Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.

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Macrophage plasticity and polarization: in vivo veritas

Macrophage Diversity Enhances Tumor Progression and Metastasis

Evidence from clinical and experimental studies indicates that macrophages promote solid-tumour progression and metastasis. Macrophages are educated by the tumour microenvironment, so that they adopt a trophic role that facilitates angiogenesis, matrix breakdown and tumour-cell motility — all of which are elements of the metastatic process. During an inflammatory response, macrophages also produce many compounds — ranging from mutagenic oxygen and nitrogen radicals to angiogenic factors — that can contribute to cancer initiation and promotion. Macrophages therefore represent an important drug target for cancer prevention and cure.

Tumour-educated macrophages promote tumour progression and metastasis

Tumor-associated macrophages: from mechanisms to therapy.

Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes. (Cancer Res 2006; 66(2): 605-12)

https://cancerres.aacrjournals.org/content/canres/66/2/605.full.pdf

Distinct Role of Macrophages in Different Tumor Microenvironments

Background Endomyocardial biopsy (EMB) is the “gold standard” in cardiac allograft acute cellular rejection (ACR) diagnosis, but it is invasive. ACR prediction at organ harvest could reduce EMB frequency in low-risk recipients. ACR is reportedly associated with apoptosis and Apollon inhibits apoptosis and promotes cell survival. It is unknown whether donor myocardial tissue Apollon mRNA could predict ACR. Methods Left ventricular biopsies (LVBs) were obtained from 336 donors before and after aortic cross-clamping (ACC) and at 10, 30 and 60 minutes of reperfusion in recipients. Tissue Apollon messenger RNA (mRNA) expression was examined by real-time reverse transcript–polymerase chain reaction (RT-PCR) and correlated with ACR episodes. Results Apollon LVB expression was significantly decreased before and after ACC in donors and at 10 minutes of reperfusion (p ≤ 0.0233) in recipients who developed Grade 2R and 3R ACR as compared with those with Grade 1R or no ACR. In addition, Apollon myocardial expression was significantly decreased at 10 minutes of reperfusion in patients who developed Grade 3R ACR compared with all other ACR grades (p ≤ 0.0425). In receiver-operating characteristic curve analysis, at a cut-off level of 75.66 arbitrary units, Apollon mRNA before ACC in donors identified combined Grade 2R and 3R ACR with a sensitivity of 94% and a specificity of 96% (p Conclusions Apollon is a sensitive and specific predictor of ACR in donated cardiac allografts and may have important implications in the choice of surveillance.

Donor myocardial apollon mRNA is associated with cardiac allograft rejection.

Blockade of host CD147 by small interfering RNAs suppresses growth of human colon cancer xenografts

Purpose: Shock waves were shown to induce angiogenesis in ischemic myocardium in rodent models. In the present experiments we aimed to address safety and efficacy of direct epicardial shock wave therapy in a preclinical large animal model and to further evaluate mechanism of action of this novel therapy.

Methods: Four weeks after left anterior descending (LAD) artery ligation in pigs, animals underwent re-thoracotomy with (SW group, n=6) or without (CTR, n=5) direct epicardial shock waves (300 impulses at 0.38mJ/mm2) applied to the infarcted anterior wall. Efficacy endpoints were improvement of LVEF and induction of angiogenesis 6 weeks after shock wave therapy. Safety endpoints were hemodynamic stability during treatment and myocardial damage.

A receptor tyrosine kinase profiler was performed in human coronary artery endothelial cells to proof receptor activation.

Results: Four weeks after LAD ligation, LVEF decreased in both shock wave (43±3%, p<0.001) and control (41±4%, p=0.012) group. LVEF markedly improved in shock wave animals 6 weeks after treatment (62±9%, p=0.006), no improvement was observed in controls (41±4%, p=0.36). Quantitative histology revealed significant angiogenesis six weeks after treatment as shown by number of arterioles (CTR 2±0.4 arterioles/high power field vs. SW 9±3, p=0.004), number of capillaries (CTR 9±4 vs. SWT 53±12, p<0.001) and number of vital cells (CTR 212±32 vs. SWT 310±48, p=0.003). No acute or chronic adverse effects were observed. In-vitro experiments revealed a two- and four-fold increase in VEGF receptor 1 and 2 phosphorylation in human coronary artery endothelial cells.

Conclusions: Direct epicardial shock wave treatment in a large animal model of ischemic heart failure exerted positive effect on LVEF improvement and did not show any adverse effects. Angiogenesis was induced by stimulation of VEGF receptors. It may serve in future as an adjunct to CABG surgery.

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Direct epicardial shock wave therapy improves ventricular function in a porcine model of ischemic heart disease: evidence for induction of angiogenesis and stimulation of VEGF receptors

Abstract 4015: Abnormal Regulation of Tumor Necrosis Factor-{alpha} Receptor-associated Factor 2 and Downstream P38 Mitogen-activated Protein Kinase by Glutathione S-transferase P1-1 in Dilated Cardiomyopathy Patients

Seyedhossein Aharinejad

Papers

Donor myocardial apollon mRNA is associated with cardiac allograft rejection.

Blockade of host CD147 by small interfering RNAs suppresses growth of human colon cancer xenografts

Direct epicardial shock wave therapy improves ventricular function in a porcine model of ischemic heart disease: evidence for induction of angiogenesis and stimulation of VEGF receptors

Abstract 4015: Abnormal Regulation of Tumor Necrosis Factor-{alpha} Receptor-associated Factor 2 and Downstream P38 Mitogen-activated Protein Kinase by Glutathione S-transferase P1-1 in Dilated Cardiomyopathy Patients

Error estimation of geometrical data obtained by histomorphometry of oblique vessel sections: a computer model study