Stem cells in cancer initiation and progression

Abstract

While standard therapies can lead to an initial remission of aggressive cancers, they are often only a transient solution. The resistance and relapse that follows is driven by tumor heterogeneity and therapy-resistant populations that can reinitiate growth and promote disease progression. There is thus a significant need to understand the cell types and signaling pathways that not only contribute to cancer initiation, but also those that confer resistance and drive recurrence. Here, we discuss work showing that stem cells and progenitors may preferentially serve as a cell of origin for cancers, and that cancer stem cells can be key in driving the continued growth and functional heterogeneity of established cancers. We also describe emerging evidence for the role of developmental signals in cancer initiation, propagation, and therapy resistance and discuss how targeting these pathways may be of therapeutic value.

Cell division symmetry control and cancer stem cells

“…It has been commonly assumed that CSCs are rare in cancer tissues. The idea might be rooted in results from studying normal hematopoietic stem cells [ 69 ], and was consistent with earlier nude mice engraftment experiments to identify CSCs [ 7 , 53 – 56 ]. However, using modified xenograft protocols on more immunocompromised mouse models, ~27% of single cell transplants of unsorted patient melanoma cells successfully formed tumors [ 70 ].…”

“…Despite the long-known genetic and epigenetic heterogeneity in cancers and similarity of cancer cells to adult stem cells [ 6 ], CSCs were first experimentally identified only in the 1990s in leukemia through limiting dilutions and engraftment of cancer cells with stem-like surface markers to immune-compromised mice [ 53 , 54 ]. CSCs from glioma, breast cancers, and other solid tumors were subsequently identified [ 7 , 55 , 56 ]. Tumor reconstitution using a small number of CSCs in animal models has now become a gold-standard functional assay.…”

“…The original theory of cancer stem cells (CSC) suggests that there is a hierarchy in cancer cells, in which CSC lies at the top level [ 6 ]. A small number of CSCs could reconstitute a tumor in animal models because CSCs retain the capability of self-renewal and differentiation [ 6 , 7 ] ( Figure 1B ). The CSC model, which emphasizes epigenetic changes, is not mutually exclusive from the classical “clonal evolution” model which underscores genetic mutations during cancer development [ 8 ].…”

LPA/PKD-1 signaling promotes development of arteriolar niche that supports self-renewal of breast cancer stem cells and stemness

“…Gene expression was assessed by real-time quantitative RT-qPCR as previously described (1). The RT2 qPCR primer assays (Qiagen) or qPCR primers (IDT) for the target genes and housekeeping genes were used for PCR reactions.…”

“…In many advanced cancers, recurrence and metastasis is driven by a subpopulation of cells called cancer stem-like cells (CSCs). These cells are characterized by their enhanced tumor-initiating and self-renewal capacities (1). Al-Hajj and colleagues initially identified tumorigenic CSCs in breast cancer (BC) known as BCSCs (2).…”