Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy

Abstract

Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.

Keywords: cancer-stem cells; mesenchymal stem cells; metastasis; osteosarcomas (OSs); therapy; tumor microenvironment; tumor-associated macrophages (TAMs).

Figure 1

(a) Primary and (b; lung) metastatic osteosarcoma (OS) sections stained for CD163 (clone 10D6 Thermo Scientific). Dense infiltration of tumor-associated macrophages (TAMs) is indicated by diffuse stromal reactivity of CD163 (brown) as previously described [41].

Figure 2

Role of TAMs in OS progression. Crosstalk between OS and stromal cells—via mechanisms such as activation of signaling pathways or exchange of extracellular vesicles (EVs), makes the tumor microenvironment (TME) conducive for cancer growth. In this regard, OS cells, by releasing TGF-β or EVs-delivered, support the malignant phenotype of the MSCs that in turn secrete cytokines such as IL-6 and VEGF molecules involved in promoting angiogenesis and metastasis [133]. A heterogeneous population of TAMs, with both M1 and M2 phenotypes, infiltrates the OS tumor [4]. M2-like TAMs play a key role in tumor progression and metastasis [133]. In particular, M2-like TAMs, by releasing IL-1β, induce chemoresistance in primary OS cells [96]. In response to the inflammatory stimuli, OS cells over express IL-34 that induces M2-like TAM recruitment, vasculogenesis and OS growth [7]. M2 macrophages are also involved in the maintenance of the stem-like phenotype of CSCs [99]. However, the exact mechanism by which TAMs and CSCs communicate in OS remains to be fully investigated, together with the possibility of a bidirectional link between TAMs and MSCs, as observed in other tumor types [124,125]. High numbers of TAMs in the TME are associated with metastatic OS tissue and poor survival rates for OS patients [134]. TAMs support tumor invasiveness via the secretion of CCL18 [98], proinflammatory molecules such as COX2 that, in turn, activate the IL-6/STAT3 pathway in OS cells and MMP-9, increasing the metastatic potential of the tumor [5]. OS-derived EVs have been shown to increase the expression of M2-type markers such as TGFB2, IL-10 and CCL22 in lung OS metastasis [101]. In addition, it has also been reported that proliferative TAMs support cancer metastasis process [135].