Targeting Macrophage-Recruiting Chemokines as a Novel Therapeutic Strategy to Prevent the Progression of Solid Tumors

Abstract

Solid tumors are initiated by genetic mutations in non-hematopoietic cells and progress into invasive malignant tumors. This tumor progression often culminates in metastatic disease that is largely refractory to current therapeutic modalities and thus dramatically reduces survival of tumor patients. As solid tumors account for more than 80% of cancer-related deaths, it is necessary to develop novel therapeutic strategies to treat the diseases. An attractive strategy is to target macrophages in both primary tumors [known as tumor-associated macrophages (TAMs)] and metastatic tumors [called metastasis-associated macrophages (MAMs)]. TAMs and MAMs are abundant in most solid tumors and can promote tumor metastasis. Several studies in various models of solid tumors suggest that the accumulation of TAMs, MAMs, and their progenitor cells is regulated by chemokine ligands released by tumor and stromal cells. Consequently, these macrophage-recruiting chemokines could be potential therapeutic targets to prevent malignant tumor development through disruption of the accumulation of pro-metastatic macrophages. This review will discuss the role of chemokine ligands and their receptors in TAM and MAM accumulation in primary and secondary tumor sites, and finally discuss the therapeutic potential of inhibitors against these macrophage-recruiting chemokines.

Targeted Delivery of siRNA Lipoplexes to Cancer Cells Using Macrophage Transient Horizontal Gene Transfer

“…It could also be a unique future strategy for drug delivery to metastatic sites, as inflamed monocytes and macrophages form premetastatic niche in the metastatic process. [46] Our study found that M2 macrophages were better at transferring siRNA to cancer cells, due to the role macrophage activation plays a significant role in siRNA uptake and release.…”

“…Monocytes/macrophages present a competitive advantage for delivery into the tumor environment because of the high recruitment and proliferation that occurs during tumorigenesis. [2,46,47] Furthermore, monocyte based cell therapies already exist in other disease contexts and have shown some efficacy. [58,59] Immunogenicity must be considered; however it is likely to be similar to other types of autologous cell therapies.…”

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

“…Strong evidence indicates that the accumulation of macrophages in tumors is due to the continuous recruitment of monocytes from the circulation in response to tumor-derived factors (TDFs). These TDFs are key mediators in the crosstalk between monocytes and tumor cells and include colony-stimulating factor-1 (CSF-1), several C−C chemokine ligands, such as CCL2, also known as MCP-1 and VEGF [75,76]. CCL2 has been described as the major TDF involved in monocyte recruitment, through the CCL2-CCR2 axis.…”

A Fluorescent Activatable AND‐Gate Chemokine CCL2 Enables In Vivo Detection of Metastasis‐Associated Macrophages

“…In this model, metastasis‐associated macrophages (MAMs) and their progenitor cells (MAMPCs) accumulate in the metastatic lungs via CCL2‐CCR2 signaling . Since the accumulation of MAMs and MAMPCs promotes metastasis, these cells are regarded as attractive targets in anticancer therapy . Animals injected with E0771‐LG cancer cells formed metastatic tumours in their lungs after 2 weeks, as confirmed by whole‐body bioluminescence imaging (Figure S8).…”