Functional Relationship between Tumor-Associated Macrophages and Macrophage Colony-Stimulating Factor as Contributors to Cancer Progression - PubMed (original) (raw)

Review

Functional Relationship between Tumor-Associated Macrophages and Macrophage Colony-Stimulating Factor as Contributors to Cancer Progression

Damya Laoui et al. Front Immunol. 2014.

Abstract

The current review article describes the functional relationship between tumor-associated macrophages (TAM) as key cellular contributors to cancer malignancy on the one hand and macrophage-colony-stimulating factor (M-CSF or CSF-1) as an important molecular contributor on the other. We recapitulate the available data on expression of M-CSF and the M-CSF receptor (M-CSFR) in human tumor tissue as constituents of a stromal macrophage signature and on the limits of the predictive and prognostic value of plasma M-CSF levels. After providing an update on current insights into the nature of TAM heterogeneity at the level of M1/M2 phenotype and TAM subsets, we give an overview of experimental evidence, based on genetic, antibody-mediated, and pharmacological disruption of M-CSF/M-CSFR signaling, for the extent to which M-CSFR signaling can not only determine the TAM quantity, but can also contribute to shaping the phenotype and heterogeneity of TAM and other related tumor-infiltrating myeloid cells (TIM). Finally, we review the accumulating information on the - sometimes conflicting - effects blocking M-CSFR signaling may have on various aspects of cancer progression such as tumor growth, invasion, angiogenesis, metastasis, and resistance to therapy and we thereby discuss in how far these different effects actually reflect a contribution of TAM.

Keywords: CSF-1; CSF-1R; M-CSF; M-CSFR; M1; M2; cancer progression; tumor-associated macrophages.

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Figures

Figure 1

Figure 1

Scheme of the possible effects of TAM and of M-CSFR blockade on cancer progression. (A) Possible tumor-promoting effects of TAM. TAM can promote cancer progression and reduce the efficacy of radiotherapy, chemotherapy, immunotherapy, and anti-angiogenic therapy by a combination of different mechanisms. TAM can contribute to enhanced cancer cell numbers by (Aa) inhibiting anti-tumor immune responses and via (Ab) stimulation/maintenance of cancer cell proliferation. TAM can also exert pro-angiogenic activities by enhancing (Ac) angiogenic switching and (Ad) endothelial cell proliferation. Finally, TAM can contribute to cancer malignancy by facilitating (Ae) cancer cell invasion and (Af) seeding, extravasation, survival, and subsequent proliferation of cancer cells at metastatic sites. (B) Possible effects of M-CSFR signaling blockade on cancer progression. Depending on the tumor type/model and the blocking agents used to impede M-CSFR signaling, M-CSFR blockade has in most cases been reported to attenuate cancer progression and/or synergistically enhance the effect of chemo-, radio-, and/or immunotherapy via various effects, including (Ba) promotion of tumor-infiltrating lymphocytes (TIL) recruitment and/or activation, (Bb) enhanced phagocytosis/killing of cancer cells, (Bc) a delayed angiogenic switch, (Bd) reduced density of proliferating endothelial cells, (Be) inhibition of both TAM and cancer cell migration and invasion, (Bf) reduced metastasis. In some cases, (Bg) reduction of tumor weight and primary tumor growth has been reported. A number of studies have attributed these effects to (i) ablation of TAM numbers and/or (ii) phenotypic reprograming of TAM from tumor promoting (often M2-like) TAM to anti-tumor (often M1-like) TAM.

Figure 2

Figure 2

Examples of various types of M-CSFR signaling blocking agents mentioned throughout this manuscript. In some studies, neutralizing anti-mouse M-CSF mAb has been used for blocking M-CSF/M-CSFR signaling (66). One study also reported on the use of a murinized, polyethylene glycol-linked recombinant Fab fragment of the MCSF1-033 neutralizing rabbit anti-mouse M-CSF antibody (99). Yet, blocking mAbs targeting the extracellular domains of the M-CSFR have more frequently been documented for blocking the M-CSF/M-CSFR signaling axis. Typical examples of the latter that have been used in mouse tumor models are the rat IgG1 M279 (100) and the rat IgG2A AFS98 (101, 102). A recent report documented the generation of RG7155, a humanized anti-human M-CSFR IgG1 mAb that inhibits M-CSFR activation (106). And also the fully human IgG1 anti-human M-CSFR mAb IMC-CS4 is currently in clinical trials (107). M-CSFR signaling has also been inhibited via pharmacological, small molecule inhibitors targeting the intracellular catalytic domains of the receptor involved in signal transduction. A number of these tyrosine kinase inhibitors, such as CYC11645, Ki20227, GW2580, or BLZ945, have been screened for highly selective inhibition of M-CSFR signaling, very potent IC50 values for M-CSFR and at least a 100-fold lower inhibitory activity for other tested receptor tyrosine kinases (, –110). Also the PLX3397 tyrosine kinase inhibitor has been used, which has higher M-CSFR inhibitory activity as compared to GW2580, but which is less specific since it inhibits the c-Kit receptor tyrosine kinase with similar potency as the M-CSFR tyrosine kinase (105). In one study, the actual contribution of M-CSFR blockade in the effect of PLX3397 has been assessed by comparing it with the specific cKit tyrosine kinase inhibitor imatinib and PLX5622, an M-CSFR-specific inhibitor of equal potency to PLX3397 that does not appreciably inhibit Kit (111).

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