Abstract
Tumor-Associated Macrophages (TAM) are key components of the reactive stroma of tumors. In most, although not all cancers, their presence is associated with poor patient prognosis. In addition to releasing cytokines and growth factors for tumor and endothelial cells, a distinguished feature of TAM is their high-rate degradation of the extra-cellular matrix. This incessant stroma remodelling favours the release of matrix-bound growth factors and promotes tumor cell motility and invasion. In addition, TAM produce matrix proteins, some of which are typical of the neoplastic tissues. The gene expression profile of TAM isolated from human tumors reveals a matrix-related signature with the up-regulation of genes coding for different matrix proteins, as well as several proteolytic enzymes. Among ECM components are: osteopontin, osteoactivin, collagens and fibronectin, including also a truncated isoform of fibronectin termed migration stimulation factor. In addition to serve as structural proteins, these matrix components have key functions in the regulation of the vessel network, in the inductionof tumor cell motility and degradation of cellular debris. Among proteolytic enzymes are: matrix metalloproteases, cathepsins, lysosomal and ADAM proteases, and the urokinase-type plasminogen activator. The degrading activity of TAM, coupled to the production of bio-active ECM proteins, co-operate to the build-up and maintenance of an inflammatory micro-environment which eventually promotes tumor progression.
Highlights
Mononuclear phagocytes are essential cells for wound healing and tumors can be described as wounds that never heal [1]
Among the well documented pro-tumor functions of Tumor-Associated Macrophages (TAM) is the production of many growth factors for tumor cells and for the nascent blood and lymphatic vessels, which are essential for the neo-angiogenesis switch and tumor proliferation
Among the classical extracellular matrix (ECM) proteins that we found up-regulated in TAM and in tumor-conditioned macrophages was fibronectin [98]
Summary
Mononuclear phagocytes are essential cells for wound healing and tumors can be described as wounds that never heal [1]. The ECM contains a wide range of growth factors that are bound in an inactive form to matricellular proteins, but can be rapidly released and activated in case of need, for example during tissue repair [5,6,7] Neoplastic cells modify their stroma and vasculature through production and secretion of different growth factors and cytokines. ECM degradation has several important consequences: altered stiffness and composition of the ECM; fragmentation of basement membranes, which facilitates the motility and invasive ability of tumor cells; deregulated organization of the vessel network All these processes, initially guided by tumor cells and gradually involving the contribution of host cells, lead to the construction of a reactive stroma where the cross-talk and signalling between the diverse cell types and ECM proteins is outside the normal control. We will review the role of tumor macrophages in neoplastic tissues, in particular their important contribution to the continuous remodelling of the tumor stroma
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