To investigate the role of macrophages in tumor progression under sorafenib treatment and to explore whether combination of drugs that deplete macrophages improved the antitumor effect of sorafenib.
Tumor growth, lung metastasis, and tumor angiogenesis were observed in HCCLM3-R and SMMC7721, two human hepatocellular carcinoma xenograft nude mouse models, when treated with sorafenib (30 mg/kg daily, n = 6 per group) or a vehicle as control. Macrophage infiltration was measured in the peripheral blood and in sorafenib-treated tumor by immunohistochemistry and flow cytometry with F4/80 antibody and CD11b antibody. The effect of macrophage depletion on tumor angiogenesis and metastasis after sorafenib treatment, using two drug target macrophages, zoledronic acid (ZA) and clodrolip, was measured in the two models of hepatocellular carcinoma.
Although sorafenib significantly inhibited tumor growth and lung metastasis, it induced a significant increase in peripheral recruitment and intratumoral infiltration of F4/80- and CD11b-positive cells, which was accompanied with elevation of colony-stimulating factor-1, stromal-derived factor 1alpha, and vascular endothelial growth factor in the tumor and elevation of plasma colony-stimulating factor-1 and mouse vascular endothelial growth factor in peripheral blood, suggesting the role of macrophages in tumor progression under sorafenib treatment. Depletion of macrophages by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis, and lung metastasis compared with mice treated with sorafenib alone. ZA was more effective than clodrolip.
Macrophages may have an important role in tumor progression under sorafenib treatment. ZA is promising when combined with sorafenib to enhance its antitumor effect.
"It has been shown that TAM depletion reprograms the immunosuppressive tumor microenvironment and creates an antitumor immune microenvironment in breast cancer and liver cancer.23,32 TAMs may be a therapeutic target in other tumors, such as prostate cancer, renal cell carcinoma, and osteosarcoma.31,33,34 "
[Show abstract][Hide abstract] ABSTRACT: Tumor-associated macrophages play an important role in tumor growth and progression. These macrophages are heterogeneous with diverse functions, eg, M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth. In this study, we found that IFNγ and/or celecoxib (cyclooxygenase-2 inhibitor) treatment consistently inhibited tumor growth in a mouse lung cancer model. IFNγ alone and celecoxib alone increased the percentage of M1 macrophages but decreased the percentage of M2 macrophages in the tumors, and thus the M2/M1 macrophage ratio was reduced to 1.1 and 1.7 by IFNγ alone and celecoxib alone, respectively, compared to the M2/M1 macrophage ratio of 4.4 in the control group. A combination of IFNγ and celecoxib treatment reduced the M2/M1 macrophage ratio to 0.8. Furthermore, IFNγ and/or celecoxib treatment decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, as well as the density of microvessels in the tumors, compared to the control group. This study provides the proof of principle that IFNγ and/or celecoxib treatment may inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio in the tumor microenvironment, suggesting that IFNγ and celecoxib have potential to be further optimized into a new anticancer therapy.
Drug Design, Development and Therapy 09/2014; 8:1527-38. DOI:10.2147/DDDT.S66302 · 3.03 Impact Factor
"Until now, liposome-encapsulated Clodronate has documented its efficacy in vitro and in preclinical investigations for the transient suppression of macrophage functions , . However, liposome technology shows some limitations linked to industrial applicability  and toxic effects in mice , . Thus, a safe delivery system to selectively target bisphosphonates to macrophages is still needed and an alternative approach could be represented by the use of autologous engineered RBCs. "
[Show abstract][Hide abstract] ABSTRACT: Bisphosphonates, besides being important drugs for the treatment of various bone diseases, could also be used to induce apoptosis in macrophage-like and cancer cells. However, their activity in vivo is limited by a short plasma half-life and rapid uptake within bone. Therefore, several delivery systems have been proposed to modify their pharmacokinetic profile and biodistribution. Among these, red blood cells (RBCs) represent one of the most promising biological carriers. The aim of this study was to select the best performing compound among Clodronate, Pamidronate, Ibandronate and Zoledronate in killing macrophages and to investigate RBCs as innovative carrier system to selectively target bisphosphonates to macrophages. To this end, the encapsulation of the selected bisphosphonates in autologous RBCs as well as the effect on macrophages, both in vitro and in vivo were studied. This work shows that, among the tested bisphosphonates, Zoledronate has proven to be the most active molecule. Human and murine RBCs have been successfully loaded with Zoledronate by a procedure of hypotonic dialysis and isotonic resealing, obtaining a dose-dependent drug entrapment with a maximal loading of 7.96±2.03, 6.95±3.9 and 7.0±1.89 µmoles of Zoledronate/ml of packed RBCs for human, Swiss and Balb/C murine RBCs, respectively. Engineered RBCs were able to detach human and murine macrophages in vitro, leading to a detachment of 66±8%, 67±8% and 60.5±3.5% for human, Swiss and Balb/C RBCs, respectively. The in vivo efficacy of loaded RBCs was tested in Balb/C mice administering 59 µg/mouse of RBC-encapsulated Zoledronate. By a single administration, depletion of 29.0±16.38% hepatic macrophages and of 67.84±5.48% spleen macrophages was obtained, confirming the ability of encapsulated Zoledronate to deplete macrophages in vivo. In conclusion, RBCs loaded with Zoledronate should be considered a suitable system for targeted delivery to macrophages, both in vitro and in vivo.
PLoS ONE 06/2014; 9(6):e101260. DOI:10.1371/journal.pone.0101260 · 3.23 Impact Factor
"The pro-angiogenic function of TAMs was also thoroughly investigated in animal cancer models. Accumulating evidences show that TAM depletion results in the decrease of tumor angiogenesis (31, 41), while TAM enhancement exhibits the opposing effect (42). For example, it has been shown that genetic depletion of macrophages in PyMT mammary tumor model delays the angiogenic switch, whereas restoring macrophage infiltration rescues the vessel phenotype (31). "
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis, the formation of new blood vessels, as well as inflammation with massive infiltration of leukocytes are hallmarks of various tumor entities. Various epidemiological, clinical, and experimental studies have not only demonstrated a link between chronic inflammation and cancer onset but also shown that immune cells from the bone marrow such as tumor-infiltrating macrophages significantly influence tumor progression. Tumor angiogenesis is critical for tumor development as tumors have to establish a blood supply in order to progress. Although tumor cells were first believed to fuel tumor angiogenesis, numerous studies have shown that the tumor microenvironment and infiltrating immune cell subsets are important for regulating the process of tumor angiogenesis. These infiltrates involve the adaptive immune system including several types of lymphocytes as well as cells of the innate immunity such as macrophages, neutrophils, eosinophils, mast cells, dendritic cells, and natural killer cells. Besides their known immune function, these cells are now recognized for their crucial role in regulating the formation and the remodeling of blood vessels in the tumor. In this review, we will discuss for each cell type the mechanisms that regulate the vascular phenotype and its impact on tumor growth and metastasis.
Frontiers in Oncology 04/2014; 4:69. DOI:10.3389/fonc.2014.00069
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