Levels of KLF4 can be manipulated by diverse agonists such as sta

Levels of KLF4 can be manipulated by diverse agonists such as statins, resveratrol, bortezomib and dietary compounds, so these factors could be influential for TAM re-education.[130] Although still learn more preliminary, the association among c-Myc, STAT6 and M2 polarization has been proposed by recent studies. As reported, c-Myc up-regulated IL-4-mediated STAT6 activation and elevated the expression of 45% of the genes correlated with alternative activation of macrophages.[131] In contrast, c-Myc inhibition blocked the expression of some pro-tumoral genes.[131] Other proteins and signalling pathways known

to promote M2-like properties of macrophages are also the potential targets for tumour therapy. They include peroxisome Aurora Kinase inhibitor proliferator-activated receptor (PPARs), HIFs, Ets family member 2 (Ets2), Decoy receptor

(DcR3) and mammalian target of rapamycin (mTOR). First, PPAR-γ can promote M2 type differentiation of human macrophages by acting as a transcriptional inhibitor of NF-κB.[132] PPAR-α plays a role in macrophages by antagonizing M1 polarization and supporting M2 polarization.[133] As synthetic inhibitors of PPAR-α/γ have now been identified, the evaluation of their role in TAM-targeted therapy is essential. Second, HIFs are a hopeful target because of their over-expression in TAMs residing in the hypoxic tumour microenvironment and their ability to induce the production of angiogenic factors, including VEGF, platelet-derived growth factor-β, NOS2, fibroblast growth factor 2, IL-8 and cyclooxygenase-2.[134] In fact, macrophage-targeted depletion of HIF-1α reduced tumour

growth in mice.[135] Therefore, it would be interesting to see whether blocking HIFs could slow or halt tumour recovery. Third, Ets2 is a direct effector of the M-CSF signalling pathway, and so facilitates the formation of M2 macrophage. Zabuawala et al.[136] demonstrated that an Ets2-driven transcriptional program in TAMs could promote Montelukast Sodium the angiogenesis and metastasis of murine breast cancer. Interestingly, an Ets2-TAM gene signature consisting of 133 genes retrospectively predicted overall survival of breast cancer patients.[136] Investigations of DcR3 and mTOR are also interesting.[137, 138] Several anti-tumour drugs that are able to suppress M2 macrophages will be introduced as follows. (i) Histidine-rich glycoprotein (HRG): HRG can skew TAMs to M1 type by down-regulation of PIGF, a member of the VEGF family, and can combat tumour malignancy by enhancing immunity and vessel normalization.[26] Macrophages are a direct target of HRG; and re-education of TAMs is essential for HRG-mediated anticancer effects.[26, 139] (ii) Copper chelate (CuNG): A novel CuNG was demonstrated to modulate the cytokine profile of TAMs isolated from chemotherapy-resistant or radiotherapy-resistant cancer patients.

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