Inhibition of M2-like macrophages by all-trans retinoic acid prevents cancer initiation and stemness in osteosarcoma cells

Abstract

Emerging evidence indicates that M2-polarized tumor-associated macrophages (TAMs) directly participate in tumor initiation, progression and metastasis. However, to date, few studies have investigated novel strategies for inhibiting TAMs in order to overcome osteosarcoma. In this study, we reported that M2 macrophages were enriched in osteosarcoma tissues from patients, and M2-polarized TAMs enhanced cancer initiation and stemness of osteosarcoma cells, thereby establishing M2-polarized TAMs as a therapeutic target for blocking osteosarcoma formation. We also found that all-trans retinoic acid (ATRA) weakened TAM-induced osteosarcoma tumor formation by inhibiting M2 polarization of TAMs in vivo, and inhibited the colony formation, as well as sphereformation capacity of osteosarcoma cells promoted by M2-type macrophages in vitro. Furthermore, M2-type macrophages enhanced cancer stem cells (CSCs) properties as assessed by increasing the numbers of CD117 + Stro-1 + cells accompanied by the upregulation of CSC markers (CD133, CXCR4, Nanog, and Oct4), which could clearly be reduced by ATRA. Taken together, the results of this study demonstrated the role of M2-polarized TAMs in osteosarcoma initiation and stemness by activating CSCs, and indicated that ATRA treatment is a promising approach for treating osteosarcoma by preventing M2 polarization of TAMs.

Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy

“…Moreover, Shao X et al observed a higher percentage of CD209 + M2-TAMs in primary OS. Additionally, inhibition by ATRA reduced tumorigenesis in OS by blocking M2-polarization and, more interestingly, suppressed the stem-like properties of OS cells such as the colony formation capability, reduced the number of CD117 + /Stro-1 + cells and the expression of stemness genes [ 99 ].…”

“…Inhibiting TAMs resulted in a decreased number of tumor initiating cells and increased the chemoresistance response in pancreatic tumors [ 123 ]. More recently, it has been suggested that the involvement of M2-TAMs, in tumor initiation, acts by inducing the stem-like phenotype of the cancer stem cell in OS [ 99 ]. However, the TAMs-CSCs crosslink in OS remains to be fully understood.…”

Retracted Article: Macrophage-derived exosomes mediate osteosarcoma cell behavior by activating AKT signaling

“…5,6 A previous study demonstrated that inhibition of M2-like macrophages prevents osteosarcoma cell initiation and stemness. 7 Intriguingly, several studies conrmed that macrophages showed positive outcomes of osteosarcoma patients during diagnosis. 8,9 However, the potential role and mechanism of macrophages on osteosarcoma progression are still not yet known.…”

Chenopodium Quinoa and Salvia Hispanica Provide Immunonutritional Agonists to Ameliorate Hepatocarcinoma Severity under a High-Fat Diet

“…Accumulating evidence indicates that tumor elimination at early stages of development may be more dependent on tumor phenotype than on origin [ 22 ]. Thus, given the previously established intricate link between lipid and hepatic iron homeostasis [ 23 , 24 ] and their link to cancer [ 21 , 25 ], it was examined how the production of bioactive hepcidin compares in HCC developing mice receiving PIs ( Figure 1 E).…”