICs. Metastasis formation was almost exclusively driven by self-renewing LT-TICs. Our results demonstrate that tumor initiation, self-renewal, and metastasis formation are limited to particular subpopulations of TICs in primary human colon cancer. We identify LT-TICs as a quantifiable target for therapies aimed toward eradication of self-renewing tumorigenic and metastatic colon cancer cells.

Normal vs cancer thyroid stem cells: the road to transformation

“…However, initiation and maintenance of the tumour seem to be dynamic processes, characterised by the transition between the self-renewing and transient amplifying phenotypes ( Figure 5). 59,60 CSCs are identified due to their ability to self-renew and are represented by: (i) longterm TICs (LT-TICs) able to maintain tumour formation after serial xeno-transplantations and involved in metastasis formation; (ii) delayed contributing TICs (DC-TICs), active only in secondary or tertiary tumour xenografts ( Figure 5). 59 The peculiar feature of CSCs concerns the pronounced tendency to undergo symmetric division as compared with normal SCs.…”

“…59,60 CSCs are identified due to their ability to self-renew and are represented by: (i) longterm TICs (LT-TICs) able to maintain tumour formation after serial xeno-transplantations and involved in metastasis formation; (ii) delayed contributing TICs (DC-TICs), active only in secondary or tertiary tumour xenografts ( Figure 5). 59 The peculiar feature of CSCs concerns the pronounced tendency to undergo symmetric division as compared with normal SCs. This drift is driven by major genetic and epigenetic events conferring unlimited lifespan and to CSCs, which are ultimately responsible for tumour growth and progression.…”

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].…”