The role of tumor-associated macrophages and soluble mediators in pulmonary metastatic melanoma

Abstract

Skin malignant melanoma is a highly aggressive skin tumor, which is also a major cause of skin cancer-related mortality. It can spread from a relatively small primary tumor and metastasize to multiple locations, including lymph nodes, lungs, liver, bone, and brain. What's more metastatic melanoma is the main cause of its high mortality. Among all organs, the lung is one of the most common distant metastatic sites of melanoma, and the mortality rate of melanoma lung metastasis is also very high. Elucidating the mechanisms involved in the pulmonary metastasis of cutaneous melanoma will not only help to provide possible explanations for its etiology and progression but may also help to provide potential new therapeutic targets for its treatment. Increasing evidence suggests that tumor-associated macrophages (TAMs) play an important regulatory role in the migration and metastasis of various malignant tumors. Tumor-targeted therapy, targeting tumor-associated macrophages is thus attracting attention, particularly for advanced tumors and metastatic tumors. However, the relevant role of tumor-associated macrophages in cutaneous melanoma lung metastasis is still unclear. This review will present an overview of the origin, classification, polarization, recruitment, regulation and targeting treatment of tumor-associated macrophages, as well as the soluble mediators involved in these processes and a summary of their possible role in lung metastasis from cutaneous malignant melanoma. This review particularly aims to provide insight into mechanisms and potential therapeutic targets to readers, interested in pulmonary metastasis melanoma.

Keywords: melanoma; pulmonary metastatic melanoma; soluble mediators; targeted therapy; tumor-associated macrophages (TAMs).

Figure 1

The source, function, classification, and recruitment of TAMs. The picture displayed that TAMs are derived from blood mononuclear cells from bone marrow hematopoietic stem cells, called monocyte-derived TAMs (or tumor-induced TAMs) and yolk sac progenitors, and reside in organs such as the lung, brain, liver, and skin. Macrophages polarized in tumors are divided into M1 (classically activated macrophages) and M2 (alternatively activated macrophages), and M2 macrophages can be further divided into Ma, Mb, Mc, and Md subtypes. M1 macrophages are characterized by the secretion of pro-inflammatory cytokines involved in anti-infective responses, and the immunosuppressive phenotype of M2 macrophages tends toward tissue repair and tumor progression; TAMs are activated by cytokines, growth factors, etc. can be recruited to tumor sites.

Figure 2

TAMs are involved tumor metastasis. The picture illustrated that TAMs are involved in every step of the metastatic cascade, including the formation of pre-metastatic ecological sites, invasion of tumor cells, survival of circulating tumor cells, extravasation and colonization of tumor cells, and the involvement of TAMs in regulating the epithelial-mesenchymal transition (EMT) process that promotes the formation of liver, brain, lung, bone and lymph node metastases.

Figure 3

TAMs regulation This picture demonstrates that the production, phenotype and function of TAMs are regulated in epigenetic, transcriptional, metabolic or other different ways. These modulations influence tumorigenesis, metastasis and drug resistance on Pulmonary metastases in melanoma can also be influenced by the regulation of TAMs.

Figure 4

TAMs targeted treatment strategies The picture showed that inhibition of recruitment or proliferation of TAMs, depletion of TAMs, reprogramming of TAMs and targeting of TAMs-associated immune checkpoints are all capable of targeting TAMs for effective anti-tumor therapy. These strategies can likewise be referred to for targeting TAMs for the treatment of pulmonary metastatic melanoma.