Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer

Lima, Márcio Silva Miguel; Santos, Liliane Dos; Turri, José Antonio Orellana; Nonogaki, Suely; Buim, Marcilei Eliza Cavicchioli; Lima, Joema Felipe; Pinheiro, João de Jesus Viana; Osório, Cynthia Aparecida Bueno de Toledo; Soares, Fernando Augusto; Freitas, Vanessa M.

doi:10.1159/000446244

Cited by 29 publications

(22 citation statements)

References 62 publications

(46 reference statements)

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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: 83%

“…In this study, by loss-of-function study, genetic silencing of ADAMTS4 showed no obvious implications on cell proliferation and invasive capacity of CRC cells with high ADAMTS4 expression, but remarkably suppressed tumor in vivo, indicating the regulatory roles of ADAMTS4 are largely dependent on ECM. Extensive remodeling of the normal ECM in cancers can progress via the degradation of preexisting ECM molecules, such as aggrecan, brevican, and versican [12]. Alterations in the extracellular environment are critical for tumor initiation and progression.…”

Section: Discussionmentioning

confidence: 99%

“…However, the functions, mechanisms of activation, and substrates of most ADAMTS members remain largely unexplored [10]. In cancers, ADAMTSs can play both oncogenic and tumor-protective roles through regulating matrix-degradation, angiogenesis and metastasis [8,[11][12][13][14][15][16]. Moreover, ADAMTSs mutation is significantly associated with improved chemotherapy sensitivity and progression-free survival in ovarian cancer [17].…”

Section: Introductionmentioning

confidence: 99%

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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: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…The cleavage of proteoglycans like aggrecan and versican by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) in epithelial ovarian cancer has been demonstrated and is considered of prognostic value (75).…”

Section: Proteoglycansmentioning

confidence: 99%

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

et al. 2020

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The tumor microenvironment (TME) is composed of various cell types embedded in an altered extracellular matrix (ECM). ECM not only serves as a support for tumor cell but also regulates cell-cell or cell-matrix cross-talks. Alterations in ECM may be induced by hypoxia and acidosis, by oxygen free radicals generated by infiltrating inflammatory cells or by tumor-or stromal cell-secreted proteases. A poorer diagnosis for patients is often associated with ECM alterations. Tumor ECM proteome, also named cancer matrisome, is strongly altered, and different ECM protein signatures may be defined to serve as prognostic biomarkers. Collagen network reorganization facilitates tumor cell invasion. Proteoglycan expression and location are modified in the TME and affect cell invasion and metastatic dissemination. ECM macromolecule degradation by proteases may induce the release of angiogenic growth factors but also the release of proteoglycan-derived or ECM protein fragments, named matrikines or matricryptins. This review will focus on current knowledge and new insights in ECM alterations, degradation, and reticulation through cross-linking enzymes and on the role of ECM fragments in the control of cancer progression and their potential use as biomarkers in cancer diagnosis and prognosis.

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“…In addition, TFPI-2 is a binding partner and substrate of ADAMTS1 [147]. ADAMTSs were found to be upregulated in EOC tissues [148]. Thus, it is feasible that ADAMTS as well as MMPs influence coagulation factor-driven inflammatory responses in EOC tissue.…”

Section: Potential Tf-fviia-driven Inflammatory Responses Within Hmentioning

confidence: 99%

Potential Coagulation Factor-Driven Pro-Inflammatory Responses in Ovarian Cancer Tissues Associated with Insufficient O2 and Plasma Supply

Koizume¹,

Miyagi²

2017

IJMS

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Tissue factor (TF) is a cell surface receptor for coagulation factor VII (fVII). The TF-activated fVII (fVIIa) complex is an essential initiator of the extrinsic blood coagulation process. Interactions between cancer cells and immune cells via coagulation factors and adhesion molecules can promote progression of cancer, including epithelial ovarian cancer (EOC). This process is not necessarily advantageous, as tumor tissues generally undergo hypoxia due to aberrant vasculature, followed by reduced access to plasma components such as coagulation factors. However, hypoxia can activate TF expression. Expression of fVII, intercellular adhesion molecule-1 (ICAM-1), and multiple pro-inflammatory cytokines can be synergistically induced in EOC cells in response to hypoxia along with serum deprivation. Thus, pro-inflammatory responses associated with the TF-fVIIa–ICAM-1 interaction are expected within hypoxic tissues. Tumor tissue consists of multiple components such as stromal cells, interstitial fluid, albumin, and other micro-factors such as proton and metal ions. These factors, together with metabolism reprogramming in response to hypoxia and followed by functional modification of TF, may contribute to coagulation factor-driven inflammatory responses in EOC tissues. The aim of this review was to describe potential coagulation factor-driven inflammatory responses in hypoxic EOC tissues. Arguments were extended to clinical issues targeting this characteristic tumor environment.

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Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer

Cited by 29 publications

References 62 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

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

Potential Coagulation Factor-Driven Pro-Inflammatory Responses in Ovarian Cancer Tissues Associated with Insufficient O2 and Plasma Supply

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