Inhibitory effect of anti-aminopeptidase N/CD13 antibodies on fibroblast migration

Lai, Amy; Ghaffari, Abdi; Ghahary, Aziz

doi:10.1007/s11010-010-0513-7

Cited by 19 publications

(18 citation statements)

References 39 publications

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“…Given that endothelial cells, fibroblasts, pericytes, and immune cells (in particular, myeloid cells) display CD13 (13,18,19,21) Myeloid cells were the most frequent stromal cell population in the three tumor models studied (Fig. 1A).…”

Section: Resultsmentioning

confidence: 95%

“…Originally identified as a surface marker on myeloid cells (13), CD13 is a widely expressed membrane-bound metalloprotease involved in pleiotropic functions, including enzymatic cleavage of peptides, antigen presentation, and signal transduction that ultimately mediate downstream biological phenomena such as cell adhesion, proliferation, and motility (14). Diverse cell subpopulations (e.g., fibroblasts, pericytes, epithelial cells, tumor-initiating cells, and stem cells) express CD13 (15)(16)(17)(18)(19).…”

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confidence: 99%

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CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis

Dondossola

Rangel

Guzman-Rojas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Angiogenesis is fundamental to tumorigenesis and an attractive target for therapeutic intervention against cancer. We have recently demonstrated that CD13 (aminopeptidase N) expressed by nonmalignant host cells of unspecified types regulate tumor blood vessel development. Here, we compare CD13 wild-type and null bone marrow-transplanted tumor-bearing mice to show that host CD13 + bone marrow-derived cells promote cancer progression via their effect on angiogenesis. Furthermore, we have identified CD11b + CD13 + myeloid cells as the immune subpopulation directly regulating tumor blood vessel development. Finally, we show that these cells are specifically localized within the tumor microenvironment and produce proangiogenic soluble factors. Thus, CD11b + CD13 + myeloid cells constitute a population of bone marrow-derived cells that promote tumor progression and metastasis and are potential candidates for the development of targeted antiangiogenic drugs. A ngiogenesis is a rate-limiting step in the development of many solid tumors, making it an attractive target for therapeutic intervention (1). Although pharmacologic modulation of angiogenesis has shown some clinical success, negative factors such as treatment-related plasticity, drug resistance, and tumor diversity have underscored the need for a better understanding of tumor-associated blood vessel formation at a mechanistic level (2). Tumor angiogenesis is a multifactorial process involving several different cell subtypes, especially tumor stromal endothelial cells, pericytes, carcinoma-associated fibroblasts (CAFs), and bone marrow-derived cells (BMDCs) (3, 4). A variety of immune cells directly support angiogenesis, including mast cells, tumor-associated macrophages (TAMs), and Tie2-expressing macrophages (TEMs) (5-7). Endothelial cells recruit inflammatory cells to the extravascular tissue by the expression of different leukocyte adhesion molecules. In turn, immune cells produce soluble factors, such as chemokines, cytokines, and proteases, that influence endothelial cell function and angiogenesis in a paracrine fashion (5). Other studies have shown that BMDCs have the ability to differentiate into endothelial cells, possibly by conversion first to endothelial progenitors (8-10).Proteases activate growth factors and inhibit suppressive factors within tumors and are central to the angiogenic process within the tumor microenvironment (11). Studies on the involvement of aminopeptidases in tumor progression and angiogenesis have revealed a role for aminopeptidase N (CD13) expressed by stromal cells (12). Originally identified as a surface marker on myeloid cells (13), CD13 is a widely expressed membrane-bound metalloprotease involved in pleiotropic functions, including enzymatic cleavage of peptides, antigen presentation, and signal transduction that ultimately mediate downstream biological phenomena such as cell adhesion, proliferation, and motility (14). Diverse cell subpopulations (e.g., fibroblasts, pericytes, epithelial cells, tumor-initiating cells, and st...

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Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 99%

CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis

Dondossola

Rangel

Guzman-Rojas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…If this hypothesis is correct, then the reported increases in expression of both APN and MMPs in the tumor microenvironment are connected events and not simply a coincidence. In fact, new data from our laboratory show a significant increase in the expression of APN by fibroblasts when co-cultured with keratinocytes or treated with keratinocyte-derived conditioned medium (Lai et al, 2010).…”

Section: Discussionmentioning

confidence: 95%

“…APN has a very short cytoplasmic domain without any known signaling motifs (Luan and Xu, 2007) The co-distribution of SFN with APN at the leading edge of fibroblasts was unpredicted. Interestingly, an in vitro wound scratch assay revealed higher expression of APN within the migratory fibroblasts, where it co-distributed with vinculin, a migration marker (Lai et al, 2010). In addition, the inhibition of cell migration by reducing or blocking APN levels in tumor cells, lymphocytes and endothelial cells has also been reported (Terauchi et al, 2007;Proost et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

14-3-3σ associates with cell surface aminopeptidase N in the regulation of matrix metalloproteinase-1

Ghaffari

Kilani

et al. 2010

Journal of Cell Science

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SummaryMatrix metalloproteinases (MMPs) are implicated in the degradation of the extracellular matrix during development and tissue repair, as well as in pathological conditions such as tumor invasion and fibrosis. MMP expression by stromal cells is partly regulated by signals from the neighboring epithelial cells. Keratinocyte-releasable 14-3-3, or stratifin, acts as a potent MMP-1-stimulatory factor in fibroblasts. However, its mechanism of transmembrane signaling remains unknown. Ectodomain biotin labeling, serial affinity purification and mass spectroscopy analysis revealed that the stratifin associates with aminopeptidase N (APN), or CD13, at the cell surface. The transient knockdown of APN in fibroblasts eliminated the stratifin-mediated p38 MAP kinase activation and MMP-1 expression, implicating APN in a receptor-mediated transmembrane signaling event. Stratifin deletion studies implicated its C-terminus as a potential APN-binding site. Furthermore, the dephosphorylation of APN ectodomains reduced its binding affinity to the stratifin. The presence of a phosphorylated serine or threonine residue in APN has been implicated. Together, these findings provide evidence that APN is a novel cell surface receptor for stratifin and a potential target in the regulation of MMP-1 expression in epithelial-stromal cell communication.

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“…This protein exists also in a soluble form. APN/CD13 is a ubiquitous enzyme present in a wide variety of human organs, tissues, and cell types, including the placenta, human umbilical vein endothelial cells, monocytes, lymphocytes T, hypothalamus, and epithelial intestinal cells [41]. It has various mechanisms of action: enzymatic cleavage of peptides, endocytosis, and signal transduction [42].…”

Section: Discussionmentioning

confidence: 99%

High Aminopeptidase N/CD13 Levels Characterize Human Amniotic Mesenchymal Stem Cells and Drive Their Increased Adipogenic Potential in Obese Women

Iaffaldano

Nardelli

Raia

et al. 2013

Stem Cells and Development

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Maternal obesity is associated to increased fetal risk of obesity and other metabolic diseases. Human amniotic mesenchymal stem cells (hA-MSCs) have not been characterized in obese women. The aim of this study was to isolate and compare hA-MSC immunophenotypes from obese (Ob-) and normal weight control (Co-) women, to identify alterations possibly predisposing the fetus to obesity. We enrolled 16 Ob-and 7 Co-women at delivery (mean/SEM prepregnancy body mass index: 40.3/1.8 and 22.4/1.0 kg/m 2 , respectively), and 32 not pregnant women. hA-MSCs were phenotyped by flow cytometry; several maternal and newborn clinical and biochemical parameters were also measured. The expression of membrane antigen CD13 was higher on Ob-hA-MSCs than on Co-hA-MSCs (P < 0.005). Also, serum levels of CD13 at delivery were higher in Ob-versus Co-pregnant women and correlated with CD13 antigen expression on Ob-hA-MSCs (r 2 = 0.84, P < 0.0001). Adipogenesis induction experiments revealed that Ob-hA-MSCs had a higher adipogenic potential than Co-hA-MSCs as witnessed by higher peroxisome proliferator-activated receptor gamma and aP2 mRNA levels (P < 0.05 and P < 0.05, respectively), at postinduction day 14 associated with increased CD13 mRNA levels from baseline to day 4 postinduction (P < 0.05). Adipogenesis was similar in the two sets of hA-MSCs after CD13 silencing, whereas it was increased in Co-hA-MSCs after CD13 overexpression. CD13 expression was high also in Ob-h-MSCs from umbilical cords or visceral adipose tissue of not pregnant women. In conclusion, antigen CD13, by influencing the adipogenic potential of hA-MSCs, could be an in utero risk factor for obesity. Our data strengthen the hypothesis that high levels of serum and MSC CD13 are obesity markers.

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Inhibitory effect of anti-aminopeptidase N/CD13 antibodies on fibroblast migration

Cited by 19 publications

References 39 publications

CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis

CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis

14-3-3σ associates with cell surface aminopeptidase N in the regulation of matrix metalloproteinase-1

High Aminopeptidase N/CD13 Levels Characterize Human Amniotic Mesenchymal Stem Cells and Drive Their Increased Adipogenic Potential in Obese Women

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