OPN and αvβ3 Expression are Predictors of Disease Severity and Worse Prognosis in Hepatocellular Carcinoma

Jin, Y.; Chen, Jianning; Feng, Zhichun; Zhang, Zhigang; Fan, Wenzhe; Wang, Yu; Li, Jiaping

doi:10.1371/journal.pone.0087930

Cited by 20 publications

(14 citation statements)

References 27 publications

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“…Recent findings from immunohistochemical studies report integrin α v β 3 expression in 77 % of investigated HCC specimens whereas expression was detectable only in 22 % of normal liver tissue [13]. Patients with detectable integrin α v β 3 expression had a significantly worse survival, indicating a prognostic role of this integrin in patients with HCC.…”

Section: Introductionmentioning

confidence: 99%

[68Ga]NODAGA-RGD – Metabolic stability, biodistribution, and dosimetry data from patients with hepatocellular carcinoma and liver cirrhosis

Haubner

Finkenstedt

Stegmayr

et al. 2016

Eur J Nucl Med Mol Imaging

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PurposeThis study was designed to determine safety, tolerability, and radiation burden of a [68Ga]NODAGA-RGD-PET for imaging integrin αvβ3 expression in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Moreover, metabolic stability and biokinetic data were compiled.MethodsAfter injection of 154–184 MBq [68Ga]NODAGA-RGD three consecutive PET/CT scans were acquired starting 8.3 ± 2.1, 36.9 ± 2.8, and 75.1 ± 3.4 min after tracer injection. For metabolite analysis, blood and urine samples were analyzed by HPLC. For dosimetry studies, residence time VOIs were placed in the corresponding organs. The OLINDA/EXM program was used to estimate the absorbed radiation dose.ResultsThe radiopharmaceutical was well tolerated and no drug-related adverse effects were observed. No metabolites could be detected in blood (30 and 60 min p.i.) and urine (60 min p.i.). [68Ga]NODAGA-RGD showed rapid and predominantly renal elimination. Background radioactivity in blood, intestine, lung, and muscle tissue was low (%ID/l 60 min p.i. was 0.56 ± 0.43, 0.54 ± 0.39, 0.22 ± 0.05, and 0.16 ± 0.8, respectively). The calculated effective dose was 21.5 ± 5.4 μSv/MBq, and the highest absorbed radiation dose was found for the urinary bladder wall (0.26 ± 0.09 mSv/MBq). No increased uptake of the tracer was found in HCC compared with the background liver tissue.Conclusions[68Ga]NODAGA-RGD uptake in the HCCs lesions was not sufficient to use this tracer for imaging these tumors. [68Ga]NODAGA-RGD was well tolerated and metabolically stable. Due to rapid renal excretion, background radioactivity was low in most of the body, resulting in low radiation burden and indicating the potential of [68Ga]NODAGA-RGD PET for non-invasive determination of integrin αvβ3 expression.

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Section: Introductionmentioning

confidence: 99%

[68Ga]NODAGA-RGD – Metabolic stability, biodistribution, and dosimetry data from patients with hepatocellular carcinoma and liver cirrhosis

Haubner

Finkenstedt

Stegmayr

et al. 2016

Eur J Nucl Med Mol Imaging

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“…In prostate cancer, CCN3 is a potential therapeutic target for prevention of bone metastasis via inhibition of the FAK/Akt/p38/NF-κB signaling pathway 14 . Since αvβ3 integrin is the receptor for CCN3, it is interesting to note that patients with high expression of αvβ3 also had significantly shorter survival 15 . However, the precise physiological function and mechanism of action of CCN3 in HCC malignancy remain vague 4 .…”

Section: Discussionmentioning

confidence: 99%

CCN3 is a therapeutic target relating enhanced stemness and coagulation in hepatocellular carcinoma

Jia

Xue

Zhang

et al. 2017

Sci Rep

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The general prognosis of patients with hepatocellular carcinoma (HCC) remains extremely dismal, due to the high frequency of metastasis. Since 2003, our research group has explored the gene expression profiles of metastasized HCC tissue samples and identified a significant upregulation of CCN3. However, the role and precise pathological function of CCN3 remains elusive. We showed that CCN3 is associated with the poor prognosis of patients with HCC, the malignant phenotype of HCC, and vascular thrombosis. We further evaluated the negative roles of CCN3 in vitro and in vivo, and identified osteopontin (OPN), and coagulation factors tissue factor (TF) and thrombin as the leading genes downstream of CCN3, that are positively associated with HCC cell stemness. We demonstrated that overexpressed CCN3 in HCC cells leads to enhanced survival and increased number of pulmonary metastases in vivo. The elevated levels of OPN and TF were associated with signal activation of nuclear factor κB (NFκB) and extracellular signal-regulated kinases (ERK). Our findings suggest CCN3 is a potential therapeutic target that would affect the upregulation of OPN and coagulation factors, which would lead to an enhanced stemness and blood coagulation microenvironment in HCC tissue.

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“…5h). Prior work demonstrated that αvβ3 integrin expression is associated with tumor size, invasion, and metastasis of HCC, and that antisense gene transfections of αv and β3 integrin reduced proliferation in HEPG2 cells 40,41 . Our results suggest that increased degradation of integrins by LYTACs can result in significantly enhanced functional effects compared to the parent binder alone.…”

Section: Peptide-based Galnac-lytacs Degrade Integrins and Induce Antmentioning

confidence: 99%

Lysosome Targeting Chimeras (LYTACs) That Engage a Liver-Specific Asialoglycoprotein Receptor for Targeted Protein Degradation

Ahn¹,

Banik²,

Miller³

et al. 2020

Preprint

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<p>Selective protein degradation platforms have afforded new development opportunities for therapeutics and tools for biological inquiry. The first lysosome targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to an endogenous lysosome targeting receptor, the cation-independent mannose-6-phosphate receptor (CI-M6PR). Here we developed LYTACs that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosomal targeting receptor, to degrade membrane proteins in a tissue-specific manner. We conjugated antibody-based binders targeting cell-surface proteins to a tri-GalNAc motif that engages ASGPR. The resulting LYTACs directed lysosome trafficking of the bound targets and subsequent degradation. Degradation mediated by an EGFR-targeted GalNAc-LYTAC resulted in significant functional effects on the downstream kinase signaling of EGFR compared to canonical inhibition with a monoclonal antibody. Furthermore, we demonstrated that a small target binder, a 3.4 kDa peptide, can be linked to a single tri-GalNAc ligand to degrade integrins and significantly reduce cell proliferation. Site-specific chemical conjugation of one or two tri-GalNAc ligands to antibody scaffolds improved the pharmacokinetic profile of GalNAc-LYTACs <i>in vivo</i> compared to non-specific chemical conjugation. GalNAc-LYTACs represent an exciting new paradigm for cell-type restricted degradation of proteins.</p>

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OPN and αvβ3 Expression are Predictors of Disease Severity and Worse Prognosis in Hepatocellular Carcinoma

Cited by 20 publications

References 27 publications

[68Ga]NODAGA-RGD – Metabolic stability, biodistribution, and dosimetry data from patients with hepatocellular carcinoma and liver cirrhosis

[68Ga]NODAGA-RGD – Metabolic stability, biodistribution, and dosimetry data from patients with hepatocellular carcinoma and liver cirrhosis

CCN3 is a therapeutic target relating enhanced stemness and coagulation in hepatocellular carcinoma

Lysosome Targeting Chimeras (LYTACs) That Engage a Liver-Specific Asialoglycoprotein Receptor for Targeted Protein Degradation

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