Role of tumor-associated macrophages in tumor progression and invasion Alberto Mantovani & Tiziana Schioppa & Chiara Porta & Paola Allavena & Antonio Sica Published online: 12 September 2006 # Springer Science + Business Media, LLC 2006 Abstract Tumor-Associated Macrophages (TAM) repre- sent the major inflammatory component of the stroma of many tumors, able to affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated protumoral functions, in- cluding promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The protumoral role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumors and poor patient prognosis and by evidence showing that long-term use of non-steroidal anti-inflamma- tory drugs reduces the risk of several cancers. Here, we discuss evidence supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and a potential target of anti-cancer therapy. Keywords Tumor-associated macrophages . Tumor . Inflammation . NF-κB . Metastasis . Hypoxia 1 Introduction Epidemiological studies have revealed that chronic inflam- mation predisposes to different forms of cancer and that usage of non-steroidal anti-inflammatory agents is associ- ated with protection against various tumors. An inflamma- tory component is present in the microenvironment of most neoplastic tissues, including those not causally related to an obvious inflammatory process. Hallmarks of cancer-associ- ated inflammation include: the infiltration of white blood cells; the presence of polypeptide messengers of inflamma- tion (cytokines and chemokines); the occurrence of tissue remodeling and angiogenesis. Already in the late 1970s it was found that a major leukocyte population present in tumors, the so-called tumor-associated macrophages (TAM), promote tumor growth [1, 2]. Accordingly, in many but not all human tumors, a high frequency of infiltrating TAM is associated to poor prognosis. Interestingly, this pathological finding has re-emerged in the post-genomic era: genes associated to leukocyte or macrophage infiltration (e.g., CD68) are part of molecular signatures which herald poor prognosis in lymphomas and breast carcinoma [3]. Gene modified mice, including some with cell-specific targeted gene inactivation, allowed dissection of molecular pathways of inflammation leading to tumor promotion, as well as the initial analysis of the role of distinct elements of the inflammatory process in different steps of tumor pro- gression. TNF, IL-1, the macrophage growth and attractant factor CSF-1, CCL2, a chemokine originally described as a tumor-derived macrophage attractant, the prostaglandin producing enzyme cyclooxygenase 2, the master inflam- matory transcription factor NF-κB, enzymes involved in tissue remodeling, all are essential elements for carcino- genesis and/or for acquisition of a metastatic phenotype in diverse organs including skin, liver, mammary gland, intestine [4–9]. Here we will review available information on the role of myelomonocytic cells, tumor-associated macrophages (TAM) in particular, in tumor invasion and metastasis (Fig. 1). Cancer Metastasis Rev (2006) 25:315–322 DOI 10.1007/s10555-006-9001-7 A. Mantovani (*) : C. Porta : P. Allavena : A. Sica Istituto Clinico Humanitas, 20089 Rozzano, Milan, Italy e-mail: alberto.mantovani@humanitas.it A. Mantovani Centro di Eccellenza per l’Innovazione Diagnostica e Terapeutica, Institute of Pathology, State University of Milan, 20133 Milan, Italy T. Schioppa Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy