ADAMTS4 and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice

Rao, Nithya; Zhao, Ke; Liu, Hongrui; Ho, C.K.; Kumar, Saran; Xiang, Wei; Zhu, Yi‐Zhun; Ge, Ruowen

doi:10.1002/ijc.28037

Cited by 43 publications

(42 citation statements)

References 32 publications

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“…Combined with the clinical follow-ups, we identified the overexpressed ADAMTS4 as a crucial factor in CRC progression. Consistently, the overexpressed prolife of ADAMTS4 has been reported in several cancers including glioblastoma [25], head and neck cancer [26], melanoma [27], and epithelial ovarian cancer [12]. By immunochemical analysis of a CRC tissue microarray, we confirmed that ADAMTS4 expression was elevated in CRC tissues compared to normal tissues and predicted a poor prognosis in CRC.…”

Section: Discussionsupporting

confidence: 63%

Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

Chen

Luo

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. Methods: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. Results: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. Conclusion: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.

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Section: Discussionsupporting

confidence: 63%

Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

Chen

Luo

Zhou

et al. 2018

Cell Physiol Biochem

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“…C-terminal processing of the full-length ADAMTS-4 has been also reported in synovium and cartilage (15,(57)(58)(59). Recently, Rao et al (44) reported that proteolytic fragments of ADAMTS-4 containing only the C-terminal non-catalytic domains are found in cultured cells and human cancer tissues and suppress melanoma cell growth and angiogenesis in mice. Thus, processing of these domains is likely to have a large impact on the function and trafficking of ADAMTS-4 in vivo.…”

Section: Discussionmentioning

confidence: 85%

“…Because LRP1 is widely expressed in a variety of organs, we speculate that endocytic regulation of ADAMTS-4 activity occurs in various other tissues. The expression of ADAMTS-4 and ADAMTS-5 mRNAs has been reported to increase in human glioblastomas (41)(42)(43) and ADAMTS-4, and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice (44). Interestingly, ADAMTS-4 pro- motes neurite outgrowth by cleaving proteoglycans, which contributes to functional recovery after spinal cord injury (45).…”

Section: Discussionmentioning

confidence: 99%

Low Density Lipoprotein Receptor-related Protein 1 (LRP1)-mediated Endocytic Clearance of a Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4)

Yamamoto

Owen

Parker

et al. 2014

Journal of Biological Chemistry

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“…In melanoma, ADAMTS4 seems to have double-edged functions. When inactive -still carrying the propeptide -ADAMTS4 exhibits anti-tumorigenic features which is reversed upon propeptide cleavage [36].…”

Section: Discussionmentioning

confidence: 99%

“…The activity of ADAMTS4 has been associated with melanoma growth and angiogenesis in mice [36]. ADAMTS4 is activated by MT4-MMP [24].…”

Section: Discussionmentioning

confidence: 99%

Expression and Characterization of Membrane-Type 4 Matrix Metalloproteinase (MT4-MMP) and its Different Forms in Melanoma

Hieronimus¹,

Pfohl²,

Busch³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Membrane-type matrix metalloproteinases (MT-MMPs) are expressed on the cell surface and hydrolyze extracellular matrix components and signaling molecules by which they influence cancer cell migration and metastasis. Two of the six known MT-MMPs are anchored to the plasma membrane via a GPI anchor, one of which is MT4-MMP. Only little is known about MT4-MMP expression, synthesis, regulation and degradation. Methods: We analyzed several human cancer cell lines as well as tissue homogenates using Western blotting and quantitative PCR for the expression of MT4-MMP. Organelles of SK-Mel-28 cells were separated using continuous Iodixanol gradients. Glycosylation of the SK-Mel-28 protein was studied via glucosidases and site directed mutagenesis of the MT4-MMP cDNA prior to transfection. Results: We found the MT4-MMP highly expressed in human melanoma cell lines as well as skin and melanoma tissue samples. Three forms of MT4-MMP with molecular masses of 45 kDa, 58 kDa and 69 kDa were detected. Further, we demonstrate that the 58 kDa form is the mature protein in the cell membrane, while the 69 kDa form is its precursor found in intracellular compartments. The 69 kDa forms are processed by furin cleavage in the Golgi apparatus. Moreover, we identified Asn 318 as the single N-glycosylation site of MT4-MMP. Conclusion: We demonstrate the novel expression of MT4-MMP in melanocytic tissues and propose a precursor/product-relationship of the different forms of MT4-MMP in melanoma cells.

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ADAMTS4 and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice

Cited by 43 publications

References 32 publications

Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

Low Density Lipoprotein Receptor-related Protein 1 (LRP1)-mediated Endocytic Clearance of a Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4)

Expression and Characterization of Membrane-Type 4 Matrix Metalloproteinase (MT4-MMP) and its Different Forms in Melanoma

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