Trends in Immunology
Volume 28, Issue 12, December 2007, Pages 519-524
Journal home page for Trends in Immunology

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Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications

https://doi.org/10.1016/j.it.2007.09.004Get rights and content

Tumor-infiltrating myeloid cells are involved in crucial processes during tumor development. A subset of monocytes that express the angiopoietin receptor Tie2 play an important role in tumor angiogenesis. Selective depletion of these Tie2-expressing monocytes (TEMs) in tumor-bearing mice inhibits tumor angiogenesis and growth, suggesting that they might regulate angiogenic processes in tumors by providing paracrine support to nascent blood vessels. TEMs have also been identified in human blood and tumors. We discuss here the therapeutic opportunities emanating from the discovery of TEMs, which include the identification of new antitumor targets, monitoring TEMs as surrogate markers for clinical responses in cancer patients, and the possible use of TEMs as cellular vehicles for gene delivery to tumors.

Section snippets

Role of bone marrow-derived cells in tumor angiogenesis

During physiological angiogenesis, new blood vessels are formed through a well-orchestrated series of events, which include endothelial cell (EC) proliferation, their migration toward angiogenic stimuli, recruitment of perivascular support cells, functional lumen formation, and blood flow 1, 2. During development and organogenesis, the activation of molecular and cellular programs that control angiogenesis is tightly regulated by an assortment of positive and negative mediators (pro- and

Tie2-expressing monocytes and tumor angiogenesis

Although our studies have shown that putative BM-derived EPCs do not incorporate directly into tumor blood vessels, they highlighted the important contribution of hematopoietic-lineage cells in the angiogenic process 13, 23. In particular, we noted that one subset of monocytes plays an essential role in this phenomenon, those expressing the angiopoietin receptor Tie2 (Box 1). The Tie2 tyrosine kinase receptor has been shown previously to be expressed only by endothelial and hematopoietic stem

Possible role of TEMs in other diseases

We investigated the recruitment of TEMs to sites of angiogenesis other than tumors. We analysed the recruitment of gene-marked TEMs in mice that underwent partial hepatectomy 7–10 days earlier, and we found that TEMs were present in the granulation tissue surrounding the regenerating hepatic lobules [13]. Some TEMs were found in proximity to newly formed vessels, similar to tumor TEMs, suggesting that they might also contribute to promoting angiogenesis during liver regeneration. Other reports

Therapeutic opportunities: targeting TEMs or exploiting them as gene-delivery vehicles in anticancer therapy

The future identification of specific molecules expressed by TEMs in tumors could facilitate the design of novel anticancer therapies that selectively target these cells, thereby removing their proangiogenic contribution in such tissues while preserving their potential role in regulating tissue homeostasis and immunity (Box 2). The identification of gene expression by TEMs in tumors and the tumor microenvironmental factors that regulate TEM recruitment and/or function probably highlight such

Acknowledgements

C.M. and C.E.L. would like to thank Yorkshire Cancer Campaign and Breast Cancer Campaign for grant support of their work in this area. L.N. acknowledges the grant support from Associazione Italiana per la Ricerca sul Cancro (AIRC 52–2005), European Union (Tumor-Host Genomics, LSHC-CT-2005–518198), and Telethon (TIGET). M.D.P. was supported by AIRC. None of the authors have a financial interest in this work.

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