Macrophage polarization in tumour progression

Sica, Antonio; Larghi, Paola; Mancino, Alessandra; Rubino, Luca; Porta, Chiara; Totaro, Maria Grazia; Rimoldi, Monica; Biswas, Subhra K.; Allavena, Paola; Mantovani, Alberto

doi:10.1016/j.semcancer.2008.03.004

Cited by 1,084 publications

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“…Clinical and experimental evidence has highlighted that a major leukocyte population present in tumors, the so-called tumorassociated macrophages (TAM), is the principal component of the leukocyte infiltrate supporting tumor growth [1]. As macrophages represent a primary line of the innate or front-line defense mechanisms, this evidence has also underlined the ''immune paradox'' represented by TAM [2]. Over the past years, the mechanisms supporting the pro-tumoral functions of TAM have been increasingly clarified and in several experimental tumor models, the activation of an inflammatory response (most frequently mediated by macrophages) has been shown to play an essential role for full neoplastic transformation and progression.…”

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confidence: 99%

“…Indeed, previous studies demonstrated in preclinical cancer models that inhibition of IL-10 activity in combination with TLR agonists (e.g. CpG) switched infiltrating macrophages from M2 to M1 and triggered innate immune response, debulking large tumors [2]. This emerging paradigm suggests that inhibition of mechanisms and molecules mediating M2-type macrophages and/or Th2-type CD4 1 T-cell responses or activation of mechanisms fostering M1-type inflammation and/or Th1-type immunity is a promising therapeutic strategy against cancer.…”

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Convergent pathways of macrophage polarization: The role of B cells

et al. 2010

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The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote infiltration of leukocyte populations, among which tumor-associated macrophages (TAM) represent a paradigm for cancer-promoting inflammation. TAM orchestrate various aspects of cancer, including diversion and skewing of adaptive responses, cell growth, angiogenesis, matrix deposition and remodelling, the construction of a metastatic niche and actual metastasis, response to hormones and chemotherapeutic agents. Several lines of evidence indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, suggesting that during tumor progression macrophages undergo a phenotypic ''switch'', eventually exhibiting the alternatively activated, ''M2'', phenotype that is associated with immunosuppression, promotion of tumor angiogenesis and metastasis. Although recent studies have attempted to address the role of microenvironmental signals on TAM ''reprogramming'', the interplay between innate and adaptive immunity is emerging as a crucial step of this event. In this issue of the European Journal of Immunology, a study demonstrates that B1 lymphocytes expressing IL-10 play a key role in promoting a pro-tumoral M2-biased phenotype of macrophages. This article defines a new in vivo pathway of macrophage polarization and suggests that targeting B cells is a possible therapeutic intervention to reinstate anticancer functions by TAM. Clinical and experimental evidence has highlighted that a major leukocyte population present in tumors, the so-called tumorassociated macrophages (TAM), is the principal component of the leukocyte infiltrate supporting tumor growth [1]. As macrophages represent a primary line of the innate or front-line defense mechanisms, this evidence has also underlined the ''immune paradox'' represented by TAM [2]. Over the past years, the mechanisms supporting the pro-tumoral functions of TAM have been increasingly clarified and in several experimental tumor models, the activation of an inflammatory response (most frequently mediated by macrophages) has been shown to play an essential role for full neoplastic transformation and progression. Recent reports have established that the acquisition of protumoral M2 functions by TAM is driven by various cytokines and signals expressed within the tumor microenvironment [3]. Among these, IL-10, PGE2, TGF-b and CSF-1 were reported to induce the M2-polarization of macrophages [3][4][5]. Based on the In a model of mammary carcinoma, myeloid-derived suppressor cells were shown to contribute to tumor progression by suppressing T-cell activation and inducing an M2-like phenotype of TAM, (increased IL-10 and decreased IL-12 production) [10].The role of B cells in solid tumor development is well characterized, for example B-cell-deficient mice (mMT) exhibited resistance to several type of syngeneic tumors, including EL4 lymphoma, MC38 colon carcinoma and B16 or D5 melanoma [9]. A first original report on B cells and can...

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Convergent pathways of macrophage polarization: The role of B cells

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“…The exact reasons underlying this change in phenotype remain to be determined. In any case, the shift towards AAM in Ccr5 À/À mice may not only play an important and previously unappreciated role in the attenuation of chronic renal allograft rejection, but may also apply to other chronic inflammatory diseases and may even be relevant for tumor biology, since tumor-associated macrophages resemble AAM in many aspects [45]. The finding that Ccr5 deficiency profoundly affects the functional phenotype of macrophages does not only provide important novel insights into the role of chemokine receptors for the activation of leukocyte subpopulations, but may also be helpful for the development of new therapeutic strategies trying to target this important chemokine receptor.…”

Section: Discussionmentioning

confidence: 99%

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

et al. 2009

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The chemokine (C-C motif) receptor 5 (CCR5) has been implicated in experimental and clinical allograft rejection. To dissect the function of CCR5 in acute and chronic renal allograft rejection, bilaterally nephrectomized WT and Ccr5 À/À C57BL/6 mice were used as recipients of WT BALB/c renal allografts and analyzed 7 and 42 days after transplantation. Lesion scores (glomerular damage, vascular rejection, tubulointerstitial inflammation) and numbers of CD4 1 , CD8 1 , CD11c 1 and alpha smooth muscle actin (aSMA) 1 cells were reduced in allografts from Ccr5 À/À recipients during the chronic phase. Increasing creatinine levels indicated deterioration of allograft function over time. While mRNA expression of Th1-associated markers decreased between 7 and 42 days, Th2-associated markers increased. Markers for alternatively activated macrophages (arginase 1, chitinase 3-like 3, resistin-like a, mannose receptor, C type 1), were strongly upregulated (mRNA and/or protein level) only in allografts from Ccr5 À/À recipients at 42 days. Ccr5 deficiency shifted intragraft immune responses during the chronic phase towards the Th2 type and led to accumulation of alternatively activated macrophages. Additionally, splenocytes from unchallenged Ccr5 À/À mice showed significantly increased arginase 1 and mannose receptor 1 mRNA levels, suggesting constitutive alternative activation of splenic macrophages. We conclude that Ccr5 deficiency favors alternative macrophage activation. This finding may be relevant for other inflammatory diseases that involve macrophage activation and may also influence future therapeutic strategies targeting CCR5.

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“…According to their polarization status, tissue macrophages were originally categorized on a linear scale from pro-inflammatory M1-macrophages (classically activated) to anti-inflammatory M2-macrophages (alternatively activated) as the two extreme ends of the scale [45][46][47]. Although still commonly used, and useful for conceptual understanding, the applicability of the M1/M2-classification is limited due to its oversimplification of the functional diversity of macrophages [6,45].…”

Section: Development and Functions Of Macrophagesmentioning

confidence: 99%

“…In more established tumors, TAMs produce factors that contribute to tumor growth, angiogenesis, immune suppression, and tissue remodeling. In addition, TAMs can promote metastatic spread of cancer cells [26,47,64,65]. In this review, we will focus on new insights in the pro-tumor functions of TAMs and describe how understanding these functions can benefit anti-tumor therapy.…”

Section: Functions Of Tumor-associated Macrophagesmentioning

confidence: 99%

Monocytes and Macrophages in Cancer: Development and Functions

Richards

Hettinger

Feuerer

2012

Cancer Microenvironment

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Monocytes and tumor-associated macrophages are part of the myeloid family, a group of hematopoietic derived cells. Monocytes are direct precursors of hematopoietic stem cell-derived macrophages. After their recruitment into the tumor tissue, they can differentiate into tumor-associated macrophages, a very heterogeneous cell population in terms of phenotype and pro-tumor function, supporting tumor initiation, local progression and distant metastasis. Therefore, targeting monocytes and macrophages is a promising immunotherapeutic approach. This review will focus on the development of monocytes as macrophage precursors, the functions of tumorassociated macrophages and the possibility of interfering with tumor development and progression by targeting these myeloid cells.

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Macrophage polarization in tumour progression

Cited by 1,084 publications

References 71 publications

Convergent pathways of macrophage polarization: The role of B cells

Convergent pathways of macrophage polarization: The role of B cells

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

Monocytes and Macrophages in Cancer: Development and Functions

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