ABSTRACT INTERNATIONAL POST

Title of the Project: Role of TIE2-Expressing Macrophages in Tumor Angiogenesis and
Resistance to Antiangiogenic Therapy
Angiogenesis and Tumor Targeting Unit
Principal Investigator: Michele De Palma, PhD
Abstract
It is increasingly appreciated that tumor-associated macrophages (TAMs) support tumor growth
by diverse mechanisms, one of which is the promotion of angiogenesis. However, TAMs comprise
functionally distinct subpopulations or differentiation states. One particular TAM subset, the TIE2expressing macrophages (TEMs), has been shown by us and others to play an important role in
tumor angiogenesis. TEMs express the angiopoietin (ANG) receptor TIE2 along with a wide array
of macrophage markers. The specific elimination of TEMs in mouse tumor models inhibits tumor
angiogenesis, while the overall numbers of TIE2-negative TAMs and neutrophils recruited to the
tumors remain unchanged. These data suggest that TEMs are a major determinant of TAMs’
proangiogenic activity, and that such activity must be non-redundant. Furthermore, we and others
have shown that TEMs (i) express several proangiogenic factors other than VEGF; (ii) promote
VEGF-independent angiogenesis; (iii) mediate evasive resistance to antiangiogenic therapy. The
clinical relevance of these findings is supported by the identification of proangiogenic TEMs in
human tumors.
Collectively, the aforementioned data suggest that TEMs may play a pivotal role in the
promotion of tumor angiogenesis, both in untreated and treated tumors. We will study the
biological bases of TEMs’ proangiogenic activity, particularly by focusing on the role of the
ANG2/TIE2 signaling pathway in these cells. To this aim, we will either neutralize ANG2
pharmacologically or knock-down the TIE2 receptor specifically in TEMs by using a novel,
conditional gene knock-down lentiviral vector platform. We will also address the complexity and
heterogeneity of TAMs in tumors, by utilizing novel mouse models, generated in our laboratory,
that enable the visualization and genetic depletion of defined TAM subpopulations. Assessing the
specific contribution of TEMs and other TAM subpopulations to tumor angiogenesis may have
important implications for the design of improved anticancer therapies.
Selected publications
Coffelt S, Lewis CE, Naldini L, Brown JM, Ferrara N, De Palma M. Elusive identities and overlapping
phenotypes of proangiogenic myeloid cells in tumors.
Am J Pathol. 2010 Apr;176(4):1564-76.
Pucci F, Venneri MA, Biziato D, Nonis A, Moi D, Sica A, Di Serio C, Naldini L, De Palma M. A distinguishing
gene signature shared by tumor-infiltrating Tie2-expressing monocytes (TEMs), blood "resident" monocytes
and embryonic macrophages suggests common functions and developmental relationships.
Blood. 2009 Jul 23;114(4):901-14.
De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Mazzoleni S, Sitia G, Moi D, Venneri MA, Indraccolo S,
Falini A, Guidotti LG, Galli R, Naldini L. Tumor-targeted Interferon-α Delivery by Tie2-Expressing Monocytes
Inhibits Tumor Growth and Metastasis.
Cancer Cell, 2008 Oct 7;14(4):299-311.
De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2 Identifies a
Hematopoietic Lineage of Pro-Angiogenic Monocytes Required for Tumor Vessel Formation and a
Mesenchymal Population of Pericyte Progenitors.
Cancer Cell. 2005 Sep; 8(3):211-26.
De Palma M, Venneri MA, Roca C, Naldini L. Targeting Exogenous Genes to Tumor Angiogenesis by
Transplantation of Genetically Modified Hematopoietic Stem Cells.
Nature Med. 2003 Jun;9(6):789-95.