Cancer stem cells and macrophages: molecular connections and future perspectives against cancer

Abstract

Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.

Macrophages and cancer stem cells: a malevolent alliance

“…Furthermore, TAMs actively produce several proteolytic enzymes, such as matrix metalloproteases, serine proteases and cathepsins, thereby enhancing the remodeling of the tumor stroma and favoring the metastatic process of cancer cells (Liguori et al 2011 ; Zhang et al 2017 ; Sangaletti et al 2014 ; Chen et al 2011 ; Steenbrugge et al 2018 ; Wang et al 2011 , 2018 ; Aras and Zaidi 2017 ). While it is well established that TAMs display these supporting functions on the proliferating cancer cells, relatively few studies have addressed the impact of TAMs on the specific population of tumor-initiating cells or Cancer Stem Cells (CSCs) (Chen et al 2021 ; Raggi et al 2016 ; Aramini et al 2021 ; Fan et al 2014 ; Jinushi et al 2011 ; Osman et al 2020 ).…”

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

“…Below the two stem cells is a list of the various cells coexisting in the niche, with their bidirectional exchange of signals. With their collaboration with MSCs, normal cancer cells and non-stem/non cancer cells are essential for many specific CSC activities [ 20 , 29 , 30 , 31 , 32 , 35 , 40 ].…”

“…Among the processes involved are tumor resistance, metastasis, angiogenesis, and maintenance of stemness and immune suppression [ 21 , 23 , 36 , 41 , 42 , 43 ]. The main role of EVs also includes their fusion with macrophages and other immune cells [ 30 , 31 ]. CSCs and their EVs are able to modulate cancer cell proliferation by the release of proteins [ 44 , 45 , 46 ] and miRNAs [ 30 , 47 , 48 , 49 , 50 , 51 ].…”

“…Tumor-initiating CSCs shape their microenvironment into immunosuppressive barriers and pro-tumorigenic niches, all including filtered immune cells, which are most often macrophages and lymphocytes [ 69 , 70 ]. The interactions between macrophages and CSCs contribute to the development, association, and dissemination of tumor-associated cells dependent on the signaling of miRNAs released from EV cargoes [ 31 , 74 ]. A few processes, promoted by the miR-1468-5p, induce the immune escape of tumors via the immunosuppressive reprogramming of lymphatic vessels [ 52 ].…”

“…Within niches, some of the general properties of stem cells and their vesicles depend on the cooperation of CSCs with MSCs [ 27 , 28 ]. Stem cells and their EVs are not alone but are accompanied by other cells and EVs: non-stem cancer cells (referred to in this review as normal cancer cells), fibroblasts, immune cells (macrophages, lymphocytes, and others) and other cells, are all involved as cooperators in cancer function [ 24 , 29 , 30 , 31 , 32 ] ( Table 1 ). The tumor microenvironment (TME) ( Figure 2 ), which is different from the non-cancer microenvironment, coincides in space with niches and other areas of cancer development and growth [ 24 , 25 ].…”