Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression

Abstract

Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth. The existence of a BM reservoir of EPCs, and the selective involvement of EPCs in neovascularization, have attracted considerable interest because these cells represent novel target for therapeutic intervention. In addition, EPCs are also being used as pharmacodynamic surrogate markers for monitoring cancer progression, as well as for optimizing efficacy of anti-angiogenic therapies in the clinic. This review will focus primarily on recent advances and emerging concepts in the field of EPC biology and discuss ongoing debates involving the role of EPCs in tumor neovascularization. For detailed information on the in vitro characterization of EPCs contribution to non-tumor pathologies, the reader is directed towards several excellent reviews and publications [F. Bertolini, Y. Shaked, P. Mancuso and R.S. Kerbel, Nat. Rev., Cancer 6 (2006) 835-845. [1]] [J.M. Hill, T. Finkel and A.A. Quyyumi, Vox Sang. 87 Suppl 2 (2004) 31-37. [2]] [A.Y. Khakoo and T. Finkel, Annu. Rev. Med. 56 (2005) 79-101. [3]] [H.G. Kopp, C.A. Ramos and S. Rafii, Curr. Opin. Hematol. 13 (2006) 175-181. [4]; K.K. Hirschi, D.A. Ingram and M.C. Yoder, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1584-1595. [5]; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87-102. [6]] and reviews by Bertolini, Voest and Yoder in this issue.

Figure 1. BM cells are recruited at the periphery of pulmonary metastatic lesions

Wild type mice were lethally irradiated and transplanted with GFP+ BM. Following stable BM engraftment RFP expressing LLC cells were implanted in the flank of these mice. Following primary tumor growth, LLCs metastasized to the lungs. Immunohistochemical evaluation of the lung sections showed presence of BM-derived GFP⁺ cells, CD31⁺ mature vessels (magenta) in the RFP+ metastatic lesions. The dotted line separates the host tissue from the metastasis. DAPI was used to stain the nucleus of all cells. (Image courtesy of Dr. Dingcheng Gao, Weill Cornell University Medical Center)

Figure 2. BM-derived endothelial cells are luminally incorporated in tumor neovasculature of both murine and human tumors

(A) High resolution image of a representative nascent CD31+ blood vessel in LLC tumor (day 6–8) showing a luminally incorporated BM-derived GFP⁺ CD31⁺ VE-cadherin⁺ co-expressing endothelial cell (arrow). The BM-derived endothelial cells had a single nucleus, GFP and CD31 signals were localized to the same individual cell, and VE-cadherin was localized to the endothelial cell junction. Scale bar, 20 µM. L, Lumen (Image courtesy of Nolan et al. Genes and Dev 2007). (B–D) Analysis of secondary tumors that developed in humans previously transplanted with HSCs from a sex-mismatched donor show that tumor endothelial cells are donor-derived as determined by sex chromosome FISH analysis. C: Blood vessel of a male with colon cancer who had not undergone bone marrow transplantation showing endothelial cells with Y chromosome FISH signal (white arrows). D: Section of a thyroid cancer in a female after male bone marrow transplant. Blood vessel with one endothelial cell showing a Y chromosome FISH signal (white arrow). E: Section of male glossal mucoepidermoid carcinoma after female bone marrow transplant. Endothelial cell with two X chromosome FISH signals (white arrow). A single X chromosome (green arrow) positive endothelial cell is presumably derived from male recipient cells. Note that yellow arrows point to CD45-positive cells with a Y chromosome signal. Endothelial cells were stained with von Willebrand Factor (red) and leukocytes with anti-CD45 antibody (yellow). (Image from Peters et al. Nature Med. 2005).