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cancer stem cell

Stem cells in tumor angiogenesis

Shentong Fang,Petri Salven

PII:S0022-2828(10)00403-7

DOI:doi:10.1016/j.yjmcc.2010.10.024

Reference:YJMCC6945

To appear in:Journal of Molecular and Cellular Cardiology

Received date:23July2010

Revised date:19October2010

Accepted date:19October2010

Please cite this article as:Fang Shentong,Salven Petri,Stem cells in tumor angiogenesis, Journal of Molecular and Cellular Cardiology(2010),doi:10.1016/j.yjmcc.2010.10.024

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A C C E P T E D M A N U S C

R I P T

Stem cells in tumor angiogenesis

Shentong Fang and Petri Salven Molecular Cancer Biology Program & Department of Pathology, University of Helsinki, POB 63, 00014 Helsinki, Finland.

Corresponding author: Petri Salven, Molecular Cancer Biology Program & Department of Pathology, University of Helsinki, POB 63, 00014 Helsinki,

Finland. Phone +358-9-19125384; e-mail: petri.salven@helsinki.fi

A C C E P T E D M A N U S C R I P T Abstract

Contribution from diverse tissue-specific stem cell types is required to create the cell populations necessary for the activation of angiogenesis and neovascular growth in

cancer. Bone marrow (BM) -derived circulating endothelial progenitors (EPCs) that would differentiate to bona fide endothelial cells (ECs) were previously believed to be necessary for tumor angiogenesis. However, numerous recent studies demonstrate that EPCs are not needed for tumor angiogenesis, and indicate EPCs to be artifactual rather than physiological. It is evident that tumor infiltrating hematopoietic cells produced by BM-residing hematopoietic stem cells (HSCs) may contribute to tumor angiogenesis in a paracrine manner by stimulating ECs or by remodeling the extracellular matrix. Therefore, identification of the various hematopoietic cell subpopulations that are critical for tumor angiogenesis and better understanding of their proangiogenic functions and mechanisms of action has potential therapeutic significance. Stem and progenitor cell subsets for also other vascular or perivascular cell types such as pericytes or mesenchymal/stromal cells may provide critical contributions to the growing neovasculature. Furthermore, we hypothesize that the existence of a yet undiscovered -and largely unsearched- tissue-specific adult vascular endothelial stem cell (VESC) would provide completely novel targeted approaches to block pathological angiogenesis and cancer growth.

A C C E P T E D M A N U S C R I P T 1. Introduction

Vasculature is essential in embryonic development and in the development and homeostasis of adult tissues. Angiogenesis is also actively involved in a wide variety

of pathological events, such as wound repair and metabolic diseases [1, 2]. As early as 1971, Judah Folkman proposed the hypothesis that tumor growth is dependent on the formation of new blood vessels and inhibition of tumor angiogenesis would be an effective strategy to treat human cancer [3]. The increasing use of antiangiogenic drugs for the treatment of cancer and the development of compounds that interfere with different angiogenic pathways have now indeed emerged from decades of extensive basic and clinical research. Four major pathways regulating EC proliferation and vascular growth have received enormous attention: VEGF-A/VEGFR2 signaling pathway, PDGF-B and its receptor PDGFR-β, angiopoietins and Tie2 receptor, and DII 4- Notch 1 pathway [4]. Most current anti-angiogenic strategies for cancer treatment are focused on compounds blocking the VEGF-A/VEGFR2 pathway.

Blood vessel growth is thought to occur through vasculogenesis, angiogenesis, arteriogenesis, and collateral growth [1, 2]. While small vessels consist of only endothelial cells (ECs), larger blood vessels comprise also mural pericytes and vascular smooth muscle cells. De novo blood vessels are formed through a series of events, including EC activation and proliferation, migration towards angiogenic stimuli, and the recruitment of perivascular support cells [2]. Tumor-associated stromal cells, such as infiltrating leukocytes and fibroblasts, have also been implicated in the process [5]. Growing attention is paid to the role of bone marrow derived cells in tumor angiogenesis [6]. Obviously, contribution from diverse tissue-specific stem cell types is required to create the cell populations necessary for the activation of angiogenesis and neovascular growth. The aim of this review is to consider how different adult stem cell populations and their progeny participate in angiogenesis during tumor growth.

A C C E P T E D M A N U S C R I P T 2. Hematopoietic stem cell contribution to tumor angiogenesis by endothelial differentiation: the endothelial progenitor or precursor (EPC) hypothesis

Prior to 1997, the predominant concept behind new blood vessel formation in adults

was believed to be angiogenesis [7, 8]. In 1997, Asahara et al. reported in Science that they had purified a population of putative endothelial cell progenitors (EPCs) from human peripheral blood displaying properties of ECs in vitro and in ischemia animal models, and proposed the bone marrow (BM) as a source of circulating progenitor cells that differentiate to bona fide ECs during postnatal vascular growth [9]. The concept of EPCs was for over a decade widely disseminated as an essential mechanism leading to neoangiogenesis and tumor growth promotion [10-12], and studies with C57BL/6 mice with tagged BM estimated that the BM-derived EPCs could constitute as much as half of all ECs in tumor neovessels [13]. However, numerous recent in vivo studies utilizing carefully controlled experiments and abundant physiologically relevant settings including cancer growth [14-32] have not been able detect significant EPC contribution to neoangiogenic ECs, and they have also been unable to repeat the original experiments introducing the EPC hypothesis. Various studies have also shown that the cells detected in the commonly used EPC assays are in fact white blood cells [31, 33-37]. Indeed, the term EPC may in many previous studies have been used to describe paracrine effector cells possibly contributing to angiogenesis (see below), rather than to portray stem or progenitor cells capable of differentiating to ECs [38, 39]. Taken together, although EPCs are elusive moving targets that always seem to be proposed to emerge in yet another specific model system, they appear to be impossible to verify in carefully controlled experiments indicating true EPCs (circulating cells that differentiate to bona fide ECs) to be artifactual rather than physiological [25].

3. Hematopoietic stem cell contribution to tumor angiogenesis by paracrine mechanisms

A C C E P T E D M A N U S C R I P T There is compelling evidence that circulating cells produced by the hematopoietic stem cells (HSCs) residing in the BM play an important role in promoting angiogenesis [6, 40, 41]. Chemokine-mediated retention of BM-derived hematopoietic cells in close proximity to angiogenic vessels enhances in situ proliferation of

endothelial cells via secreting proangiogenic activities distinct from locally induced activities [42]. BM-derived proangiogenic and/or tumor-infiltrating cells are heterogeneous and include myeloid blood cells such as monocytes, macrophages, and granulocytes and neutrophils [43], as well as tumor associated macrophages (TAM), Tie2 expressing mononuclear (TEM) cells and myeloid derived suppressor cells (MDSCs) [6] (Fig. 1). Myeloid-lineage BMDCs are thought to promote angiogenesis in tumors in a paracrine manner by expressing various factors that promote the growth and expansion of de novo vessels from the pre-existing vasculature - either by stimulating ECs or by remodeling the extracellular matrix [5, 6, 44].

3.1 Tie2-expressing mononuclear (TEM) cells

The importance of Tie2-expressing mononuclear (TEM) cells in promoting tumor growth was described by De Palma and coworkers who showed that TEM cells are recruited to angiogenic sites of the tumor and that substantial angiogenic inhibition is achieved by eliminating this specific population [14]. Later, De Palma further discovered that TEM cells promote tumor angiogenesis in a paracrine manner and account for major proangiogenic activity of myeloid cells in tumors [20]. They studied the Tie2+ cell types by generating transgenic mice which express conditionally toxic gene thymidine kinase (tk) controlled by Tie2p/e LV[TgN(Tie2-tk)], in which all proliferating cells expressing tk could be selectively killed by the administration of GCV. The mice were transplanted with subcutaneous mammary tumors and were then divided into two groups: one was treated with GCV to eliminate TEM cells during tumor growth and the other was left untreated. Compared with untreated controls, the GCV treated tumors showed complete elimination of the TEM cells, exhibiting a marked reduction in angiogenesis and

A C C E P T E D M A N U S C R I P T growth.

3.2 Tumor associated macrophages (TAMs)

Macrophages in tumors are often termed tumor associated macrophages (TAMs). Higher numbers of TAMs are located in malignant tumors than in normal tissues [45, 46]. Studies have shown a correlation between high numbers of TAMs in human tumors and increased microvessel density [47, 48]. It is well known that TAMs may support tumor growth and neovascularization and stimulate angiogenesis by producing a wide array of angiogenic cytokines or by producing extracellular matrix-degrading proteases, which then release various angiogenic factors [40, 49].

3.3 Myeloid derived suppressor cells (MDSCs)

The myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells comprising immature myeloid progenitors for neutrophils, monocytes and dendritic cells [6]. In mice, MDSCs have been termed as CD11b+Gr1+ cells [50]. They can be grouped into two subpopulations: CD11b+Gr1+high cells which resemble neutrophils, and CD11b+Gr1+low cells similar to immature neutrophils [51]. In tumors, MDSCs are thought to promote tumor progression mainly by immunosuppression [40, 52]. They could inhibit the immune response and suppress T cell activation [53]. MDSCs are potently immunosuppressive and effectively suppress the anti-tumor functions of T and natural killer (NK) cells, along with DC maturation

[51, 53-55]. Once recruited to tumors, these cells suppress the anti-tumor functions of T and NK cells by the production of arginase 1 and iNOS among other factors [56, 57]. They also secrete proangiogenic factors such as VEGF and MMP9 and accelerate vessel remodeling to promote tumor progression [50, 58-60].

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3.4 Neutrophils, eosinophils, mast cells and dentritic cells (DCs)

Neutrophils are the most numerous leukocytes in circulation and are involved in acute inflammatory responses in order to destroy invading microorganisms, thus forming an essential part of the innate immune system. Tumor neutrophils initially originate from myeloid progenitor cells derived from the BM [61]. Elevated numbers of neutrophils have been observed in patients with gastric or colon cancer [62, 63]. CXC chemokines are thought to stimulate the migration of neutrophils across the vasculature to recruit into the tumors [63, 64]. Several in vivo studies using various models of angiogenesis have clearly shown that neutrophils induce neovascularization processes. The depletion of Gr-1 mediated neutrophils has been demonstrated to strongly reduce angiogenesis in matrigel with CXCL1 or CXCL8 compared to controls [65]. Furthermore, the infiltrating neutrophils have a crucial role in activating angiogenesis during the early stage of carcinogenesis [66]. It has been shown that the transient depletion of neutrophils could significantly suppress VEGF and thus remarkably reduce the frequency of the initial angiogenic switch, as tumor infiltrating neutrophils, along with macrophages, are two major sources of MMP-9 in the angiogenic stages of pancreatic islet carcinogenesis [66].

Increased levels of eosinophils, another subpopulation of white blood cells, and have been found in human tumors [67]. How eosinophils contribute to angiogenesis in vivo is still not completely understood. Eosinophil infiltration probably induces angiogenic responses in vivo through the production of CCL11 [68]. Also mast cells originate from the BM and circulate as immature cells and migrate to tissues where they finally mature. They recruit into tumors and are frequently found in close contact with blood vessels within the tumor microenvironment [69]. Increased numbers of mast cells have been observed in various tumors, and increased mast cell density correlates positively with increased microvessel density in many human tumors [70]. The importance of mast cells for tumor angiogenesis has been addressed by several studies. The angiogenic response to implanted B16-BL6 melanoma in mast cell deficient

A C C E P T E D M A N U S C R I P T W/Wv mice was showed to be slower and less intense than in the wild type mice [71], and with bone-marrow repair of the mast cell deficiency, angiogenic response could be fully restored [71]. Furthermore, mast cells are also a rich source of preformed angiogenic cytokines and growth factors, such as VEGF, bFGF, MMP9, and IL-6 [72].

The degranulation of tumor-associated mast cells might be releasing these proangiogenic factors within the tumor microenvironment and thus promoting angiogenesis.

Dentritic cells (DCs) are crucial regulators of adaptive immune responses and are viewed as the major professional antigen presenting cells (APC), with a unique ability to induce both primary and secondary T- and B-cell responses, as well as immune tolerance [73]. Gabrilovich et al. identified VEGF as a factor which influences DC maturation without affecting the function of relatively mature DCs in vitro [54]. Tumor –derived factors, such as VEGF, might be restricting the maturation of myeloid dentritic cells (DCs) and their subsequent accumulation to tumor tissues. Some in vivo studies have shown that tumor DCs also possess proangiogenic properties [74]. Tumor associated plasmacytoid dendritic cells could induce angiogenesis by producing TNF αand IL-8, while myeloid dendritic cells were absent from malignant ascites [74].

3.5 Platelets

In addition to their abilities on hemostasis, there are data indicating that platelets are also involved in processes such as angiogenesis, tissue regeneration and tumor metastasis [75]. Through the release of cytokines, chemokines and the presentation of several adhesion molecules, platelets are a rich source of both angiogenic (VEGF, ANG-1, PDGF) [76-80] and antiangiogeneic [81] factors upon activation. It has been shown that higher serum levels of VEGF per platelet count were in correlated with cancer progression for patients with breast, renal and colorectal tumors [80, 82, 83]. In

A C C E P T E D M A N U S C R I P T accordance, large numbers of activated platelets, associated with a high level of VEGF expression and ongoing angiogenesis, were observed in soft tissue tumors [84]. Moreover, VEGF secreted by platelets could also stimulate their own precursors, megakaryocytes [77]. More recently, a platelet-derived lipid-lysophosphatidic acid

(LPA), a water soluble biolipid, was found to have growth-factor-like signaling properties [85]. LPA exerts its activity either in an autocrine or paracrine fashion, activates downstream signaling pathways leading to cell proliferation, increased survival and enhanced migration and thus affects angiogenesis [86]. It has also been shown that platelets support angiogenic [87] and inflamed [88] microvessel integrity through the prevention of hemorrhage at angiogenesis and inflammation sites and may thus have an impact on tumor vessel integrity and homeostasis.

4. Pericyte stem/progenitor cells ?

Endothelial cells, forming a monolayer throughout the vessel wall, are covered by pericytes and vascular smooth muscle cells (vSMCs). Pericytes are thought to affect EC functions through paracrine effects and cell –cell contact to promote the stabilization of blood vessels and to provide permeability control [89-92]. Rajantie et al. consistently observed high numbers of BM-derived periendothelial cells in close contact with the underlying endothelial cells [19]. Subpopulations of these cells expressed NG2 proteoglycan, a developing pericyte specific marker. Later, the existence of pericyte progenitor cells (PPCs) originating from the BM was proposed by Song et al. who observed PDGFR-?+ pericyte progenitors (PPPs) in an endogenous mouse model of pancreatic tumorigenesis [93]. PPPs in these tumors were described to be able to differentiate into mature pericytes, expressing the markers NG2, -SMA, and desmin. A subset of PDGFR-?+ PPCs was found to be recruited from the BM to perivascular sites within tumors, as these BM-derived cells expressed hematopoietic markers such as stem cell antigen-1 (Sca-1) and CD11b [93].

A C C E P T E D M A N U S C R I P T 5. Bone marrow derived mesenchymal stem/ stromal cells

Mesenchymal stem cells (MSCs) are non-hematopoietic precursor cells residing in the BM, which could contribute to the maintenance and regeneration of a variety of

connective tissues [94]. BM-derived MSCs have been described as non-hematopoietic precursors characterized by the expression of some adhesion molecules and stromal cell markers such as CD73, CD105 and CD44 in the absence of hematopoietic markers and the endothelial marker CD31 [94-96]. These cells have attracted interest because they have been shown to contribute to the tumor micro-environment and to influence tumor growth and progression, and because of their potential role as vehicles for anti-cancer agents [94, 97, 98]. There is evidence indicating that BM-derived mesenchymal cells could contribute to tumor angiogenesis by providing a supportive role as carcinoma associated fibroblasts [99-101]. Some evidence has also suggested that BM-derived cells might contribute to fibroblasts in tumor stroma area [102]. About 25% of α-SMA positive myofibroblasts, and some vimentin-expressing fibroblasts were found to derive from the BM in pancreatic insulinoma in mice [102]. MSC-derived fibroblasts have also been shown to increase tumor growth in mice. Ramasamy et al. reported that 75% of mice injected with a mixture of tumor cells and cultured MSCs developed a tumor, whereas 12% of the animals receiving tumor cells alone showed signs of tumor growth [103]. MSC-derived fibroblasts could also promote tumor growth directly by the production of proangiogenic factors, such as VEGF, platelet derived growth factors (PDGF), fibroblast growth factor (FGF) and stromal derived factor -1 (SDF-1) [104, 105]. However, how MSCs contribute to tumor growth requires more study. Their immunosuppressive role in tumor growth has also attracted great attention and immunosuppresion induced by MSCs allows the proliferation of B16 melanoma xenografts in mice [106, 107].

A C C E P T E D M A N U S C R I P T 6. Vascular endothelial stem cells (VESCs) ?

Despite the consensus on the importance of BM-derived cell populations in tumor neovascularization, many central questions concerning tumor neovasculization and

the origin of neovascular endothelial cells still remain unanswered. Where are the de novo ECs coming from during physiological and pathological angiogenesis in adults? During embryogenesis, the early blood vessels develop by aggregation of de-novo-forming angioblasts into a primitive vascular plexus (vasculogenesis). Embryonic blood vessels arise from endothelial precursors, which share an origin with haematopoietic progenitors [108-110], but the origin of new ECs in adults is not known [24, 37, 111]. Are ECs produced by duplication of mature endothelial cells in a similar manner as was described for pancreatic beta-cells [112], or by are all new ECs in adults being produced stem cells, as is well documented for differentiated cells in the skin and intestine [113, 114]? Low numbers of cells with endothelial characteristics and high proliferative potential have been described in umbilical cord blood or in peripheral blood [36, 115-117]. Is it possible that there is a rare vascular endothelial stem cell (VESC) population residing somewhere, for example in the vessel wall, that is responsible for the neovascularization and capable of producing very high numbers of endothelial daughter cells? Or could end differentiated ECs perhaps acquire more stem cell-like characteristics in angiogenic situations such as cancer? Such central questions about the contribution of stem cells to vascular growth and to tumor angiogenesis still remain unanswered and largely unstudied.

7. Concluding remarks

It is evident that tumor infiltrating hematopoietic cells produced by BM-residing HSCs may contribute to tumor angiogenesis. These infiltrating hematopoietic cells can release paracrine angiogenic factors or create permissive conditions that induce the growth of locally derived blood vessels [20, 44, 118-121]. In future studies, much

A C C E P T E D M A N U S C R I P T greater attention will need to be paid to better enumeration and identification of the various hematopoietic cell subpopulations that are critical for tumor angiogenesis, and in exploring their functions and potential therapeutic implications. Due to the heterogeneity of tumor infiltrating host cells and their complex and diverse

interactions, the specific mechanisms of action of these cell subsets and their exact roles in vascular processes such as induction of sprouting, vessel remodeling, maturation, stabilization, etc. will be challenging to dissect. In addition to proangiogenic perivascular or stromal cells, cells with endothelial characteristics and high proliferative potential may be found within the vascular system [36, 115-117]. A high proliferative potential would be an essential attribute for ECs participating in vascular homeostasis and repair, as well as in pathological neoangiogenesis. Endothelial cell diversity revealed by global gene expression profiling suggest that ECs might actually comprise many distinct cell types [122]. Together, these findings bring into question whether individual vascular segments could possess niches of vascular endothelial stem cells (VESCs) (Fig.1). If existent, VESCs would provide completely novel therapeutic means to restore tissue vascularization, as well as new targeted approaches to block pathological angiogenesis and cancer growth.

A C C E P T E D M A N U S C R I P T

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Figure 1: Contribution from diverse tissue-specific stem cell types is neeeded to create the cell populations necessary for the activation of angiogenesis and neovascular growth in cancer. Various subpopulatons of tumor infiltrating hematopoietic cells that are all produced by bone marrow (BM) -residing hematopoietic stem cells (HSCs) contribute to tumor angiogenesis in a paracrine manner by producing angiogenic factors or by creating permissive conditions that induce the growth of locally derived blood vessels. Stem and progenitor cell subsets for other vascular or perivascular cell types such as pericytes or mesenchymal/stromal cells may also provide critical contribution to the growing tumor neovasculature. Importantly, yet undiscovered adult vascular endothelial stem cells (VESCs) might provide a direct contribution to tumor angiogenesis by producing massive amounts of endothelial daughter cells. Abbreviations: TEMs: Tie2-expressing mononuclear cells; TAMs: Tumor associated macrophages; MDSCs: Myeloid derived suppressor cells; DCs: dentritic cells

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