BBA - Reviews on Cancer (v.1796, #1)

Increasing evidence implicates an important role for a variety of bone marrow derived cells (BMDCs) in tumor angiogenesis and metastatic tumor growth. These cells are derived either from the hematopoietic or mesenchymal cell lineage, and they are distinguished, in part, by the expression of the panhematopoietic marker ‐ CD45. Some of these cell populations can colonize tumors perivascularily, and appear to promote angiogenesis and tumor cell proliferation by paracraine mechanisms, whereas others can contribute “directly” to the growth of tumor vessel capillaries or metastases. In this review we focus in particular on the role of hemangiocytes or recruited bone marrow derived circulating cells (RBCCs) in neovascularization, the contribution of VEGFR1+ hematopoietic stem cells and endothelial precursor cells in metastasis, and the involvement of myeloid derived suppressor CD11b+/Gr‐1+ cells in the resistance of tumors to certain antiangiogenic drugs, e.g., VEGF blocking antibodies.

There is a growing interest in understanding the complex interactions between bone marrow-derived myeloid-lineage cells and angiogenesis in tumors. Such interest has been revived recently by the observation that tumor-infiltrating myeloid cells convey proangiogenic programs that can counteract the activity of antiangiogenic drugs in mouse tumor models. Among myeloid cells, Tie2-expressing monocytes (TEMs) appear to have nonredundant function in promoting tumor angiogenesis and growth in mouse models. The identification and functional characterization of TEMs in mice and humans may provide novel molecular targets for anticancer therapy. Moreover, TEMs may be exploited to deliver antitumor drugs specifically to the tumor microenvironment.
Keywords: Tie2; Monocyte; Tumor angiogenesis; Proangiogenic cell; Gene transfer; Lentiviral vector; Interferon-alpha; Gene therapy;

Tumor-associated macrophages: Effectors of angiogenesis and tumor progression by Seth B. Coffelt; Russell Hughes; Claire E. Lewis (11-18).
Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population in many tumor types residing in both perivascular and avascular, hypoxic regions of these tissues. Analysis of TAMs in human tumor biopsies has shown that they express a variety of tumor-promoting factors and evidence from transgenic murine tumor models has provided unequivocal evidence for the importance of these cells in driving angiogenesis, lymphangiogenesis, immunosuppression, and metastasis. This review will summarize the mechanisms by which monocytes are recruited into tumors, their myriad, tumor-promoting functions within tumors, and the influence of the tumor microenvironment in driving these activities. We also discuss recent attempts to both target/destroy TAMs and exploit them as delivery vehicles for anti-cancer gene therapy.
Keywords: Myeloid cells; Macrophage; Tumor; Angiogenesis; Lymphangiogenesis; Immunosuppression; Metastasis;

Mast cells in tumor growth: Angiogenesis, tissue remodelling and immune-modulation by Steven Maltby; Khashayarsha Khazaie; Kelly M. McNagny (19-26).
There is a growing acceptance that tumor-infiltrating myeloid cells play an active role in tumor growth and mast cells are one of the earliest cell types to infiltrate developing tumors. Mast cells accumulate at the boundary between healthy tissues and malignancies and are often found in close association with blood vessels within the tumor microenvironment. They express many pro-angiogenic compounds, and may play an early role in angiogenesis within developing tumors. Mast cells also remodel extracellular matrix during wound healing, and this function is subverted in tumor growth, promoting tumor spread and metastasis. In addition, mast cells modulate immune responses by dampening immune rejection or directing immune cell recruitment, depending on local stimuli. In this review, we focus on key roles for mast cells in angiogenesis, tissue remodelling and immune modulation and highlight recent findings on the integral role that mast cells play in tumor growth. New findings suggest that mast cells may serve as a novel therapeutic target for cancer treatment and that inhibiting mast cell function may lead to tumor regression.
Keywords: Mast cell; Angiogenesis; Remodelling; Immune-modulation; Cancer; Immunity;

The multiple personality disorder phenotype(s) of circulating endothelial cells in cancer by Francesco Bertolini; Patrizia Mancuso; Paola Braidotti; Yuval Shaked; Robert S. Kerbel (27-32).
Circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs) are currently being investigated in a variety of diseases as markers of vascular turnover or damage and, also in the case of CEPs, vasculogenesis. CEPs appear to have a “catalytic” role in different steps of cancer progression and recurrence after therapy, and there are preclinical and clinical data suggesting that CEC enumeration might be useful to select and stratify patients who are candidates for anti-angiogenic treatments. In some types of cancer, CECs and CEPs might be one of the possible hidden identities of cancer stem cells. The definition of CEC and CEP phenotype and the standardization of CEC and CEP enumeration strategies are highly desirable goals in order to exploit these cells as reliable biomarkers in oncology clinical trials.
Keywords: Angiogenesis; Endothelial cells; Endothelial progenitors;

Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression by Dingcheng Gao; Daniel Nolan; Kevin McDonnell; Linda Vahdat; Robert Benezra; Nasser Altorki; Vivek Mittal (33-40).
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. ] [J.M. Hill, T. Finkel and A.A. Quyyumi, Vox Sang. 87 Suppl 2 (2004) 31–37. ] [A.Y. Khakoo and T. Finkel, Annu. Rev. Med. 56 (2005) 79–101. ] [H.G. Kopp, C.A. Ramos and S. Rafii, Curr. Opin. Hematol. 13 (2006) 175–181. ; K.K. Hirschi, D.A. Ingram and M.C. Yoder, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1584–1595. ; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87–102. ] and reviews by Bertolini, Voest and Yoder in this issue.
Keywords: Bone marrow; EPCs; HSCs; Chemotherapy; Bone marrow transaplantation; Metastasis; Angiogenesis;

It is generally accepted that angiogenesis plays a major role in tumor growth and numerous targeting agents directed against angiogenesis pathways have been developed and approved for clinical use. In the past years the concept of angiogenesis has developed into a multi-faceted process in which, besides local activation and division of endothelial cells, bone marrow derived progenitor cells (BMDPCs) contribute to neovascularization. A multitude of preclinical and clinical data indicates that the release of BMDPCs influences the response to certain anti-cancer modalities. In this review we provide an overview of all the preclinical and clinical studies contributing to this hypothesis and translate these findings to the clinic by pointing out the clinical implications these findings might have. The recent insight in the mechanism of a systemic host response, in response to various treatment modalities has shed new light on the mechanism of tumor regrowth, early recurrence and metastasis formation during or after treatment. This provides various new targets for therapy which can be used to improve conventional chemotherapy. Furthermore it provides a potential explanation why bevacizumab selectively enhances the effectiveness of only certain types of chemotherapy.
Keywords: Angiogenesis; Endothelial progenitor cells; Growth factors; Anti-angiogenic agents;

Interest in the regulation of blood vessel formation as a mechanism to permit unregulated tumor cell growth was a prescient hypothesis of Dr. Judah Folkman nearly 3 decades ago. Understanding the cellular and molecular mechanisms that affect the recruitment, expansion, and turnover of the tumor microvasculature continues to evolve. While the fundamental paradigms for improving blood flow to growing, injured, diseased, or tumor infiltrated tissues are well known, the potential role of bone marrow derived circulating endothelial progenitor cells (EPCs) to function as postnatal vasculogenic precursors for tumor microvasculature has become a controversial premise. We will briefly review some recently published high profile papers that appear to derive polar interpretations for the role of EPCs in the angiogenic switch and discuss possible reasons for the disparate views in work conducted in both mouse and man.
Keywords: Endothelial progenitor cell; Hematopoietic progenitor cell; Neoangiogenesis; Circulating endothelial cell; Endothelial colony forming cell;