The ALCAM Shedding by the Metalloprotease ADAM17/TACE Is Involved in Motility of Ovarian Carcinoma Cells

Rosso, Ombretta; Piazza, Tiziana; Bongarzone, Italia; Rossello, Armando; Mezzanzanica, Delia; Canevari, Silvana; Orengo, Anna Maria; Puppo, Andrea; Ferrini, Silvano; Fabbi, Marina

doi:10.1158/1541-7786.mcr-07-0060

Cited by 96 publications

(127 citation statements)

References 28 publications

(42 reference statements)

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“…Further evidence was provided by the reduction in NIM1-TIMP3 clones CM of syndecan4 and ALCAM (activated leukocyte cell adhesion molecule), the two other proteins whose shedding is mediated by TACE/ ADAM17 (Fata et al, 2001;Rosso et al, 2007), as reported later. We determined the effect of TIMP3 on NIM1 growth rate by different approaches.…”

Section: Resultsmentioning

confidence: 52%

“…As anticipated earlier, we investigated the status of syndecan4 and ALCAM, the two proteins involved in cell adhesion and regulated by shedding mediated by ADAM17/TACE, a TIMP3-sensitive metalloprotease (Fata et al, 2001;Rosso et al, 2007). The soluble form of syndecan4 was less abundant in CM of NIM1-TIMP3 clones with respect to control, as demonstrated by immune dot blot (Figure 7a, top).…”

Section: Analysis Of Proteins Mediating Timp3 Effectsmentioning

confidence: 61%

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TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

et al. 2011

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Papillary thyroid carcinoma (PTC) arises from the thyroid follicular epithelium and represents the most frequent thyroid malignancy. PTC is associated with gene rearrangements generating RET/PTC and TRK oncogenes, and to the BRAFV600E activating point mutation. A role of tumor-suppressor genes in the pathogenesis of PTC has not been assessed yet. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene, encoding a metalloproteinases inhibitor and capable of inhibiting growth, angiogenesis, invasion and metastasis of several cancers, was found to be silenced by promoter methylation in a consistent fraction of PTCs, in association with tumor aggressiveness and BRAFV600E mutation, thus suggesting an oncosuppressor role. To explore this possibility, in this study we performed gene expression and functional studies. Analysis of gene expression data produced in our laboratory as well as meta-analysis of publicly available data sets confirmed the downregulation of TIMP3 gene expression in PTC with respect to normal thyroid. The functional consequences of TIMP3 downregulation were investigated in the PTC-derived NIM1 cell line, in which the expression of TIMP3 is silenced. Restoration of TIMP3 expression by exposure to soluble TIMP3 protein or by complementary DNA transfection had no effect on the growth rate of NIM1 cells. Instead, it affected the adhesive, migratory and invasive capabilities of NIM1 cells by modulating several proteins involved in these processes. A striking effect was observed in vivo, as TIMP3 reduced the tumorigenicity of NIM1 cells by repressing angiogenesis and macrophage infiltration. Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC.

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Section: Resultsmentioning

confidence: 52%

Section: Analysis Of Proteins Mediating Timp3 Effectsmentioning

confidence: 61%

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

et al. 2011

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“…ADAM17 has been discovered to be an important proteolytic sheddase of ALCAM . This mechanism can enhance tumour cell motility and migratory capacity, hence increasing the invasive and metastatic potential (Rosso et al, 2007). We could show that ADAM17 is significantly overexpressed in pancreatic cancer compared with normal pancreatic tissue.…”

Section: Discussionmentioning

confidence: 81%

“…Rosso et al (2007) observed that this process is involved in the motility of epithelial ovarian carcinoma cells. They postulated that the disruption of the ALCAM-mediated adhesiveness is a relevant step, which increased the invasiveness of tumour cells.…”

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confidence: 98%

Increased expression of ALCAM/CD166 in pancreatic cancer is an independent prognostic marker for poor survival and early tumour relapse

et al. 2009

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BACKGROUND: ALCAM (activated leucocyte cell adhesion molecule, synonym CD166) is a cell adhesion molecule, which belongs to the Ig superfamily. Disruption of the ALCAM-mediated adhesiveness by proteolytic sheddases such as ADAM17 has been suggested to have a relevant impact on tumour invasion. Although the expression of ALCAM is a valuable prognostic and predictive marker in several types of epithelial tumours, its role as a prognostic marker in pancreatic cancer has not yet been reported. METHODS: In this study, paraffin-embedded samples of 97 patients with pancreatic cancer undergoing potentially curative resection were immunostained against ALCAM, ADAM17 and CK19. Expression of ALCAM and ADAM17 was semiquantitatively evaluated and correlated to clinical and histopathological parameters. RESULTS: We could show that in normal pancreatic tissue, ALCAM is predominantly expressed at the cellular membrane, whereas in pancreatic tumour cells, it is mainly localised in the cytoplasm. In addition, univariate and multivariate analyses show that increased expression of ALCAM is an adverse prognostic factor for recurrence-free and overall survival. Overexpression of ADAM17 in pancreatic cancer, however, failed to be a significant prognostic marker and was not coexpressed with ALCAM. CONCLUSIONS: Our findings support the hypothesis that the disruption of ALCAM-mediated adhesiveness is a relevant step in pancreatic cancer progression. Moreover, ALCAM overexpression is a relevant independent prognostic marker for poor survival and early tumour relapse in pancreatic cancer.

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“…To rule out the involvement of closely related ADAM10 in the regulatory process (30,31), both ADAM17 and ADAM10 activities were determined in response to irradiation. Interestingly, irradiation only increased ADAM17 but not ADAM10 activity in a dose-dependent way ( Fig.…”

Section: Ir Induces Posttranslational Modification and Activation Of mentioning

confidence: 99%

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

Sharma

Bender

Zimmermann

et al. 2016

Clinical Cancer Research

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Purpose: Ionizing radiation (IR) induces intracellular signaling processes as part of a treatment-induced stress response. Here we investigate IR-induced ADAM17 activation and the role of ADAM17-shed factors for radiation resistance in non-small cell lung cancer.Experimental Design: Large-scale secretome profiling was performed using antibody arrays. Secretion kinetics of ADAM17 substrates was determined using ELISA across multiple in vitro and in vivo models of non-small cell lung cancer. Clonogenic survival and tumor xenograft assays were performed to determine radiosensitization by ADAM17 inhibition.Results: On the basis of a large-scale secretome screening, we investigated secretion of auto-or paracrine factors in non-small cell lung cancer in response to irradiation and discovered the ADAM17 network as a crucial mediator of resistance to IR. Irradiation induced a dose-dependent increase of furin-mediated cleavage of the ADAM17 proform to active ADAM17, which resulted in enhanced ADAM17 activity in vitro and in vivo. Genetic or pharmacologic targeting of ADAM17 suppressed IR-induced shedding of secreted factors, downregulated ErbB signaling in otherwise cetuximab-resistant target cells, and enhanced IRinduced cytotoxicity. The combined treatment modality of IR with the ADAM17 inhibitor TMI-005 resulted in a supra-additive antitumor response in vivo demonstrating the potential of ADAM17 targeting in combination with radiotherapy.Conclusions: Radiotherapy activates ADAM17 in non-small cell lung cancer, which results in shedding of multiple survival factors, growth factor pathway activation, and IR-induced treatment resistance. We provide a sound rationale for repositioning ADAM17 inhibitors as short-term adjuvants to improve the radiotherapy outcome of non-small cell lung cancer. Clin Cancer Res; 22(17); 4428-39. Ó2016 AACR.

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The ALCAM Shedding by the Metalloprotease ADAM17/TACE Is Involved in Motility of Ovarian Carcinoma Cells

Cited by 96 publications

References 28 publications

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

Increased expression of ALCAM/CD166 in pancreatic cancer is an independent prognostic marker for poor survival and early tumour relapse

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

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