Macrophages and cancer stem cells: a malevolent alliance

Abstract

Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.

Keywords: Cancer stem cells; GPNMB; Stemness; Tumor associated macrophages.

Fig. 1

Paracrine mechanisms of interaction between cancer stem cells (CSCs) and tumor-associated macrophages (TAM). CSCs produce chemotactic factors (CCL2, CCL3, CCL5, CCL8, CXCL12) to recruit circulating monocytes in the tumor; moreover, they shape macrophage polarization towards an M2-like, pro-tumoral, phenotype by secreting IL-4, IL-6, IL-10, IL-13, TGFβ. On the macrophage side, TAMs support CSCs and their niche by secreting IL-6, IL-1β, TGFβ, TNF-α, CCL5, CCL8, MGF-E8, hCAP-18/LL-37, GPNMB. This figure was made with Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0. Unported License (https://smart.servier.com)

Fig. 2

Juxtacrine mechanisms of interaction between cancer stem cells (CSCs) and tumor-associated macrophages (TAM). CSCs upregulate the enzyme hyaluronan synthase 2 (HAS2), which induces the formation of a layer of pericellular hyaluronan (HA) that facilitates their attachment to TAMs, via the CD44 receptor. Upon this interaction, TAMs produce the growth factor PDGF-BB, which enhances CSC self-renewal; moreover, it activates signaling pathways important for CSC maintenance (e.g.PI3K–4EBP1–SOX2). CSCs express CD90 and the receptor EphA4, which bind to CD11b and Ephrin, respectively. These interactions activate the Src/NFkB pathway, and together with the LSECtin and BTN3A3 they support and drive cancer stemness. Finally, CSCs downregulate MHC molecules and CD80, while upregulating PD-1L, CD47, B7-H3 to escape from the immune system recognition. This figure was made with Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0. Unported License (https://smart.servier.com)

Fig. 3

The soluble protein GPNMB produced by macrophages induces cancer stemness via CD44 and IL-33. Cancer cells stimulate in macrophages the production of GPNMB by M-CSF and tumor derived factors. GPNMB can be cleaved from the membrane by metalloproteinases, such as ADAM10. Soluble GPNMB binds to the CD44 receptor and triggers the release of IL-33. This cytokine, through the binding to its receptor IL-1RL1, is able to expand the population of CSCs, and to stimulate macrophages to produce TGFβ, promoting CSC invasion and resistance to drugs. This figure was made with Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0. Unported License (https://smart.servier.com)