Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies

Abstract

Cancer stem cells (CSCs) are a unique subset of cells within tumors with stemlike properties that have been proposed to be key drivers of tumor initiation and progression. CSCs are functionally defined by their unlimited self-renewal capacity and their ability to initiate tumor formation in vivo. Like normal stem cells, CSCs exist in a cellular niche comprised of numerous cell types including tumor-associated macrophages (TAMs) which provides a unique microenvironment to protect and promote CSC functions. TAMs provide pivotal signals to promote CSC survival, self-renewal, maintenance, and migratory ability, and in turn, CSCs deliver tumor-promoting cues to TAMs that further enhance tumorigenesis. Studies in the last decade have aimed to understand the molecular mediators of CSCs and TAMs, and recent advances have begun to elucidate the complex cross talk that occurs between these two cell types. In this review, we discuss the molecular interactions that define CSC-TAM cross talk at each stage of tumor progression and examine the clinical implications of targeting these interactions.

Figure 1

The CSC model. Over time, CSCs acquire phenotypes and characteristics of normal stem cells such as unlimited self-renewal and the capacity to divide indefinitely and at the same time maintain the ability to generate multiple cell lineages, including differentiated progenies. A CSC can thus divide (1) asymmetrically (differentiation) giving rise to one CSC and a specialized differentiated cell or (2) symmetrically (self-renewal) giving rise to two identical CSCs. In both cases, the capacity of self-renewal remains intact and ensures the survival of the CSC pool and supports the hierarchical model of tumor cell heterogeneity.

Figure 2

The CSC niche and tumor microenvironment. At center stage is the CSC, in contact with a complex and dynamic cellular network, including daughter cancer cells, stellate cells (in the case of HCC and PDAC), cancer-associated fibroblasts (CAFs), and immune cells, which include T-cells, monocytes, neutrophils, and tumor-associated macrophages (TAMs). Nourished by the circulatory system, these cells communicate with one another and directly with the CSC via secreted factors, forming a positive feedback loop that promotes CSC tumorigenicity and metastasis.

Figure 3

Macrophage plasticity and characterization. The binary M1/M2 classification of macrophages suggests that human macrophages exist as either proinflammatory M1 macrophages or protumor M2 TAMs, which can be identified based on the expression of cell surface cell membrane markers. This concept has been challenged by the identification of numerous TAM subtypes (angiogenesis-promoting TAM, metastasis-promoting TAM, immunosuppressive TAM, and CSC-promoting TAM) that exist within the primary tumor and metastatic sites. The existence of a specific TAM subtype is driven by the interaction of macrophages with factors secreted by the tumor microenvironment, leading to transcriptional rewiring of TAMs with a specific gene signature profile. TAMs are highly plastic and can shift between subtypes based on tumor-specific signals and stimuli.

Figure 4

TAM-secreted factors regulate CSC phenotypes. TAMs have been shown to secrete LL-37, ISG15, IL-17, EGF, IL-6, MFGE-8, and IL-8 (among others), which in turn activate MAPK, STAT3/NFκB, and other yet-to-be-defined signaling pathways, leading to the activation of CSC properties, such as self-renewal, chemoresistance, migration, and invasion.