Clinical Significance of Aminopeptidase N in Non–Small Cell Lung Cancer

Tokuhara, Takaya; Hattori, Noboru; Ishida, Hidemi; Hirai, Tatsuya; Higashiyama, Masahiko; Kodama, Ken; Miyake, Masayuki

doi:10.1158/1078-0432.ccr-06-0338

Cited by 146 publications

(154 citation statements)

References 37 publications

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…48 Furthermore, the overall survival rate of patients with CD151-positive non-small-cell lung cancer is reported to be much lower than that of CD151-negative patients, suggesting that high CD151 gene expression is a marker of poor prognosis in human lung carcinomas. 27 All these data support the notion that CD151 is a positive effecter of metastasis. As CD151 is able to bind with various integrin species, especially a3b1 and a6b4 integrins, it has been suggested that CD151-integrin protein complexes may play a role in cell motility probably through modulation of the interaction between integrin and ECM such as laminin-5 24 and also activation of focal adhesion kinase.…”

Section: Promatrilysin-1 Activation Through Interaction With Cd151 T supporting

confidence: 63%

See 1 more Smart Citation

Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151

Shiomi

Inoki

Kataoka

et al. 2005

Laboratory Investigation

View full text Add to dashboard Cite

Matrix metalloproteinase-7 (MMP-7) (also known as matrilysin-1) is secreted as a proenzyme (proMMP-7) and plays a key role in the degradation of various extracellular matrix (ECM) and non-ECM molecules after activation. To identify the binding proteins related to proMMP-7 activation, a human lung cDNA library was screened by yeast two-hybrid system using proMMP-7 as bait. We identified a candidate molecule CD151, which is a member of the transmembrane 4 superfamily. Complex formation of proMMP-7 with CD151 was demonstrated by immunoprecipitation of the molecules from CaR-1 cells, a human rectal carcinoma cell line, expressing both proMMP-7 and CD151, and CD151 stable transfectants incubated with proMMP-7. Yeast twohybrid assays using deletion mutants of proMMP-7 and CD151 suggested an interaction between the propeptide of proMMP-7 and the COOH-terminal extracellular loop of CD151. The binding activity of 125 I-labeled proMMP-7 to CD151 on the cell membranes was shown with CD151 stable transfectants. Laser-scanning confocal microscopy demonstrated that proMMP-7 colocalizes with CD151 on the cell membranes of CD151 stable transfectants and CaR-1 cells. In situ zymography using crosslinked carboxymethylated transferrin, a substrate of MMP-7, demonstrated proteinase activity on and around CD151 stable transfectants and CaR-1 cells, while the activity was abolished by their treatment with MMP inhibitors, anti-MMP-7 antibody or anti-CD151 antibody. In human lung adenocarcinoma tissues, colocalization of MMP-7 and CD151 was demonstrated on the carcinoma cells. Metalloproteinase activity was present in these tissues and could be inhibited by antibodies to MMP-7 or CD151. These data demonstrate for the first time that proMMP-7 is captured and activated on the cell membranes through interaction with CD151, and suggest the possibility that similar to the MT1-MMP/MMP-2 system, MMP-7 is involved in the pericellular activation mechanism mediated by CD151, a crucial step in proteolysis on the cell membranes under various pathophysiological conditions including cancer invasion and metastasis.

show abstract

Section: Promatrilysin-1 Activation Through Interaction With Cd151 T supporting

confidence: 63%

“…It has also been reported that the prognosis of patients with lung carcinoma is poorer in CD151-positive patients than in CD151-negative patients. 27 However, limited information is available concerning the mechanisms of CD151-mediated metastasis or interaction of CD151 with proteins other than integrins.…”

mentioning

confidence: 99%

Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151

Shiomi

Inoki

Kataoka

et al. 2005

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Relating our work to the clinical importance of APN, analysis of human lung carcinoma tissue revealed that stromal fibroblasts are the most numerous of the APN-positive cells, and their APN expression correlated positively with increased angiogenesis and poor prognosis; similar results were obtained in patients with pancreatic carcinoma (13,(37)(38)(39). These observations suggest that tumor cells might secrete growth factors to induce a sustained APN expression in normal lung cells, which thus provide a favorable local environment (i.e., a "niche") for metastases.…”

Section: Discussionsupporting

confidence: 62%

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Guzman-Rojas

Rangel

Salameh

et al. 2012

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

117

View full text Add to dashboard Cite

Processes that promote cancer progression such as angiogenesis require a functional interplay between malignant and nonmalignant cells in the tumor microenvironment. The metalloprotease aminopeptidase N (APN; CD13) is often overexpressed in tumor cells and has been implicated in angiogenesis and cancer progression. Our previous studies of APN-null mice revealed impaired neoangiogenesis in model systems without cancer cells and suggested the hypothesis that APN expressed by nonmalignant cells might promote tumor growth. We tested this hypothesis by comparing the effects of APN deficiency in allografted malignant (tumor) and nonmalignant (host) cells on tumor growth and metastasis in APNnull mice. In two independent tumor graft models, APN activity in both the tumors and the host cells cooperate to promote tumor vascularization and growth. Loss of APN expression by the host and/ or the malignant cells also impaired lung metastasis in experimental mouse models. Thus, cooperation in APN expression by both cancer cells and nonmalignant stromal cells within the tumor microenvironment promotes angiogenesis, tumor growth, and metastasis.lung cancer | melanoma | proteolytic activity | shRNA | tumorigenesis A minopeptidase N (APN, CD13; EC 3.4.11.2) is a widely expressed type II membrane-bound metalloprotease (1, 2). It functions in the enzymatic cleavage of peptides, in endocytosis, and as a signaling molecule and has been implicated in the regulation of complex and diverse processes, including cell migration, cell survival, viral uptake, and angiogenesis (3). APN has also been linked specifically to cancer, having been identified as a cellsurface marker for malignant myeloid cells (4-7) and reaching high levels of expression in association with the progression of tumors, including breast, ovarian, and prostate cancer (8-14). Indeed, vascular endothelial growth factor (VEGF), a key angiogenesis regulator, induces the expression of APN at an early stage of tumor growth (15), again highlighting the role of this enzyme in angiogenesis, a process crucial for sustained growth of most solid tumors (16). Studies of bestatin, a CD13 inhibitor and antiangiogenic agent, also suggest that APN enzymatic activity is relevant for tumorigenesis (17,18). Nevertheless, the substrates of APN in the context of angiogenesis are still unknown. The only well-defined substrate is angiotensin III in the renin-angiotensin pathway, in which APN cleaves the NH 2 -terminal arginine residue of angiotensin III to form angiotensin IV. Consistent with several lines of evidence, we have previously identified APN as a target for inhibition of tumor vascularization and growth (18)(19)(20).Tumor growth relies on a complex microenvironment in which malignant cells cooperate with various other cell types: endothelial cells of the blood and lymphatic circulation, mesenchymal stromal cells/cancer-associated fibroblasts, and a variety of bone marrow-derived cells such as myeloid-derived suppressor cells and lymphocytes (21, 22). Some of these cell populations c...

show abstract

“…4 CD151, one of the most important of the tetraspanins, has been extensively studied, especially in connection with the progression and prognosis of malignant tumors, including breast cancer, colon cancer, prostate cancer, and HCC. [5][6][7][8] Initial evidence for the involvement of CD151 in metastasis came from a study that showed specific in vivo inhibition of metastasis in a human epidermoid carcinoma by an unknown antibody. Since then, reduction of CD151 expression in primary melanocytes by small interfering RNA (siRNA) has been shown to result in the loss of motility, whereas it has little effect on the steady-state levels of integrins.…”

mentioning

confidence: 99%

CD151 Modulates Expression of Matrix Metalloproteinase 9 and Promotes Neoangiogenesis and Progression of Hepatocellular Carcinoma

et al. 2010

View full text Add to dashboard Cite

Tetraspanin CD151 is involved in several pathological activities associated with tumor progression, including neoangiogenesis. However, the role and molecular mechanism of CD151 in the neoangiogenesis of hepatocellular carcinoma (HCC) remain enigmatic. We found that the level of expression of matrix metalloproteinase 9 (MMP9) was positively associated with CD151 expression in HCC cells. We developed a zone-by-zone blockade and demonstrated that overexpression of CD151 in HCC cells facilitated MMP9 expression through a phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3b (GSK-3b)/Snail signaling pathway. In contrast, down-regulation of CD151 expression impaired the ability of HCC cells to form microvessels in vitro and reduced their in vivo metastatic potential. In a clinical setting, a significant correlation of the expression of CD151 with MMP9 expression and with microvessel density (MVD) was revealed by Pearson correlation analysis of HCC patients. The postoperative 3-, 5-, and 7-year overall survival rates of HCC patients with CD151 high in comparison with the other groups. Multivariate Cox proportional hazards analysis showed that the concomitant overexpression of CD151, MMP9, and MVD was an independent marker for predicting poor prognosis of HCC. Conclusion: Overexpression of CD151 up-regulated the expression of MMP9 through the PI3K/Akt/GSK-3b/Snail pathway. CD151-dependent neoangiogenesis appeared to promote the progression of HCC, and this suggests that CD151 may be useful as a high-priority therapeutic target for antiangiogenesis in HCC. (HEPATOLOGY 2010;52:183-196) Abbreviations: AFP, alpha-fetoprotein; AKT, protein kinase B; bFGF, basic fibroblast growth factor; CDC42, cell division control protein 42 homologue; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GSK, glycogen synthase kinase; H&E, hematoxylin and eosin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HR, hazard ratio; HUVEC, human umbilical vein endothelial cell; LY294002, 2-morpholin-4-yl-8-phenylchromen-4-one; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; MVD, microvessel density; NA, not adopted; NS, not significant; OS, overall survival; PI3K, phosphatidylinositol-3-kinase; qRT-PCR, quantitative real-time polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; shRNA, short hairpin RNA; siRNA, small interfering RNA; TNM, tumor node metastasis; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene; VEGF, vascular endothelial growth factor.From the

show abstract

Clinical Significance of Aminopeptidase N in Non–Small Cell Lung Cancer

Cited by 146 publications

References 37 publications

Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151

Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

CD151 Modulates Expression of Matrix Metalloproteinase 9 and Promotes Neoangiogenesis and Progression of Hepatocellular Carcinoma

Contact Info

Product

Resources

About