Abstract
It is now well recognized that myeloid cells of the innate immunity infiltrating the tumor micro-environment, instead of halting tumor progression, favour the proliferation of tumor cells and their invasive ability. In particular, macrophages represent the most abundant leukocyte population recruited at tumor sites, from early stages till the occurrence of metastasis. Tumor-Associated Macrophages (TAMs) are crucial determinants of cancer cell survival and proliferation; they efficiently trigger neo-angiogenesis and matrix degradation and suppress potential anti-tumor adaptive immune responses. Established evidence demonstrated that high density of infiltrating TAMs is usually associated with fast tumor progression and resistance to anti-cancer therapies. Targeting of TAMs or modulation of their functions is now actively pursued. In this review we discuss recent knowledge and current therapeutic approaches behind TAMs. A better understanding of their features, heterogeneity in particular, and of their tumor-promoting functions is essential to better design TAM-centered therapeutic interventions. Understanding of how best to combine TAM-targeted approaches and conventional chemotherapy or immunotherapy, holds promise for successful anti-cancer treatments.
Highlights
Tumor tissues are composed by a heterogeneous mixture of normal and neoplastic cells, whose dynamic interactions are crucial elements for tumor progression
The importance of the CSF1-epidermal growth factor (EGF) pathway in transendothelial migration of cancer cells and metastasis formation has been recently confirmed by the use of CSF1R antagonists, which inhibited the migration of both cell types [72]
Other Tumor-Associated Macrophages (TAMs) mediators are involved in Extracellular matrix (ECM) remodelling and contribute to enhanced tumor cell invasion: osteonectin, enhances ECM-tumor cell interaction and migration [74]; cathepsin proteases, that degrade the matrix and release sequestered growth factors [2]; TGFβ, that promotes epithelial-to-mesenchymal transition in tumor cells [75]; chemokines, such as CCL18, that promotes invasiveness by activating tumor cell adherence to ECM [76]
Summary
Tumor tissues are composed by a heterogeneous mixture of normal and neoplastic cells, whose dynamic interactions are crucial elements for tumor progression. Recent studies revealed that host production of soluble factors like E-FABP or HRG can induce M1 polarization in macrophages, promoting antitumor immune responses (recruitment of CD8+ effector T cells and NK lymphocytes), vessel flow normalization, and reducing tumor growth and metastatic spread [41,42,43]. With tumor progression, the microenvironment enriches of growth factors and inflammatory mediators that cause a bias from a type 1-like inflammatory response to a type 2 phenotype [2, 3, 44,45,46] These changes strongly condition tumor macrophages and newly recruited monocytes, so that they switch to different functional programmes and generally acquire pro-tumoral functions. TAMs shape the type of the leukocyte infiltrate: by releasing chemokines (e.g., CCL17, CCL18, CCL22) that mostly recruit immune suppressive Treg or Th2 cells devoid of cytotoxic function, they facilitate mechanisms of tumor immune escape [51]
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