Cancer stem cells and their niche

Abstract

The unique characteristics of stem cells, specifically pluripotency and self-renewal, are critical for sustaining the lifelong functionality of organs. Stem cells reside in a special microenvironment called the niche. Stem cells interact with the niche via adhesion molecules and exchange molecular signals that maintain the specific features of stem cells. A better understanding of the nature of stem cells and their niches is expected to provide an alternative approach to the treatment of various serious diseases, including cancer, in clinical practice. It has been suggested that tumor tissue contains a type of stem cell referred to as a cancer stem cell. Interestingly, there are a number of molecules that are commonly expressed in normal and cancer stem cells that lead to different phenomena depending on the local conditions. In this review, the hematopoietic system is used as an example to show how stem cells interact with different niches. The regulatory mechanisms of two kinds of bone marrow niche, osteoblastic and vascular, are covered in this review. Furthermore, the involvement of the niche in cancer stem cell regulation, tumor invasion and metastasis, and its response to oxidative stress is described, and novel therapeutic approaches involving the interactions between cancer stem cells and their niches are addressed.

Figure 1

Extracellular perturbations affect the stem cell and/or progenitor in which genetic mutations have accumulated. Under these conditions, transformed stem cells show sustained self‐renewal, and the progenitors that have been affected acquire the capacity for self‐renewal. Both types of cells are called cancer stem cells. At a certain point, cancer stem cells give rise to cancer cells, which are more differentiated than stem cells, but not fully mature as observed in chronic myeloid leukemia. At some point after this stage, further differentiation is blocked and cancer cells aggressively proliferate as is typically observed in acute myeloid leukemia.

Figure 2

Schematic model of the molecular mechanism regulating a hematopoietic stem cell (HSC) in an osteoblastic niche in bone marrow. Molecular interactions between HSC and osteoblasts, factors secreted by osteoblasts, extracellular matrix, or CXCL12‐abundant reticular (CAR) cells as a whole determine HSC behavior and fate, including the balance between quiescence and proliferation or differentiation. For a detailed list of molecules, see Table 2.

Figure 3

Stem cells, whether normal or cancer, in general reside in a hypoxic niche where self‐renewal and differentiation activity is balanced. With an increase in oxygen levels, proliferation becomes a dominant feature mediated by an increase in p38 MAPK and p16^ink4a. This transiently leads to the expansion of the progenitors, which results in a long‐term decrease in the stem cell pool and its eventual exhaustion. ROS, reactive oxygen species.