Targeting tumor-associated macrophages as a novel strategy against breast cancer

Abstract

Tumor-associated macrophages (TAMs) are associated with tumor progression and metastasis. Here, we demonstrate for the first time that legumain, a member of the asparaginyl endopeptidase family functioning as a stress protein, overexpressed by TAMs, provides an ideal target molecule. In fact, a legumain-based DNA vaccine served as a tool to prove this point, as it induced a robust CD8 + T cell response against TAMs, which dramatically reduced their density in tumor tissues and resulted in a marked decrease in proangiogenic factors released by TAMs such as TGF-b, TNF-a, MMP-9, and VEGF. This, in turn, led to a suppression of both tumor angiogenesis and tumor growth and metastasis. Importantly, the success of this strategy was demonstrated in murine models of metastatic breast, colon, and non-small cell lung cancers, where 75% of vaccinated mice survived lethal tumor cell challenges and 62% were completely free of metastases. In conclusion, decreasing the number of TAMs in the tumor stroma effectively altered the tumor microenvironment involved in tumor angiogenesis and progression to markedly suppress tumor growth and metastasis. Gaining better insights into the mechanisms required for an effective intervention in tumor growth and metastasis may ultimately lead to new therapeutic targets and better anticancer strategies. IntroductionA novel antitumor strategy is immunization against molecules overexpressed by tumor-associated macrophages (TAMs) and thereby remodel the tumor microenvironment that attracts these macrophages and mediates their function (1, 2). TAMs consist primarily of a polarized M2 (F4/80 + /CD206 + ) macrophage population with little cytotoxicity for tumor cells because of their limited production of NO and proinflammatory cytokines (3). TAMs also possess poor antigen-presenting capability and effectively suppress T cell activation. In fact, these macrophages of M2 phenotype actually promote tumor cell proliferation and metastasis by secreting a wide range of growth and proangiogenic factors as well as metalloproteinases and by their involvement in signaling circuits that regulate the function of fibroblasts in the tumor stroma (4). In recent studies, anti-TAM effects induced by small molecule inhibitors contributed to tumor suppression (5, 6). For example, the antineoplastic agent Yondelis has a selective cytotoxic effect on TAMs, thereby significantly reducing their production of IL-6 and CCL2, which, in turn, contribute to growth suppression of inflammation-associated human tumors (7). Another such example is provided by a biphosphonate compound, zoledronic acid, that suppresses MMP-9 secretion by TAMs, thereby inhibiting tumor metalloproteinase activity and diminishing the association of VEGF with its tyrosine kinase receptors on proliferating endothelial cells (8). In a different experimental model, the chemokine CCL5 was shown to be key in the recruitment of TAMs, and an antagonist of this chemokine reduced the tumor infiltrate and slowed tumor growth (9). Hence, although the therapeutic ta...

Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival

“…KLA fusion peptides with a targeting sequence have been used previously to kill tumor cells selectively (21,22). Because TAMs facilitate immune evasion of cancer, many have hypothesized that their selective ablation can assist anticancer therapy (23)(24)(25). We synthesized M2pepKLA and scM2pepKLA fusion peptides to test if these constructs can mediate selective ablation of TAMs and delay tumor growth in mice.…”

Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development

“…Lin and colleagues showed that decreasing macrophage infi ltration in tumors resulted in the inhibition of tumor angiogenesis & and delayed tumor development (Lin and Pollard, 2007). Further studies have found that TAMs express a broad range of pro-angiogenic factors that positively regulate angiogenesis, including vascular endothelial growth factor (VEGF) (Bolat et al, 2006), basic fi broblast growth factors (bFGF) (Bolat et al, 2006), tumor necrosis factor (TNF-α), and transforming growth factor-β (TGF-β) (Luo et al, 2006). These TAM-secreted factors explain the role of TAMs in tumor development.…”

Working hypothesis to redefine endothelial progenitor cells

“…19 It now appears that aside from angiogenesis and arteriogenesis, circulatory system remodeling in the adult may indeed involve the recruitment of not only endothelial progenitors but also a plurality of cells in an intricate collaboration. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Sprouted endothelium may line the vessel lumen while other cells support vessel formation through secretion of cytokines and modification of the extracellular space. [40][41][42][43][44][45] Although each cell type appears to be fundamentally different, all cell types involved in postnatal vasculogenesis have been lumped into the single term 'EPC'.…”