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CD47, a multi-facetted target for cancer immunotherapy

 

Valerie R Wiersma1, Peter E van Bommel1, Marco de Bruyn2, Wijnand Helfrich1, Edwin Bremer1,3

1University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Translational Surgical Oncology, and
2Department of Obstetrics & Gynecology, Groningen, The Netherlands
3Exeter University Medical School, Devon, UK

 

October 2014

Corresponding author: Edwin Bremer, University of Groningen, University Medical Center
Groningen, Department of Surgery, Translational Surgical Oncology, The Netherlands,
Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
e-mail: e.bremer@umcg.nl,
Phone: +31-503611340; Fax: +31-503632796

 

 

Short title:

CD47 in tumor biology and immunity

 

Abstract

CD47 is a ubiquitously expressed immunoregulatory protein best known for its so-called 'don't eat me' function that prevents phagocytic removal of healthy cells by the immune system. Many types of cancer present high levels of this don't eat me signal on their surface, thereby disrupting anti-cancer immune responses. Based on this observation, CD47 has become a prominent target in the field of cancer immunotherapy. Indeed, pre-clinical studies have shown therapeutic benefit of anti-CD47 antibodies in solid cancers and most notably B-cell malignancies. However, CD47 is also involved in various other important cellular processes, such as angiogenesis, cancer cell death and regulation of T-cell immunity, which can be modulated via interactions with thrombospondin-1. The therapeutic outcome of CD47-targeted immunotherapy therefore relies on the combined effects of all these processes. Here we will review the various physiological functions of CD47 and their implications in cancer biology. Further, we will review ongoing efforts and provide perspectives for exploiting CD47 as an immunotherapeutic target in cancer.

 

Key words:

CD47; Signal regulatory protein α (SIRP α); Thrombospondin-1 (TSP-1); cancer (immune) therapy; phagocytosis; angiogenesis.

 

Introduction

CD47 is a 50 kDa transmembrane immunoglobulin protein comprising a heavily glycosylated N-terminal IgV domain followed by a pentaspanin transmembrane domain and a short cytoplasmic tail (Lindberg et al., 1993). CD47 is best known for its pivotal role in preventing phagocytic removal of healthy cells by binding to phagocyte-expressed signal regulatory protein alpha (SIRPα). SIRPα is an inhibitory receptor that, once triggered, suppresses phagocytosis. This CD47/SIRPα axis is an important homeostatic mechanism preventing removal of healthy normal cells that express CD47. Reversely, down-regulation of CD47 on damaged, aged and superfluous cells ensures their timely removal. This function of CD47 in cellular turn-over was first established in red blood cells almost 2 decades ago and is now held to be a general homeostatic system (Oldenborg et al., 2000).
Both solid and hematologic malignancies overexpress CD47 and, thereby, essentially hijack this homeostatic system to evade phagocytic clearance (Jaiswal et al., 2009; Chao et al., 2011b; Jaiswal et al., 2009; Chao et al., 2010a; Chao et al., 2011a; Zhao et al., 2011; Willingham et al., 2012; Rendtlew Danielsen et al., 2007; Edris et al., 2012). Therapeutic interventions that block CD47-SIRPα interaction have been found to promote phagocytic elimination of such CD47 overexpressing tumor cells and are poised for clinical evaluation (Chao et al., 2010a; Tseng et al., 2013; Theocharides et al., 2012; Majeti et al., 2009; Chao et al., 2011b; Chao et al., 2011a; Willingham et al., 2012; Edris et al., 2012).
CD47 also impacts on various other biological processes via binding to alternate receptors or due to signaling through its intracellular cytoplasmic domain. For instance, interaction of CD47 with thrombospondin-1 (TSP-1) or vascular endothelial growth factor receptor 2 (VEGFR2) inhibits angiogenesis and thereby limits tumor growth. Further, cross-linking of CD47 expressed on tumor cells via e.g. TSP-1 can directly induce cell death in breast cancer cells and leukemia (Mateo et al., 1999; Saumet et al., 2005; Manna and Frazier, 2004). Finally, CD47 expressed on immune cells can both positively and negatively regulates immunity, i.e. innate immune cells such as neutrophils, as well as adaptive immunity, i.e. DC maturation and T-cell activity.
Thus, CD47 has a complex and multifactorial role in anti-cancer immunity and cancer biology (figure 1). Correspondingly, the outcome of therapeutic targeting of CD47 will depend on expression, binding affinity and relative levels of its diverse ligands. In this review, we will first review expression patterns of CD47 and its binding partners in normal tissue and cancer. Second, we will discuss the multi-facetted biological effect of CD47 and its ligands in cancer and immunity. Further, we will discuss the current state-of-the-art as well as identify challenges and opportunities CD47 as target in cancer (immuno)therapy.

Figure 1: CD47 has a complex and multifactorial role in anti-cancer immunity and cancer biology. CD47 is involved in regulation of the activity of different immune cell types, and can induce direct cancer cell death when it is crosslinked. In addition, CD47 is involved in angiogenesis. All these aspects are discussed in this review.

 

Tissue distribution and regulation of CD47 and binding partners

 

Expression of CD47 in normal cells and cancer

CD47 is expressed on almost all normal human cells, as evaluated by mRNA expression and immunohistochemical staining, and occurs in four highly conserved isoforms that differ only in the length of their cytoplasmic domain, ranging from 3 to 36 amino acids (Reinhold et al., 1995). These isoforms arise due to alternative splicing of the CD47 mRNA. Splice form 2 contains the second largest cytoplasmic tail and is most abundantly expressed, whereas neuronal tissue almost exclusively express splice form 4 (Reinhold et al., 1995). Of note, the functional and clinical implications of the respective isoforms in normal biology as well as in cancer remain unclear.
CD47 was first identified as an antigen expressed on ovarian carcinoma (Poels et al., 1986), but is overexpressed in many solid tumors and hematologic malignancies (Jaiswal et al., 2009; Chao et al., 2010a; Chao et al., 2011a; Zhao et al., 2011; Willingham et al., 2012; Rendtlew Danielsen et al., 2007; Edris et al., 2012). High levels of CD47 are also found on human bladder tumor-initiating cells and leukemic stem cells (Majeti et al., 2009; Chan et al., 2009).
Increased CD47 mRNA levels are an independent negative prognostic factor in multiple types of cancer (Majeti et al., 2009; Chao et al., 2010a; Chao et al., 2010a; Chao et al., 2011a; Willingham et al., 2012). Further, increased protein expression of CD47 associates with poor clinical outcome in among others ovarian cancer and glioblastoma, (Majeti et al., 2009; Chao et al., 2010a; Chao et al., 2011a; Willingham et al., 2012). Moreover, high CD47 levels associate with various adverse characteristics, such as developmental stage of the tumor, adverse molecular subtype, and resistance to therapy (Rendtlew Danielsen et al., 2007; Chao et al., 2010a; Zhao et al., 2011; Edris et al., 2012). Interestingly, high levels of CD47 expression in the bone marrow of breast cancer patients lead to a significant reduction in disease free survival (Nagahara et al., 2010).

 

Expression of CD47 binding partners SIRPα and TSP-1 in normal cells and cancer

The best characterized binding partner of CD47 is SIRPα (also termed CD172a or SHPS-1). SIRPα is a transmembrane protein consisting of three extracellular Ig-like domains, a transmembrane domain and an intracellular tail containing four immunoreceptor tyrosinebased inhibitory motifs (ITIMs) (Barclay and Van den Berg, 2014). SIRPα belongs to the signal regulatory protein receptor family, which is subdivided in a SIRPα and SIRPβ subgroup. Expression of SIRPα is restricted to phagocytes (macrophages, granulocytes and DCs) and neuronal cells (Fujioka et al., 1996). In addition to SIRPα, CD47 can bind to SIRPβ2 (also termed SIRPγ) albeit with a lower affinity than SIRPα (Piccio et al., 2005). SIRPβ2 is among others expressed on CD3-positive T-cells (Seiffert et al., 2001).
SIRPα expression in cancer has not been extensively evaluated, but in primary brain tumor biopsies and astrocytoma cell lines SIRPα expression was detected. Of note, this tumor expressed SIRPα was underglycosylated compared to SIRPα expressed on Chinese hamster ovary (CHO) cells (Chen et al., 2004), suggestive of a higher affinity for CD47 (see also section of posttranslational glycosylation below). In contrast to solid tumors, SIRPα is notably down-regulated in primary hematopoietic cells and myeloid blasts from AML patients (Seiffert et al., 1999). This down-regulation may be related to the reported induction of apoptosis and growth inhibition by SIRPα in AML cells (Irandoust et al., 2013).
Another important binding partner of CD47 is TSP-1, the first endogenous ligand identified for CD47. TSP-1 is a large matricellular and homotrimeric glycoprotein (430kDa) comprising at least six different structural domains of which the C-terminal domain binds to CD47 (Roberts, 2005). TSP-1 itself is a pleiotropic protein important for platelet aggregation, cell-cell and cell-matrix interactions, and negative regulation of (neo)vascularization. TSP-1 is secreted by various normal cell types, i.e. endothelial cells, smooth muscle cells and monocytes/macrophages. Further, TSP-1 is a major constituent of the extracellular matrix in normal tissues and cancer.
Preclinical evidence suggests that there is an inverse correlation with a decrease in TSP-1 and an increase in CD47 mRNA levels in a prostate cancer model (Vallbo and Damber, 2005). Similarly, TSP-1 expression is inversely correlated with malignant progression in preclinical models as well as in patients with various types of cancer, including melanoma, breast, lung and bladder cancer (Papadaki et al., 2009; Ioachim et al., 2012; Zabrenetzky et al., 1994; Grossfeld et al., 1997). In line with this, TSP-1 over-expression reduced the tumorigenic potential of human cutaneous squamous cell carcinoma (Streit et al., 1999) and breast carcinoma (Weinstat-Saslow et al., 1994).
Of note, oncogenic transformation of the well-established tumor suppressor p53 negatively affects TSP-1 expression, with reduced TSP-1 expression levels in ovarian carcinoma being associated with overexpression of p53 (Alvarez et al., 2001). Similarly, p53 mutation correlated with low TSP-1 levels in bladder cancer (Grossfeld et al., 1997). Further, survival of p53-null/TSP-1-null mice was significantly reduced survival compared to TSP-1-expressing p53-null mice due to naturally arising tumors (Lawler et al., 2001). Thus, TSP-1 has tumor suppressor activity in certain cancers and its expression may be deregulated by oncogenic p53 mutation.

 

Regulation of CD47 expression and activity

Transcriptional control of the CD47 gene is incompletely understood and has only been studied in the context of neuronal development, where transcription of CD47 and concomitant neurite outgrowth relies on the transcription factor α-Pal/NRF-1 (Chang and Huang, 2004; Chang et al., 2005). Similarly, the mechanism underlying constitutive upregulation of CD47 during transformation and progression is as yet unclear, although CD47 can be transiently upregulated by mobilizing cytokines in hematopoietic stem cells (Jaiswal et al., 2009). The latter has been speculated to be a physiological response mechanism exploited by hematologic malignancies.
CD47 expression is also subject to post-transcriptional regulation by micro RNAs (miRNAs). Aberrant overexpression of CD47 correlates with downregulation of miRNA-133a in esophageal squamous cell carcinoma and colorectal cancer (Suzuki et al., 2012; Dong et al., 2013). Reporter construct studies validated the ability of miR-133a to directly inhibit CD47 transcription in vitro. Several other regulatory miRNAs were identified, i.e. miR-155 in multiple sclerosis (MS) and miR-141 in Hirschsprung's disease (Junker et al., 2009; Tang et al., 2013). Both miRs were found to target the 3'UTR of the CD47 mRNA. In MS lesions, upregulation of microRNAs was proposed to reduce CD47 thereby releasing macrophages from inhibitory control and promoting phagocytosis of myelin (Junker et al., 2009). Further, hypermethylation of a CpG Island in the promoter region of miR-141 has been linked to increased expression of CD47 (Tang et al., 2013).
CD47 is also subject to post-translational modifications, most notably glycosylation. CD47 has a number of N-terminal glycosylation sites that directly affect cell surface display and regulate interaction with extracellular ligands. For instance, deglycosylated CD47 has a higher avidity for SIRPα than glycosylated CD47 and, vice versa, deglycosylated SIRPα has a higher avidity for CD47 (Subramanian et al., 2007; Subramanian et al., 2006). Reversely, hyperglycosylated SIRPα can disrupt CD47/SIRPα interactions (Ogura et al., 2004). Of note, site-directed mutagenesis of N-linked glycosylation sites inhibited cell surface localization of CD47 in yeast models (Parthasarathy et al., 2006), although similar mutagenesis did not affect membrane localization of human CD47 in CHO cells (Subramanian et al., 2006). Aberrant glycosylation of either CD47 or SIRPα can also alter downstream responses, with differentially glycosylated SIRPα rendering B16 melanoma cells resistant to CD47-induced inhibition of motility (Ogura et al., 2004). In addition, a heavily glycosylated (>250 kD) form of CD47 has been detected in primary and transformed T-cells, endothelial cells and vascular smooth muscle cells (Kaur et al., 2011). This modification was located distally from the SIRPα binding site, but was required for TSP-1 mediated inhibitory signaling in T-cells. Although not evaluated in the context of cancer as of yet, deregulation of these mechanisms may play a role in cancer pathogenesis.

 

The diverse immunoregulatory effects of CD47 in cancer

 

Controlling phagocytic activity through CD47/SIRPα interaction

SIRPα is an important negative regulator of phagocyte activity that, upon binding by CD47 to its N-terminal IgV domain, is phosphorylated on ITIM motifs leading to concomitant activation of SHP-1 and SHP-2 phosphatases (Hatherley et al., 2008; Kharitonenkov et al., 1997; Okazawa et al., 2005). Downstream events include inhibition of myosin IIA accumulation at the phagocytic synapse (Tsai and Discher, 2008) and suppression of respiratory burst in phagocytes (van Beek et al., 2012). In line with the hypothesis that CD47 overexpression suppresses phagocytosis, ectopic overexpression of CD47 in CD47lo MOLM-13 myeloid leukemia cells inhibited in vitro and in vivo phagocytosis and increased tumor outgrowth (Jaiswal et al., 2009). Reversely, dissemination of Raji NHL cells was strongly reduced after shRNA knockdown of CD47 (Chao et al., 2011b). In addition, disruption of CD47-SIRPα signaling by either mutagenesis of macrophage-expressed SIRPα or by treatment with recombinant SIRPα-Fc eliminated AML xenografts (Theocharides et al., 2012). Thus, cancer cells escape from phagocytic removal by upregulation of CD47 expression, which inhibits myeloid cell activity by binding to SIRPα (figure 2A).

Figure 2: The diverse immunoregulatory effects of CD47. A. The interaction of CD47 (over) expressed on cancer cells with signal regulatory protein α (SIRPα) on phagocytes results in inhibition of phagocytosis. B. CD47 is also expressed on T-cells where it regulates diverse processes upon ligation by TSP-1 or anti-CD47 antibodies. Most of these are anti-inflammatory, as the differentiation of naïve T-cells into Th1 is inhibited, whereas Treg differentiation is induced. Further, binding of CD47 results in reduced proliferation or even T-cell death. However, depending on the context, CD47 ligation can also induce T-cell proliferation and activation.

 

Controlling T-cell differentiation through "reverse" CD47 signaling

Whereas regulatory effects by CD47 on phagocytes is due to SIRPα signaling, regulatory effects on T-cells mainly stem from signaling through T-cell expressed CD47. Specifically, CD47 binding by TSP-1 (or SIRPα) can also trigger CD47 intracellular signaling in immune cells and thereby affect the immunological outcome in cancer. Treatment of naïve T-cells (CD4+CD25-) with TSP-1 or an anti-CD47 mAb upregulated expression of transcription factor FoxP3 and promoted the formation of regulatory T-cells (Tregs) (Grimbert et al., 2006; Baumgartner et al., 2008). Correspondingly, elevated serum TSP-1 levels positively correlated with the percentage of Tregs in peripheral blood of advanced melanoma patients (Baumgartner et al., 2008). CD47 activation on naïve T-cells also inhibited the differentiation of these cells into T helper 1 (Th1) effector cells (Avice et al., 2000). Specifically, incubation of umbicilical cord blood mononuclear cells with a CD47 antibody in the presence of Th1-differentiating conditions (IL-12+anti-IL4 mAb) reduced both IFN-γ and IL-2 production. This inhibition was also obtained when using F(ab')2 fragments of the CD47 mAb or an TSP-1 derived CD47-binding peptide. Mechanistically it was uncovered that the reduced Th1 differentiation upon CD47 ligation was caused by T-cell unresponsiveness toward IL-12 (Avice et al., 2000; Latour et al., 2001). In line with this, murine CD47-/- T-cells had elevated levels of Th1-lineage transcription factor Tbet, leading to higher levels of IFNγ production and Th1 differentiation than CD47 expressing cells, both in vitro and in vivo (Bouguermouh et al., 2008). Thus, CD47-signaling on T-cells has a two-fold effect, namely the enhanced differentiation of naïve T-cells into Tregs and reduced differentiation into Th1-cells (figure 2B). Of note, Th1 cells are the most effective helper T-cells during anti-tumor immune responses that control development and persistence of cytotoxic tumor-specific T-cells (Knutson and Disis, 2005). Therefore, the anti-cancer effect of CD47-targeted agents may be partly attributable to CD47-mediated reduction in Treg formation and an enhanced induction of Th1 cells via T-cell expressed CD47.

 

Controlling T-cell activity through "reverse" CD47 signaling

CD47-signaling can have a diverse and paradoxical outcome ranging from induction of T-cell death to activation of T-cells. For instance, CD47 ligation e.g. through soluble or immobilized TSP-1 induced a state of T-cell anergy characterized by unresponsiveness to T-cell receptor (TCR) stimulation and a lack of proliferation and IL-2 production (Avice et al., 2001; Li et al., 2001). In addition, CD47 ligation on T-cells can directly induce cell death, although contrasting data has been reported. Specifically, in one study anti-CD47 antibodies did not affect resting T-cells, but induced cell death in anti-CD3 stimulated T-cells (Pettersen et al., 1999). Reversely, in a second study, resting T-cells were sensitive toward CD47 crosslinking, whereas anti-CD3 T-activated T-cells proved resistant (Mateo et al., 2002). The reason for this discrepancy is not known, but might relate to different isolation methods and/or use of different soluble or cross-linked anti-CD3 mAbs.
These studies indicate that CD47 ligation mainly serves to shut-down T-cell immune responses (figure 2B). However, CD47 can also act as T-cell co-stimulator leading to enhanced proliferation upon cross-linking of anti-CD47 and anti-CD3 antibodies (Reinhold et al., 1997; Waclavicek et al., 1997). Notably, the anti-CD47 and anti-CD3 antibodies needed to be on the same surface, with a total lack of T-cell co-stimulation when one or both antibodies were provided in solution. Hence, it was hypothesized that anti-CD47 antibodies mimick a co-stimulatory signal provided by antigen presenting cells like DCs. In line with this, a soluble anti-CD47 antibody inhibited T-cell proliferation in co-cultures of T-cells and monocyte-derived DCs (Waclavicek et al., 1997). Further, in Jurkat leukemic T-cells interaction of CD47 with TSP-1 or SIRPα on inflammatory vascular endothelium induced recruitment of lymphocytes into inflammatory tissues (Ticchioni et al., 2001).
Of note, CD47 was also recently reported to directly associate with vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) expressed on T-cells (Kaur et al., 2014). In T-cells, VEGF induced VEGFR phosphorylation inhibits T-cells proliferation and TCR signaling and thus acts as an inhibitory pathway. As also reported in endothelial cells (see anti-angiogenic effects via CD47), VEGFR-2/CD47 interaction was disrupted by TSP-1 or CD47 binding peptide. TSP-1 or the CD47 binding peptide blocked VEGFR phosphorylation in wildtype, but not CD47-/- T-cells. Of note, CD47 also regulated expression of both VEGF and VEGFR, with CD47-/- cells having significantly higher levels of both proteins. Thus, CD47 appears to control an autocrine feedback loop in T-cells involving VEGF and VEGFR.

 

Controlling DC and neutrophil activity through "reverse" CD47 signaling

Like most cells, DCs are also characterized by surface expression of CD47. DC-expressed CD47 was found to be required for DC entry into lymphatic vessels and for DC migration under inflammatory conditions in mice (Van et al., 2006). Since pre-treatment with CD47-Fc did not further inhibit DC migration in CD47-deficient mice, these effects were due to DC-expressed CD47 and through negative signaling via e.g. SIRPα ligation. In addition, entry of CD47-/- DCs into the marginal zone of the spleen was impaired, with a reduced number of DCs in the splenic marginal zone in CD47-deficient mice (Hagnerud et al., 2006). Of note, the injection of CD47+/+ DCs but not CD47-/- DCs triggered efficient T-cell priming in CD47-/- mice, demonstrating that DC-expressed CD47 is crucial (Van et al., 2006). Thus, signaling through the intracellular CD47 domain on DCs is needed for efficient migration and entry of DCs to lymphoid organs.
On neutrophils CD47 appears to be similarly important for migration, with blocking anti-CD47 mAbs delaying neutrophil transmigration and the rate of migration correlating with neutrophil surface-expressed CD47 (Parkos et al., 1996; Liu et al., 2001). Thus, CD47 expressed on DCs and neutrophils is required to efficiently induce immune responses. The role of CD47 signaling on DCs and neutrophils in anti-cancer immune responses has not been evaluated yet, but will need to be taken into account when therapeutic targeting of CD47 is to be considered.

 

Therapeutic targeting of CD47 activity in cancer immunity

The therapeutic potential of targeting the immunoregulatory role of CD47 has been mainly investigated in the context of its anti-phagocyte activity (figure 3A) with a series of studies using monoclonal antibodies that disrupt CD47/SIRPα interaction. Anti-CD47 monoclonal antibody (mAb) B6H12 inhibited in vivo outgrowth and dissemination of xenotransplanted solid tumors and metastatic leiosarcoma as well as primary human NHL (Chao et al., 2011b; Willingham et al., 2012; Edris et al., 2012) (figure 3B). Further, in vivo outgrowth of human leukemia cells was inhibited by either CD47 or SIRPα blocking antibodies (Jaiswal et al., 2009; Majeti et al., 2009; Chao et al., 2011a). This therapeutic effect required macrophage effector cells since clonodrate depletion of macrophages abrogated any response (Jaiswal et al., 2009; Majeti et al., 2009; Chao et al., 2011a).
Nevertheless, the mechanism of CD47 antibody-mediated in vivo tumor depletion remains debated. Specifically, the dominant therapeutic mode-of-action of intact CD47 antibodies may be antibody dependent cellular cytotoxicity (ADCC) and FcR-dependent phagocytosis instead of disruption of CD47/SIRPα interaction (figure 3B). Indeed, injection of murine anti-CD47 mAb clone MIAP410 that does not affect CD47/SIRPα interaction (Han et al., 2000) also significantly inhibits tumor growth in immune competent mice (Willingham et al., 2012). Nevertheless, inhibition of CD47/SIRPα interaction alone can potentiate phagocytosis since CD47 targeted F(ab')2 fragments did induce phagocytosis of NHL cells by mouse macrophages in vitro (Chao et al., 2010a), whereas rituximab derived F(ab')2 fragments did not induce phagocytosis (figure 3C). Further, treatment of transgenic mice lacking SIRPα inhibitory signaling (by deletion of its cytoplasmic domain) with suboptimal concentrations of an anti-melanoma therapeutic antibody (mAb TA99) yielded effective anticancer activity, indicating that SIRPα-derived negative signaling limits antibody-mediated phagocytic elimination of target cells in vivo (figure 3D) (Zhao et al., 2011).
Thus, the activity of anti-CD47 blocking antibodies may partly be attributed to blocking of the CD47 don't eat me signal but perhaps for a large part also due to typical antibody effector functions upon binding to tumor-overexpressed CD47. Interestingly, in the above-described SIRPα-signaling deficient mouse model, tumor outgrowth was not affected in the absence of therapeutic antibody, indicating that relieving CD47/SIRPα signaling is not sufficient for elimination of cancerous cells (Zhao et al., 2011; Zhao et al., 2012; Soto-Pantoja et al., 2012) (figure 3D). Based on these data, the blocking of the CD47 anti-phagocytic signal may only effectively elicit phagocytosis of target cells when combined with a prominent pro-phagocytic (therapeutic antibody) signal (Chao et al., 2010b). Preclinical data support this premise, with for instance anti-CD47 mAb blocking or CD47 knockdown in SKBR3 breast cancer cells potentiating the cytotoxicity of anti-Her-2 antibody trastuzumab (Zhao et al., 2011). Moreover, combination treatment of NHL cells with rituximab and anti-CD47 potentiated their in vivo phagocytosis and elimination compared to rituximab alone (figure 3B) (Chao et al., 2011a). This synergistic enhancement also took place when an anti-CD47 F(ab')2 was co-administered with rituximab (Chao et al., 2011a) (figure 3C). Thus, probably the most effective use of releasing the brake on the immune response by blocking CD47 is in the context of combinatorial treatment with a therapeutic anti-cancer antibody.

Figure 3: Therapeutic targeting of CD47 activity in cancer immunity. A. The interaction of CD47 (over) expressed on cancer cells with signal regulatory protein α (SIRPα) on phagocytes results in inhibition of phagocytosis. B. The use of full anti-CD47 antibodies (containing an Fc-domain) prevents the interaction of CD47 with SIRPα, whereby phagocytosis is restored. This is also partly mediated by induction of ADCC via the Fcdomain of the antibody. The addition of a therapeutic antibody enhances the pro-phagocytic effect of anti-CD47 blockage. C. The use of F(ab')2 fragments of the anti-CD47 antibody (lacking the Fc-domain) showed efficacy in some studies, whereas others showed the requisite for the presence of a complete functional antibody. The addition of a therapeutic antibody enhanced the therapeutic effect of F(ab')2 fragment-mediated CD47-blockage. D. Disrupting the CD47/SIRPα signaling pathway by expressing a signaling deficient form of SIRPα (by deletion of its cytoplasmic domain), was not sufficient to eliminate cancer cells in mice. However, when these SIRPα-signaling deficient mice were treated with an therapeutic antibody, this yielded effective anticancer activity.

 

Challenges to CD47-targeting in cancer immune evasion

From the above it appears straightforward that the CD47/SIRPα interaction and reverse CD47 signaling in immune cells are prominent target for antibody-based approaches. However, there are a few open questions that remain to be addressed. First, several reports suggest CD47 can also function as an "eat me" signal in certain circumstances. For instance, a subset of old erythrocytes present in whole blood was shown to bind and to be phagocytosed via CD47-SIRPα interactions (Burger et al., 2012). Moreover, CD47/SIRPα interaction was shown to promote engulfment of apoptotic splenocytes by BAM3 macrophages (Tada et al., 2003). Transformation with CD47 also augmented phagocytosis of a CD47 negative lymphoma cell line after the induction of apoptosis. Similarly, trans-interaction of CD47 and SIRPα resulted in endocytosis of ligand-receptor complex by SIRPα-expressing cells (Kusakari et al., 2008).
Second and as also discussed earlier, CD47 can bind to SIRPβ2 (Piccio et al., 2005). The SIRPβ subfamily comprises SIRPβ1 and SIRPβ2 and has a short intracellular domain of only a few amino acids (e.g. 4 for SIRPβ1). Despite this short domain, SIRPβ family members can transmit signals, with e.g. a positively charged lysine in the transmembrane domain of SIRPβ1 mediating interactions with an immunoreceptor tyrosine-based activation motif (ITAM) containing adaptor protein. Of note, whereas SIRPβ1 does not bind to CD47 (Seiffert et al., 2001), interaction of SIRPβ2 on CD3-positive T-cells with endothelial CD47 is required for human T-cell trans-endothelial migration (Stefanidakis et al., 2008). Further, SIRPβ2 ligation by CD47 expressed on antigen-presenting cells induces T-cell proliferation (Piccio et al., 2005). Therefore, the use of CD47 blocking antibodies may also affect T-cell responses, e.g. by negatively regulating tumor-infiltration of T-cells.
Finally, it will be important to assess whether such CD47 antibodies have any effect on DC or T-cell activity through activation of reverse CD47 signaling. Of note, on DCs this CD47 signaling is required for migration and should thus be activated. In contrast, on T-cells the major effect of CD47 signaling appears to be inhibitory with induction of T-cell arrest and promotion of regulatory T-cell differentiation and should thus be inhibited. If and how to reconcile these various requisites is an outstanding question.

 

Anti-angiogenic and direct anti-cancer effects mediated by CD47

CD47 does not only affect the (cancer) immune response at various levels, but can also directly affect cancer cell biology and (neo)vascularization, i.e. tumor growth. Many of these effects can be attributed to interaction of tumor cell or endothelial cell-expressed CD47 with TSP-1. Thus, the CD47/TSP-1 axis represents an important tumor-suppressor pathway in cancer and is a prominent target for therapeutic intervention.

 

CD47/TSP-1 mediated anti-angiogenic activity

The inhibition of angiogenesis is one of the best studied effects of CD47/TSP-1 and is due to TSP-1 mediated modulation of endothelial cell adhesion, migration and proliferation (Lawler and Lawler, 2012). Indeed, vascular outgrowth of explants from melanoma cells grown in TSP-1 knock-out mice in type I collagen matrices was better compared to explants derived from wildtype animals (Isenberg et al., 2008). Exogenous addition of TSP-1 to TSP-1-/- melanoma explants reduced vascular outgrowth to levels comparable to wildtype explants. Reversely, cutaneous squamous cell carcinoma cells that overexpressed TSP-1 had a decreased tumor vessel number and size in mice (Streit et al., 1999). Similarly, overexpression of TSP-1 reduced vascularization in spontaneous mammary tumors, whereas vascularization was significantly increased in TSP-1 deficient mice (Rodriguez-Manzaneque et al., 2001).
The anti-angiogenic effects of TSP-1 were initially attributed to its binding to endothelial-expressed CD36 (Dawson et al., 1997). Specifically, native TSP-1 bound to surface immobilized CD36, an interaction that was blocked by anti-angiogenic TSP-1 peptides (Dawson et al., 1997). However, in three-dimensional collagen cultures, the anti-angiogenic effect of exogenous TSP-1 was abrogated in CD47-/- cells, but retained in CD36-/- cells (Isenberg et al., 2006), with ligation of CD36 also failing to inhibit NO-stimulated proliferation in CD47-/- cells. Furthermore, anti-angiogenic effects of TSP-1 were inhibited by a TSP-1 peptide that recognizes CD47, leading to inhibition of vascular outgrowth in TSP-1 wildtype muscle explants. Similarly, TSP-1 peptide-mediated ligation of CD47 was sufficient to inhibit NO-stimulated vascular cell responses. In line with this, overexpression of TSP-1 by tumor cells decreases tumor blood flow in response to NO in vivo, which was abrogated in mice expressing a truncated TSP-1 lacking affinity for CD47 (Isenberg et al., 2008). Importantly, inhibitory signaling of TSP-1 via CD47 takes place at relevant physiological levels of TSP-1 (picomolar range), whereas TSP-1 mediated inhibitory signaling via CD36 requires higher concentrations of TSP-1 (nanomolar range) (Isenberg et al., 2006).
Thus, TSP-1 mediated inhibition of angiogenesis is regulated via interactions with both CD36 and CD47, whereby CD47 likely acts downstream of CD36 in endothelial signaling. Therefore, CD47 is the dominant anti-angiogenic receptor for TSP-1 mediated inhibition of angiogenesis (figure 4A).

Figure 4: Anti-angiogenic and direct anti-cancer effects mediated by CD47. A. TSP-1 inhibits angiogenesis via binding to CD36 and CD47. However, TSP-1 mediated inhibition of angiogenesis by binding to CD36 is also regulated via CD47. In addition, CD47 directly interacts with vascular endothelial growth factor receptor-2 (VEGFR-2) on endothelial cells. By binding to CD47, this interaction is abrogated by TSP-1, whereby angiogenesis is inhibited. Further, TSP-1 can directly bind to VEGF, thereby preventing its interaction with VEGFR-2. B. Crosslinking of CD47 by antibodies or TSP-1 can lead to caspase-independent cancer cell death.

 

CD47 mediated regulation of angiogenesis via VEGFR-2

In addition to the above-described TSP-1/CD47-mediated inhibition of blood vessel formation, CD47 directly interacts with VEGFR-2 on endothelial cells (Kaur et al., 2010). This direct interaction between CD47 and VEGFR-2 was demonstrated using immunofluorescent co-localization analysis and co-immunoprecipitation. The association of CD47 with VEGFR was abrogated by TSP-1 or TSP-1 derived peptides that bind to CD47, but not by CD36 binding peptides. Furthermore, TSP-1 binding to CD47 prevented phosphorylation of VEGFR-2 and its downstream target Akt (Kaur et al., 2010). Thus by binding to CD47, TSP-1 prevents CD47/VEGFR interaction and subsequent downstream signaling. In addition, TSP-1 itself also directly interacts with VEGF, thereby preventing angiogenic VEGF/VEGFR interaction (Gupta et al., 1999). In line with this, knockdown of TSP-1 increased the association of VEGF with VEGFR in spontaneous murine mammary tumors (Rodriguez-Manzaneque et al., 2001). Thus, the anti-angiogenic effect of TSP-1 is also partly due to disturbing VEGF/VEGFR interaction either directly by binding to VEGF or by inhibition of CD47/ VEGFR interaction, an interaction crucial for downstream signaling (figure 4A).

 

Direct anti-cancer effects via cross linking of tumor expressed CD47

The engagement of cancer cell-expressed CD47 by soluble TSP-1 strongly inhibited in vitro growth of a panel of breast cancer cell lines or pro-myelocytic leukemia cells through induction of caspase-independent cell death (Saumet et al., 2005; Manna and Frazier, 2004). In breast cancer cell lines, cell death induction by CD47 requires Gi-mediated inhibition of protein kinase A (Manna and Frazier, 2004). Similarly, B-cell chronic lymphocytic leukemia cells undergo caspase-independent cell death dependent on cytoskeletal reorganization upon treatment with soluble TSP-1 or anti-CD47 antibody (Mateo et al., 1999; Mateo et al., 2002) (figure 4B). Of note, TSP-1 or a CD47-blocking peptide reduced cell viability and in vivo growth of cells expressing oncogenic RAS, but did not affect immortalized nontumorigenic parental cells (Kalas et al., 2013). This tumoricidal activity of TSP-1 was dependent on CD47 cross-linking and activation of cytotoxic autophagy. These experimental results are in line with the near complete loss of TSP-1 expression in RAS-transformed cells. TSP-1/CD47 interaction can also differentially affect cancer cell sensitivity toward chemotherapeutics. For instance, TSP-1 sensitized taxol-resistant prostate cancer cells to taxol treatment (Lih et al., 2006), whereas a blocking anti-CD47 antibody decreases cytotoxicity of taxol treatment. Of note, taxol resistance is partly regulated by the txr1 gene, a gene known to down-regulate TSP-1 expression. Correspondingly, treatment with a TSP-1 mimetic peptide sensitized cells to taxol by activating CD47 signaling (Lih et al., 2006). In contrast, treatment of thyroid carcinoma cells with a CD47-binding peptide reduced doxorubicin and camtothecin cytotoxicity (Rath et al., 2006). In line with this, pro-apoptotic activity of camtothecin and doxorubicin relied on down-regulation of TSP-1 expression in thyroid carcinoma (Rath et al., 2006).
Therefore, the effect of TSP-1/CD47-signaling on apoptosis is likely dependent on cancer type as well as type of therapy. In this respect, blocking of either CD47 or TSP-1 increased radiosensitivity of tumors, whereas it induced radioprotection in normal endothelial cells (Maxhimer et al., 2009). Although the mechanism of this differential response between normal and transformed cells is unknown, the in vitro suppression of CD47 did not increase the sensitivity of melanoma cells to radiation. Therefore, it was hypothesized that the observed enhanced anti-tumor effects were due to induction of tumor-specific immune responses.
Thus, although cancer cells often up-regulate CD47 expression to escape from the immune system presumably via SIRPα-mediated inhibitory signaling, cancer cells may also benefit from loss of expression of CD47. In this respect, loss of CD47 expression was also found to up-regulate c-Myc, induce cell proliferation and upregulate the self-renewal potential of endothelial cells (Kaur et al., 2013). Correspondingly, treatment with TSP-1 or the TSP-1 derived peptide 7N3, inhibited c-Myc expression in Jurkat cells, but did not effect c-Myc expression in CD47-/- cells (Kaur et al., 2013). In contrast, the use of the TSP-1 derived peptide enhanced proliferation in human astrocytoma cell lines via an Akt-dependent pathway (Sick et al., 2011). Taken together, CD47-signaling via binding to TSP-1 is involved in both tumorigenic as tumoricidal processes, although the latter seem to be the most prevalent outcome.

 

Therapeutic exploitation of CD47-mediated anti-angiogenic and direct anti-cancer effects

Based on the above, the therapeutic exploitation of CD47/TSP-1 interaction might prevent or reduce angiogenesis and tumor progression through both anti-angiogenic and possibly direct anti-cancer effects. Proof of concept for the former mechanism has been generated using a synthetic peptide, designated ABT-510, that mimics the anti-angiogenic activity of TSP-1. ABT-510 treatment significantly increased the number of patients with stable disease in patients with advanced solid malignancy (12 different types of advanced cancer, including colorectal cancer, non-small-cell-lung cancer, renal cell cancer and sarcoma) (Hoekstra et al., 2005). Further, ABT-510 was well tolerated without significant toxicity in phase I trials upon subcutaneous application in patients with advanced stages of solid cancer (Gordon et al., 2008). However, minimal antitumor activity was detected in various phase II clinical trials including in advanced renal cell carcinoma (Ebbinghaus et al., 2007), metastatic melanoma (Markovic et al., 2007) and advanced soft tissue sarcoma (Baker et al., 2008). Optimization of peptide design may be used to further increase efficacy, as evidenced by a comparative study in dogs where better responses were detected with the second-generation TSP-1 peptide ABT-898 (Sahora et al., 2012).
However, most anti-angiogenic agents are best suited in combinatorial strategies with e.g. chemotherapeutics (Ma and Waxman, 2008). In line with this, ABT-510 increased the uptake and effectiveness of cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer (Campbell et al., 2010). Further, combination treatment with ABT-510 and bevacizumab prolonged the duration of stable disease in patients with advanced solid tumors (Uronis et al., 2013). Thus, blocking of TSP-1/CD47 interaction e.g. using anti-CD47 antibodies, in further combination with anti-angiogenic and chemotherapeutic regimens may well have clinical potential. However, clinical application of this strategy will need to take into account that tumors can upon prolonged exposure eventually by-pass anti-angiogenic effects of TSP-1 (Filleur et al., 2001). In this respect, an optimal CD47-targeted strategy would provide a dual hit approach that would trigger not only anti-angiogenic activity but also direct CD47-mediated anti-cancer signaling that would sensitive cells for combinatorial strategies such as standard-of-care chemo/radiotherapy.

 

Conclusions and perspectives

CD47 is a prominent target for cancer therapy and has three main effects that should be considered in the design of CD47-based cancer therapy. The first and perhaps most studied effect is the inhibitory effect on anti-cancer immunity, which occurs through overexpression of CD47 on tumor cells and inhibition of phagocytes through SIRPα binding (figure 5A). The second effect of CD47 is its reverse signaling activity through neutrophil, DC, or T-cell expressed CD47 that can both inhibit and activate immune responses. Finally, CD47 has direct anti-cancer and anti-angiogenic activity through its interaction with TSP-1 (figure 5B). All of these different aspects have to be carefully characterized for each malignancy and possibly in each patient using appropriately identified predictive biomarkers for CD47-based immunotherapy.
Therapeutic anti-CD47 antibodies have shown promising pro-phagocytic activity in preclinical models. Further integration of CD47-targeting into bi-functional immunotherapeutics that combine CD47 blockade with alternate effector moieties may help to expand on this therapeutic effect. In this respect, we recently described an anti-CD47:TRAIL fusion protein that both induced phagocytosis via CD47 inhibition as well as induced CD47-restricted cell death in malignant B-cells (Wiersma et al., 2014) (figure 5C). In an analogous fashion, it would be interesting to evaluate whether a bispecific antibody comprising a CD47 blocking antibody fragment and antibody fragment targeting a tumor overexpressed antigen could trigger tumor-localized accretion and inhibition of negative immunoregulatory signaling by CD47. Further, an approach combining both the anti-angiogenic effects of e.g. TSP-1 peptides and the pro-phagocytic activity of anti-CD47 mAbs may yield synergistic direct and immunostimulatory effects.

Figure 5: Perspectives in CD47-targeted cancer therapy. A. Blocking CD47/SIRPα signaling by use of anti-CD47 antibodies is effective, especially when combined with other therapeutic antibodies. B. Inhibition of angiogenesis via TSP-1/CD47 mediated signaling has potent anti-cancer effects. Combining the enhancement of phagocytosis and inhibition of angiogenesis would be of interest. C. Combining CD47 blockade with alternate effector moieties may help to expand on the therapeutic effect of this approach. In this respect, the anti-CD47:TRAIL fusion protein induced phagocytosis via CD47 inhibition, especially when combined with therapeutic antibodies, as well as induced CD47-restricted cell death in malignant B-cells.

 

Finally, CD47 overexpression in cancer can also be targeted with siRNA or miRNAs that down-regulate CD47. The potential of such an approach is highlighted by the delivery of liposome encapsulated CD47 siRNA, which effectively inhibited melanoma outgrowth and metastasis (Wang et al., 2013), whereas CD47-targeted siRNA or shRNA treatment reduced migration of colon cancer cells (Broom et al., 2009; Zhang et al., 2013) and prevented in vivo dissemination of Non-Hodgkin lymphoma cells (Chao et al., 2011b). Finally, the transfection or injection of miR-133a, known to regulate CD47 expression, into mouse tumor xenografts significantly inhibited tumor outgrowth (Suzuki et al., 2012; Dong et al., 2013). Thus, siRNA or miRNA-mediated down-regulation of CD47 is a potentially interesting approach, which will however need to be performed using tumor-selective delivery systems in order to prevent systemic side-effects.
In conclusion, many different therapeutic strategies that target CD47 have already proven effective in preclinical models. The next few years are likely to witness the translation of CD47-targeting approaches into the clinic. This may hinge on development of strategies that have increased the tumor-selectivity of CD47 blocking as well as identification of optimal combinatorial strategies with e.g. standard chemo/radiotherapy or combined triggering of anti-angiogenic TSP-1 signaling.

Bibliography

Monoclonal antibody against human ovarian tumor-associated antigens.
Poels LG, Peters D, van Megen Y, Vooijs GP, Verheyen RN, Willemen A, van Niekerk CC, Jap PH, Mungyer G, Kenemans P.
J Natl Cancer Inst. 1986 May;76(5):781-91.
PMID 3517452
 
Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding.
Lindberg FP, Gresham HD, Schwarz E, Brown EJ.
J Cell Biol. 1993 Oct;123(2):485-96.
PMID 7691831
 
Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis.
Weinstat-Saslow DL, Zabrenetzky VS, VanHoutte K, Frazier WA, Roberts DD, Steeg PS.
Cancer Res. 1994 Dec 15;54(24):6504-11.
PMID 7527299
 
Expression of the extracellular matrix molecule thrombospondin inversely correlates with malignant progression in melanoma, lung and breast carcinoma cell lines.
Zabrenetzky V, Harris CC, Steeg PS, Roberts DD.
Int J Cancer. 1994 Oct 15;59(2):191-5.
PMID 7927918
 
In vivo expression of alternatively spliced forms of integrin-associated protein (CD47).
Reinhold MI, Lindberg FP, Plas D, Reynolds S, Peters MG, Brown EJ.
J Cell Sci. 1995 Nov;108 ( Pt 11):3419-25.
PMID 8586654
 
A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion.
Fujioka Y, Matozaki T, Noguchi T, Iwamatsu A, Yamao T, Takahashi N, Tsuda M, Takada T, Kasuga M.
Mol Cell Biol. 1996 Dec;16(12):6887-99.
PMID 8943344
 
CD47 mediates post-adhesive events required for neutrophil migration across polarized intestinal epithelia.
Parkos CA, Colgan SP, Liang TW, Nusrat A, Bacarra AE, Carnes DK, Madara JL.
J Cell Biol. 1996 Feb;132(3):437-50.
PMID 8636220
 
Regulation of tumor growth and metastasis by thrombospondin-1.
Roberts DD.
FASEB J. 1996 Aug;10(10):1183-91. (REVIEW)
PMID 8751720
 
Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression.
Grossfeld GD, Ginsberg DA, Stein JP, Bochner BH, Esrig D, Groshen S, Dunn M, Nichols PW, Taylor CR, Skinner DG, Cote RJ.
J Natl Cancer Inst. 1997 Feb 5;89(3):219-27.
PMID 9017002
 
CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells.
Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP.
J Cell Biol. 1997 Aug 11;138(3):707-17.
PMID 9245797
 
A family of proteins that inhibit signalling through tyrosine kinase receptors.
Kharitonenkov A, Chen Z, Sures I, Wang H, Schilling J, Ullrich A.
Nature. 1997 Mar 13;386(6621):181-6.
PMID 9062191
 
Costimulation of T cell activation by integrin-associated protein (CD47) is an adhesion-dependent, CD28-independent signaling pathway.
Reinhold MI, Lindberg FP, Kersh GJ, Allen PM, Brown EJ.
J Exp Med. 1997 Jan 6;185(1):1-11.
PMID 8996237
 
T cell stimulation via CD47: agonistic and antagonistic effects of CD47 monoclonal antibody 1/1A4.
Waclavicek M, Majdic O, Stulnig T, Berger M, Baumruker T, Knapp W, Pickl WF.
J Immunol. 1997 Dec 1;159(11):5345-54.
PMID 9548474
 
Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis.
Gupta K, Gupta P, Wild R, Ramakrishnan S, Hebbel RP.
Angiogenesis. 1999;3(2):147-58.
PMID 14517432
 
CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia.
Mateo V, Lagneaux L, Bron D, Biron G, Armant M, Delespesse G, Sarfati M.
Nat Med. 1999 Nov;5(11):1277-84.
PMID 10545994
 
CD47 signals T cell death.
Pettersen RD, Hestdal K, Olafsen MK, Lie SO, Lindberg FP.
J Immunol. 1999 Jun 15;162(12):7031-40.
PMID 10358145
 
Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47.
Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, Brown EJ, Ullrich A, Buhring HJ.
Blood. 1999 Dec 1;94(11):3633-43.
PMID 10572074
 
Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas.
Streit M, Velasco P, Brown LF, Skobe M, Richard L, Riccardi L, Lawler J, Detmar M.
Am J Pathol. 1999 Aug;155(2):441-52.
PMID 10433937
 
CD47 ligation selectively inhibits the development of human naive T cells into Th1 effectors.
Avice MN, Rubio M, Sergerie M, Delespesse G, Sarfati M.
J Immunol. 2000 Oct 15;165(8):4624-31.
PMID 11035105
 
CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation.
Han X, Sterling H, Chen Y, Saginario C, Brown EJ, Frazier WA, Lindberg FP, Vignery A.
J Biol Chem. 2000 Dec 1;275(48):37984-92.
PMID 10964914
 
Role of CD47 as a marker of self on red blood cells.
Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP.
Science. 2000 Jun 16;288(5473):2051-4.
PMID 10856220
 
Thrombospondin-1 expression in epithelial ovarian carcinoma: association with p53 status, tumor angiogenesis, and survival in platinum-treated patients.
Alvarez AA, Axelrod JR, Whitaker RS, Isner PD, Bentley RC, Dodge RK, Rodriguez GC.
Gynecol Oncol. 2001 Aug;82(2):273-8.
PMID 11531279
 
Role of CD47 in the induction of human naive T cell anergy.
Avice MN, Rubio M, Sergerie M, Delespesse G, Sarfati M.
J Immunol. 2001 Sep 1;167(5):2459-68.
PMID 11509584
 
In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects.
Filleur S, Volpert OV, Degeorges A, Voland C, Reiher F, Clezardin P, Bouck N, Cabon F.
Genes Dev. 2001 Jun 1;15(11):1373-82.
PMID 11390357
 
Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation.
Latour S, Tanaka H, Demeure C, Mateo V, Rubio M, Brown EJ, Maliszewski C, Lindberg FP, Oldenborg A, Ullrich A, Delespesse G, Sarfati M.
J Immunol. 2001 Sep 1;167(5):2547-54.
PMID 11509594
 
Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice.
Lawler J, Miao WM, Duquette M, Bouck N, Bronson RT, Hynes RO.
Am J Pathol. 2001 Nov;159(5):1949-56.
PMID 11696456
 
Thrombospondin-1 inhibits TCR-mediated T lymphocyte early activation.
Li Z, He L, Wilson K, Roberts D.
J Immunol. 2001 Feb 15;166(4):2427-36.
PMID 11160302
 
The role of CD47 in neutrophil transmigration. Increased rate of migration correlates with increased cell surface expression of CD47.
Liu Y, Merlin D, Burst SL, Pochet M, Madara JL, Parkos CA.
J Biol Chem. 2001 Oct 26;276(43):40156-66. Epub 2001 Jul 30.
PMID 11479293
 
Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor.
Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML.
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12485-90. Epub 2001 Oct 16.
PMID 11606713
 
Signal-regulatory protein alpha (SIRPalpha) but not SIRPbeta is involved in T-cell activation, binds to CD47 with high affinity, and is expressed on immature CD34(+)CD38(-) hematopoietic cells.
Seiffert M, Brossart P, Cant C, Cella M, Colonna M, Brugger W, Kanz L, Ullrich A, Buhring HJ.
Blood. 2001 May 1;97(9):2741-9.
PMID 11313266
 
Expresson of vascular endothelial growth factor, its receptors (FLT-1, KDR) and TSP-1 related to microvessel density and patient outcome in vertical growth phase melanomas.
Straume O, Akslen LA.
Am J Pathol. 2001 Jul;159(1):223-35.
PMID 11438469
 
Integrin-associated protein (CD47/IAP) contributes to T cell arrest on inflammatory vascular endothelium under flow.
Ticchioni M, Raimondi V, Lamy L, Wijdenes J, Lindberg FP, Brown EJ, Bernard A.
FASEB J. 2001 Feb;15(2):341-50.
PMID 11156950
 
Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization.
Mateo V, Brown EJ, Biron G, Rubio M, Fischer A, Deist FL, Sarfati M.
Blood. 2002 Oct 15;100(8):2882-90.
PMID 12351399
 
Tethering of apoptotic cells to phagocytes through binding of CD47 to Src homology 2 domain-bearing protein tyrosine phosphatase substrate-1.
Tada K, Tanaka M, Hanayama R, Miwa K, Shinohara A, Iwamatsu A, Nagata S.
J Immunol. 2003 Dec 1;171(11):5718-26.
PMID 14634079
 
Alpha-Pal/NRF-1 regulates the promoter of the human integrin-associated protein/CD47 gene.
Chang WT, Huang AM.
J Biol Chem. 2004 Apr 9;279(15):14542-50. Epub 2004 Jan 27.
PMID 14747477
 
Expression and activation of signal regulatory protein alpha on astrocytomas.
Chen TT, Brown EJ, Huang EJ, Seaman WE.
Cancer Res. 2004 Jan 1;64(1):117-27.
PMID 14729615
 
CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A.
Manna PP, Frazier WA.
Cancer Res. 2004 Feb 1;64(3):1026-36.
PMID 14871834
 
Resistance of B16 melanoma cells to CD47-induced negative regulation of motility as a result of aberrant N-glycosylation of SHPS-1.
Ogura T, Noguchi T, Murai-Takebe R, Hosooka T, Honma N, Kasuga M.
J Biol Chem. 2004 Apr 2;279(14):13711-20. Epub 2004 Jan 21.
PMID 14739297
 
Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma.
Poon RT, Chung KK, Cheung ST, Lau CP, Tong SW, Leung KL, Yu WC, Tuszynski GP, Fan ST.
Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4150-7.
PMID 15217952
 
A novel function of transcription factor alpha-Pal/NRF-1: increasing neurite outgrowth.
Chang WT, Chen HI, Chiou RJ, Chen CY, Huang AM.
Biochem Biophys Res Commun. 2005 Aug 19;334(1):199-206.
PMID 15992771
 
Phase I safety, pharmacokinetic, and pharmacodynamic study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced cancer.
Hoekstra R, de Vos FY, Eskens FA, Gietema JA, van der Gaast A, Groen HJ, Knight RA, Carr RA, Humerickhouse RA, Verweij J, de Vries EG.
J Clin Oncol. 2005 Aug 1;23(22):5188-97.
PMID 16051960
 
Tumor antigen-specific T helper cells in cancer immunity and immunotherapy.
Knutson KL, Disis ML.
Cancer Immunol Immunother. 2005 Aug;54(8):721-8. Epub 2005 Jan 27. (REVIEW)
PMID 16010587
 
Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system.
Okazawa H, Motegi S, Ohyama N, Ohnishi H, Tomizawa T, Kaneko Y, Oldenborg PA, Ishikawa O, Matozaki T.
J Immunol. 2005 Feb 15;174(4):2004-11.
PMID 15699129
 
Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation.
Piccio L, Vermi W, Boles KS, Fuchs A, Strader CA, Facchetti F, Cella M, Colonna M.
Blood. 2005 Mar 15;105(6):2421-7. Epub 2004 Sep 21.
PMID 15383453
 
THBS1 (thrombospondin-1).
Roberts DD.
Atlas Genet Cytogenet Oncol Haematol. 2005;9:231-3.
 
Type 3 repeat/C-terminal domain of thrombospondin-1 triggers caspase-independent cell death through CD47/alphavbeta3 in promyelocytic leukemia NB4 cells.
Saumet A, Slimane MB, Lanotte M, Lawler J, Dubernard V.
Blood. 2005 Jul 15;106(2):658-67. Epub 2005 Mar 22.
PMID 15784731
 
Thrombospondins, metallo proteases and thrombospondin receptors messenger RNA and protein expression in different tumour sublines of the Dunning prostate cancer model.
Vallbo C, Damber JE.
Acta Oncol. 2005;44(3):293-8.
PMID 16076702
 
Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25- T cells in response to inflammation.
Grimbert P, Bouguermouh S, Baba N, Nakajima T, Allakhverdi Z, Braun D, Saito H, Rubio M, Delespesse G, Sarfati M.
J Immunol. 2006 Sep 15;177(6):3534-41.
PMID 16951312
 
Deficit of CD47 results in a defect of marginal zone dendritic cells, blunted immune response to particulate antigen and impairment of skin dendritic cell migration.
Hagnerud S, Manna PP, Cella M, Stenberg A, Frazier WA, Colonna M, Oldenborg PA.
J Immunol. 2006 May 15;176(10):5772-8.
PMID 16670282
 
CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1.
Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD.
J Biol Chem. 2006 Sep 8;281(36):26069-80. Epub 2006 Jul 11.
PMID 16835222
 
Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes.
Lih CJ, Wei W, Cohen SN.
Genes Dev. 2006 Aug 1;20(15):2082-95. Epub 2006 Jul 17.
PMID 16847352
 
Post-translational regulation of expression and conformation of an immunoglobulin domain in yeast surface display.
Parthasarathy R, Subramanian S, Boder ET, Discher DE.
Biotechnol Bioeng. 2006 Jan 5;93(1):159-68.
PMID 16161151
 
The C-terminal CD47/IAP-binding domain of thrombospondin-1 prevents camptothecin- and doxorubicin-induced apoptosis in human thyroid carcinoma cells.
Rath GM, Schneider C, Dedieu S, Rothhut B, Soula-Rothhut M, Ghoneim C, Sid B, Morjani H, El Btaouri H, Martiny L.
Biochim Biophys Acta. 2006 Oct;1763(10):1125-34. Epub 2006 Aug 5.
PMID 16962673
 
Species- and cell type-specific interactions between CD47 and human SIRPalpha.
Subramanian S, Parthasarathy R, Sen S, Boder ET, Discher DE.
Blood. 2006 Mar 15;107(6):2548-56. Epub 2005 Nov 15.
PMID 16291597
 
Expression of the self-marker CD47 on dendritic cells governs their trafficking to secondary lymphoid organs.
Van VQ, Lesage S, Bouguermouh S, Gautier P, Rubio M, Levesque M, Nguyen S, Galibert L, Sarfati M.
EMBO J. 2006 Nov 29;25(23):5560-8. Epub 2006 Nov 9.
PMID 17093498
 
Phase 2 study of ABT-510 in patients with previously untreated advanced renal cell carcinoma.
Ebbinghaus S, Hussain M, Tannir N, Gordon M, Desai AA, Knight RA, Humerickhouse RA, Qian J, Gordon GB, Figlin R.
Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6689-95.
PMID 18006769
 
A phase II study of ABT-510 (thrombospondin-1 analog) for the treatment of metastatic melanoma.
Markovic SN, Suman VJ, Rao RA, Ingle JN, Kaur JS, Erickson LA, Pitot HC, Croghan GA, McWilliams RR, Merchan J, Kottschade LA, Nevala WK, Uhl CB, Allred J, Creagan ET.
Am J Clin Oncol. 2007 Jun;30(3):303-9.
PMID 17551310
 
Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma.
Rendtlew Danielsen JM, Knudsen LM, Dahl IM, Lodahl M, Rasmussen T.
Br J Haematol. 2007 Sep;138(6):756-60.
PMID 17760807
 
Phylogenetic divergence of CD47 interactions with human signal regulatory protein alpha reveals locus of species specificity. Implications for the binding site.
Subramanian S, Boder ET, Discher DE.
J Biol Chem. 2007 Jan 19;282(3):1805-18. Epub 2006 Nov 10.
PMID 17098740
 
Randomized, phase II study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced soft tissue sarcoma.
Baker LH, Rowinsky EK, Mendelson D, Humerickhouse RA, Knight RA, Qian J, Carr RA, Gordon GB, Demetri GD.
J Clin Oncol. 2008 Dec 1;26(34):5583-8. doi: 10.1200/JCO.2008.17.4706. Epub 2008 Nov 3.
PMID 18981463
 
Role of melanoma secreted thrombospondin-1 on induction of immunosuppressive regulatory T cells through CD47.
Baumgartner JM, Palmer BE, Banerjee A, McCarter MD.
J Cancer Mol. 2008;4:145-52.
 
CD47 expression on T cell is a self-control negative regulator of type 1 immune response.
Bouguermouh S, Van VQ, Martel J, Gautier P, Rubio M, Sarfati M.
J Immunol. 2008 Jun 15;180(12):8073-82.
PMID 18523271
 
A phase 1 trial of 2 dose schedules of ABT-510, an antiangiogenic, thrombospondin-1-mimetic peptide, in patients with advanced cancer.
Gordon MS, Mendelson D, Carr R, Knight RA, Humerickhouse RA, Iannone M, Stopeck AT.
Cancer. 2008 Dec 15;113(12):3420-9. doi: 10.1002/cncr.23953.
PMID 18932258
 
Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47.
Hatherley D, Graham SC, Turner J, Harlos K, Stuart DI, Barclay AN.
Mol Cell. 2008 Jul 25;31(2):266-77. doi: 10.1016/j.molcel.2008.05.026.
PMID 18657508
 
Thrombospondin 1 and vasoactive agents indirectly alter tumor blood flow.
Isenberg JS, Hyodo F, Ridnour LA, Shannon CS, Wink DA, Krishna MC, Roberts DD.
Neoplasia. 2008 Aug;10(8):886-96.
PMID 18670646
 
Trans-endocytosis of CD47 and SHPS-1 and its role in regulation of the CD47-SHPS-1 system.
Kusakari S, Ohnishi H, Jin FJ, Kaneko Y, Murata T, Murata Y, Okazawa H, Matozaki T.
J Cell Sci. 2008 Apr 15;121(Pt 8):1213-23. doi: 10.1242/jcs.025015. Epub 2008 Mar 18.
PMID 18349073
 
Combination of antiangiogenesis with chemotherapy for more effective cancer treatment.
Ma J, Waxman DJ.
Mol Cancer Ther. 2008 Dec;7(12):3670-84. doi: 10.1158/1535-7163.MCT-08-0715. (REVIEW)
PMID 19074844
 
Endothelial CD47 interaction with SIRPgamma is required for human T-cell transendothelial migration under shear flow conditions in vitro.
Stefanidakis M, Newton G, Lee WY, Parkos CA, Luscinskas FW.
Blood. 2008 Aug 15;112(4):1280-9. doi: 10.1182/blood-2008-01-134429. Epub 2008 Jun 4.
PMID 18524990
 
Inhibition of "self" engulfment through deactivation of myosin-II at the phagocytic synapse between human cells.
Tsai RK, Discher DE.
J Cell Biol. 2008 Mar 10;180(5):989-1003. doi: 10.1083/jcb.200708043.
PMID 18332220
 
CD47 regulates collagen I-induced cyclooxygenase-2 expression and intestinal epithelial cell migration.
Broom OJ, Zhang Y, Oldenborg PA, Massoumi R, Sjolander A.
PLoS One. 2009 Jul 28;4(7):e6371. doi: 10.1371/journal.pone.0006371.
PMID 19636412
 
Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells.
Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, Gill H, Presti J Jr, Chang HY, van de Rijn M, Shortliffe L, Weissman IL.
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14016-21. doi: 10.1073/pnas.0906549106. Epub 2009 Aug 4.
PMID 19666525
 
CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis.
Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, Traver D, van Rooijen N, Weissman IL.
Cell. 2009 Jul 23;138(2):271-85. doi: 10.1016/j.cell.2009.05.046.
PMID 19632178
 
MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47.
Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, Bittner R, Lassmann H, Wekerle H, Hohlfeld R, Meinl E.
Brain. 2009 Dec;132(Pt 12):3342-52. doi: 10.1093/brain/awp300.
PMID 19952055
 
CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells.
Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, van Rooijen N, Weissman IL.
Cell. 2009 Jul 23;138(2):286-99. doi: 10.1016/j.cell.2009.05.045.
PMID 19632179
 
Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling.
Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, Degraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD.
Sci Transl Med. 2009 Oct 21;1(3):3ra7. doi: 10.1126/scitranslmed.3000139.
PMID 20161613
 
Tumoral expression of TXR1 and TSP1 predicts overall survival of patients with lung adenocarcinoma treated with first-line docetaxel-gemcitabine regimen.
Papadaki C, Mavroudis D, Trypaki M, Koutsopoulos A, Stathopoulos E, Hatzidaki D, Tsakalaki E, Georgoulias V, Souglakos J.
Clin Cancer Res. 2009 Jun 1;15(11):3827-33. doi: 10.1158/1078-0432.CCR-08-3027. Epub 2009 May 12.
PMID 19435835
 
The thrombospondin-1 mimetic ABT-510 increases the uptake and effectiveness of cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer.
Campbell NE, Greenaway J, Henkin J, Moorehead RA, Petrik J.
Neoplasia. 2010 Mar;12(3):275-83.
PMID 20234821
 
Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma.
Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, Zhao F, Kohrt HE, Malumbres R, Briones J, Gascoyne RD, Lossos IS, Levy R, Weissman IL, Majeti R.
Cell. 2010a Sep 3;142(5):699-713. doi: 10.1016/j.cell.2010.07.044.
PMID 20813259
 
Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47.
Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY, Majeti R, Weissman IL.
Sci Transl Med. 2010b Dec 22;2(63):63ra94. doi: 10.1126/scitranslmed.3001375.
PMID 21178137
 
Thrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47.
Kaur S, Martin-Manso G, Pendrak ML, Garfield SH, Isenberg JS, Roberts DD.
J Biol Chem. 2010 Dec 10;285(50):38923-32. doi: 10.1074/jbc.M110.172304. Epub 2010 Oct 5.
PMID 20923780
 
Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients.
Nagahara M, Mimori K, Kataoka A, Ishii H, Tanaka F, Nakagawa T, Sato T, Ono S, Sugihara K, Mori M.
Clin Cancer Res. 2010 Sep 15;16(18):4625-35. doi: 10.1158/1078-0432.CCR-10-0349. Epub 2010 Aug 12.
PMID 20705613
 
Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia.
Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R.
Cancer Res. 2011a Feb 15;71(4):1374-84. doi: 10.1158/0008-5472.CAN-10-2238. Epub 2010 Dec 21.
PMID 21177380
 
Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy.
Chao MP, Tang C, Pachynski RK, Chin R, Majeti R, Weissman IL.
Blood. 2011b Nov 3;118(18):4890-901. doi: 10.1182/blood-2011-02-338020. Epub 2011 Aug 9.
PMID 21828138
 
Heparan sulfate modification of the transmembrane receptor CD47 is necessary for inhibition of T cell receptor signaling by thrombospondin-1.
Kaur S, Kuznetsova SA, Pendrak ML, Sipes JM, Romeo MJ, Li Z, Zhang L, Roberts DD.
J Biol Chem. 2011 Apr 29;286(17):14991-5002. doi: 10.1074/jbc.M110.179663. Epub 2011 Feb 22.
PMID 21343308
 
Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway.
Sick E, Boukhari A, Deramaudt T, Ronde P, Bucher B, Andre P, Gies JP, Takeda K.
Glia. 2011 Feb;59(2):308-19. doi: 10.1002/glia.21102.
PMID 21125662
 
CD47-signal regulatory protein-alpha (SIRPalpha) interactions form a barrier for antibody-mediated tumor cell destruction.
Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA, Finetti P, Van Egmond M, Matozaki T, Kraal G, Birnbaum D, van Elsas A, Kuijpers TW, Bertucci F, van den Berg TK.
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18342-7. doi: 10.1073/pnas.1106550108. Epub 2011 Oct 31.
PMID 22042861
 
CD47 functions as a molecular switch for erythrocyte phagocytosis.
Burger P, Hilarius-Stokman P, de Korte D, van den Berg TK, van Bruggen R.
Blood. 2012 Jun 7;119(23):5512-21. doi: 10.1182/blood-2011-10-386805. Epub 2012 Mar 16.
PMID 22427202
 
Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma.
Edris B, Weiskopf K, Volkmer AK, Volkmer JP, Willingham SB, Contreras-Trujillo H, Liu J, Majeti R, West RB, Fletcher JA, Beck AH, Weissman IL, van de Rijn M.
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6656-61. doi: 10.1073/pnas.1121629109. Epub 2012 Mar 26.
PMID 22451919
 
Thrombospondin-1 expression in breast cancer: prognostic significance and association with p53 alterations, tumour angiogenesis and extracellular matrix components.
Ioachim E, Damala K, Tsanou E, Briasoulis E, Papadiotis E, Mitselou A, Charhanti A, Doukas M, Lampri L, Arvanitis DL.
Histol Histopathol. 2012 Feb;27(2):209-16.
PMID 22207555
 
Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2.
Lawler PR, Lawler J.
Cold Spring Harb Perspect Med. 2012 May;2(5):a006627. doi: 10.1101/cshperspect.a006627. (REVIEW)
PMID 22553494
 
Prospective study of thrombospondin-1 mimetic peptides, ABT-510 and ABT-898, in dogs with soft tissue sarcoma.
Sahora AI, Rusk AW, Henkin J, McKeegan EM, Shi Y, Khanna C.
J Vet Intern Med. 2012 Sep-Oct;26(5):1169-76. doi: 10.1111/j.1939-1676.2012.00966.x. Epub 2012 Jul 21.
PMID 22816494
 
Inhibitory signaling through signal regulatory protein-alpha is not sufficient to explain the antitumor activities of CD47 antibodies.
Soto-Pantoja DR, Miller TW, Frazier WA, Roberts DD.
Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2842; author reply E2844-5. doi: 10.1073/pnas.1205441109. Epub 2012 Aug 24.
PMID 22923696
 
CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma.
Suzuki S, Yokobori T, Tanaka N, Sakai M, Sano A, Inose T, Sohda M, Nakajima M, Miyazaki T, Kato H, Kuwano H.
Oncol Rep. 2012 Aug;28(2):465-72. doi: 10.3892/or.2012.1831. Epub 2012 May 24.
PMID 22641236
 
Disruption of SIRPa signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts.
Theocharides AP, Jin L, Cheng PY, Prasolava TK, Malko AV, Ho JM, Poeppl AG, van Rooijen N, Minden MD, Danska JS, Dick JE, Wang JC.
J Exp Med. 2012 Sep 24;209(10):1883-99. Epub 2012 Sep 3.
PMID 22945919
 
SIRPalpha controls the activity of the phagocyte NADPH oxidase by restricting the expression of gp91(phox).
van Beek EM, Zarate JA, van Bruggen R, Schornagel K, Tool AT, Matozaki T, Kraal G, Roos D, van den Berg TK.
Cell Rep. 2012 Oct 25;2(4):748-55. doi: 10.1016/j.celrep.2012.08.027. Epub 2012 Sep 27.
PMID 23022485
 
The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.
Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PO, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL.
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. doi: 10.1073/pnas.1121623109. Epub 2012 Mar 26.
PMID 22451913
 
Is targeting of CD47-SIRPalpha enough for treating hematopoietic malignancy?
Zhao XW, Kuijpers TW, van den Berg TK.
Blood. 2012 May 3;119(18):4333-4; author reply 4334-5. doi: 10.1182/blood-2011-11-391367.
PMID 22555661
 
Tumor suppressor functions of miR-133a in colorectal cancer.
Dong Y, Zhao J, Wu CW, Zhang L, Liu X, Kang W, Leung WW, Zhang N, Chan FK, Sung JJ, Ng SS, Yu J.
Mol Cancer Res. 2013 Sep;11(9):1051-60. doi: 10.1158/1541-7786.MCR-13-0061. Epub 2013 May 30.
PMID 23723074
 
Engagement of SIRPalpha inhibits growth and induces programmed cell death in acute myeloid leukemia cells.
Irandoust M, Alvarez Zarate J, Hubeek I, van Beek EM, Schornagel K, Broekhuizen AJ, Akyuz M, van de Loosdrecht AA, Delwel R, Valk PJ, Sonneveld E, Kearns P, Creutzig U, Reinhardt D, de Bont ES, Coenen EA, van den Heuvel-Eibrink MM, Zwaan CM, Kaspers GJ, Cloos J, van den Berg TK.
PLoS One. 2013;8(1):e52143. doi: 10.1371/journal.pone.0052143. Epub 2013 Jan 8.
PMID 23320069
 
Thrombospondin-1 receptor mediates autophagy of RAS-expressing cancer cells and triggers tumour growth inhibition.
Kalas W, Swiderek E, Switalska M, Wietrzyk J, Rak J, Strzadala L.
Anticancer Res. 2013 Apr;33(4):1429-38.
PMID 23564783
 
Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors.
Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML, Nicolae A, Singh SP, Nie Z, Levens D, Isenberg JS, Roberts DD.
Sci Rep. 2013;3:1673. doi: 10.1038/srep01673.
PMID 23591719
 
Aberrant reduction of MiR-141 increased CD47/CUL3 in Hirschsprung's disease.
Tang W, Qin J, Tang J, Zhang H, Zhou Z, Li B, Geng Q, Wu W, Xia Y, Xu X.
Cell Physiol Biochem. 2013;32(6):1655-67. doi: 10.1159/000356601. Epub 2013 Dec 5.
PMID 24334875
 
Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response.
Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB, Seita J, Inlay MA, Weiskopf K, Miyanishi M, Weissman IL.
Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11103-8. doi: 10.1073/pnas.1305569110. Epub 2013 May 20.
PMID 23690610
 
A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.
Uronis HE, Cushman SM, Bendell JC, Blobe GC, Morse MA, Nixon AB, Dellinger A, Starr MD, Li H, Meadows K, Gockerman J, Pang H, Hurwitz HI.
Cancer Med. 2013 Jun;2(3):316-24. doi: 10.1002/cam4.65. Epub 2013 Mar 21.
PMID 23930208
 
Intravenous delivery of siRNA targeting CD47 effectively inhibits melanoma tumor growth and lung metastasis.
Wang Y, Xu Z, Guo S, Zhang L, Sharma A, Robertson GP, Huang L.
Mol Ther. 2013 Oct;21(10):1919-29. doi: 10.1038/mt.2013.135. Epub 2013 Jun 18.
PMID 23774794
 
Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration.
Zhang Y, Sime W, Juhas M, Sjolander A.
Eur J Cancer. 2013 Oct;49(15):3320-34. doi: 10.1016/j.ejca.2013.06.005. Epub 2013 Jun 26.
PMID 23810249
 
The interaction between signal regulatory protein alpha (SIRPalpha) and CD47: structure, function, and therapeutic target.
Barclay AN, Van den Berg TK.
Annu Rev Immunol. 2014;32:25-50. doi: 10.1146/annurev-immunol-032713-120142. Epub 2013 Nov 6. (REVIEW)
PMID 24215318
 
CD47 signaling regulates the immunosuppressive activity of VEGF in T cells.
Kaur S, Chang T, Singh SP, Lim L, Mannan P, Garfield SH, Pendrak ML, Soto-Pantoja DR, Rosenberg AZ, Jin S, Roberts DD.
J Immunol. 2014 Oct 15;193(8):3914-24. doi: 10.4049/jimmunol.1303116. Epub 2014 Sep 8.
PMID 25200950
 
A CD47-blocking TRAIL fusion protein with dual pro-phagocytic and pro-apoptotic anticancer activity.
Wiersma VR, He Y, Samplonius DF, van Ginkel RJ, Gerssen J, Eggleton P, Zhou J, Bremer E, Helfrich W.
Br J Haematol. 2014 Jan;164(2):304-7. doi: 10.1111/bjh.12617. Epub 2013 Oct 26.
PMID 24164421
 
Written2014-10Valerie R Wiersma, Peter E van Bommel, Marco de Bruyn, Wijnand Helfrich, Edwin Bremer
of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Translational Surgical Oncology, Groningen, The Netherlands (VRW, PEVB, WH, EB); University of Groningen, University Medical Center Groningen (UMCG), Department of Obstetrics, Gynecology, Groningen, The Netherlands (MDB); Exeter University Medical School, Devon, UK (EB)

Citation

This paper should be referenced as such :
Wiersma VR, van Bommel PE, de Bruyn M, Helfrich W, Bremer E
CD47, a multi-facetted target for cancer immunotherap
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Deep/CD47TumAndImmunoID20140.htm

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Mar 14 13:57:53 CET 2017


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