The DOI matches its Crossref record; 70 of the 71 references it cites were found in a registry or an index; 1 of the 21 sources its claims cite were checked for support.
MT1-MMP Expression Levels and Catalytic Functions Dictate LDL Receptor-Related Protein-1 Ligand Internalization Capacity in U87 Glioblastoma Cells
Open accessAbstract
Modulations in cell surface receptor ectodomain proteolytic shedding impact on receptor function and cancer biomarker expression. As such, heavily pursued therapeutic avenues have exploited LDL receptor-related protein-1 (LRP-1)-mediated capacity in internalizing Angiopep-2 (An2), a brain-penetrating peptide that allows An2–drug conjugates to cross the blood–brain tumor barrier (BBTB). Given that LRP-1 is proteolytically shed from the cell surface through matrix metalloproteinase (MMP) activity, the balance between MMP expression/function and LRP-1-mediated An2 internalization is unknown. In this study, we found that membrane type-1 (MT1)-MMP expression increased from grade 1 to 4 brain tumors, while that of LRP-1 decreased inversely. MMP pharmacological inhibitors such as Ilomastat, Doxycycline and Actinonin increased in vitro An2 internalization by up to 2.5 fold within a human grade IV-derived U87 glioblastoma cell model. Transient siRNA-mediated MT1-MMP gene silencing resulted in increased basal An2 cell surface binding and intracellular uptake, while recombinant MT1-MMP overexpression reduced both cell surface LRP-1 expression as well as An2 internalization. The addition of Ilomastat to cells overexpressing recombinant MT1-MMP restored LRP-1 expression at the cell surface and An2 uptake to levels comparable to those observed in control cells. Collectively, our data suggest that MT1-MMP expression status dictates An2-mediated internalization processes in part by regulating cell surface LRP-1 functions. Such evidence prompts preclinical evaluations of combined MMP inhibitors/An2–drug conjugate administration to potentially increase the treatment of high-MT1-MMP-expressing brain tumors.
Overview
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Written from the paper’s full text.
TL;DR
In U87 glioblastoma cells, MT1-MMP expression and catalytic activity reduce cell-surface LRP-1 and limit LRP-1-mediated Angiopep-2 (An2) internalization. MMP inhibition or MT1-MMP silencing increases An2 binding/uptake, suggesting combined MMP inhibitors with An2–drug conjugates for high-MT1-MMP brain tumors.
Key findings
- In grade 1–4 brain tumor tissue cDNA arrays, MT1-MMP transcript levels increased with tumor grade while LRP-1 transcript levels decreased inversely.
- Pharmacological MMP inhibitors Ilomastat, Doxycycline, and Actinonin increased in vitro An2 internalization by up to 2.5 fold in U87 glioblastoma cells.
- Transient siRNA-mediated MT1-MMP silencing increased basal An2 cell-surface binding and intracellular uptake, whereas recombinant MT1-MMP overexpression reduced cell-surface LRP-1 expression and An2 internalization.
- Ilomastat restored LRP-1 cell-surface expression and An2 uptake in MT1-MMP-overexpressing cells to levels comparable to controls; Ilomastat also increased LRP-1 cell-surface expression by 37% in control GFP-transfected cells, and MT1-MMP overexpression increased an LRP-1 immunoreactive cleavage product of ~250 kDa that was decreased by Ilomastat.
Methods
- Human U87 glioblastoma and DAOY medulloblastoma cell lines were used for in vitro assays; a TissueScan cDNA array covered 43 clinical brain cancer samples, including 18 WHO grade 1, 11 grade 2, 10 grade 3, and 2 grade 4 tumors.
- MT1-MMP was manipulated by transient siRNA silencing or cDNA overexpression of Wt-MT1-MMP/GFP; MMP catalytic activity was inhibited with Ilomastat, Doxycycline, or Actinonin.
- An2 binding/uptake was measured by flow cytometry and confocal microscopy; LRP-1 expression/shedding was assessed by immunofluorescence, immunoblotting, RT-qPCR, and gelatin zymography; statistics used Student’s unpaired t-test or one-way ANOVA with Dunnett post-test, p < 0.05.
Limitations
- The paper states that whether MT1-MMP could cleave additional cell-surface receptors involved in An2 internalization cannot be precluded, and that whether/how modulating intracellular trafficking of MT1-MMP and/or LRP-1 affects An2 internalization remains to be established.
- The paper states that how the MMP–LRP-1 inter-relation may alter future clinical initiatives remains to be explored.
- Evident from the text: the mechanistic work is largely in the U87 in vitro model, the grade 4 tissue-array group contained only 2 samples, and the authors note that only 10–15% of cells were transfected, which they use to explain the non-significant flow cytometry result in MT1-MMP-overexpressing cells.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
1 of 21 cited sources checked · 1 supported · 0 flagged
- Premisecitation
LRP-1 is a substrate of MT1-MMP.
“Since LRP-1 is a substrate of MT1-MMP, we specifically questioned here how the MT1-MMP-to-LRP-1 cell surface expression ratio might regulate in vitro LRP-1-mediated An2 internalization within a human glioblastoma cell model.”
Quote in the paperSubstantial claim1 of 5 sources checked- cites [34] Quinn, 1999, Characterization of the soluble form of the low density lipoprotein receptor-related protein (LRP), Exp. Cell Res. source
- cites [35] Rozanov, 2004, The low density lipoprotein receptor-related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells, J. Biol. Chem. source
- cites [36] Liu, 2009, LRP1 shedding in human brain: Roles of ADAM10 and ADAM17, Mol. Neurodegener. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [37] Selvais, 2009, Metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 ectodomain decreases endocytic clearance of endometrial matrix metalloproteinase-2 and -9 at menstruation, Endocrinology source
- cites [38] Emonard, 2014, Regulation of LRP-1 expression: Make the point, Pathol. Biol. source
- Findingown data
Differential LRP-1 expression correlated with higher cell internalization of An2.
“Such differential LRP-1 expression was also found to correlate with a higher cell internalization of an LRP-1 peptide ligand An2 (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
Ilomastat restored An2 uptake in MT1-MMP-overexpressing U87 cells to levels comparable to control cells.
“The addition of Ilomastat to cells overexpressing recombinant MT1-MMP restored LRP-1 expression at the cell surface and An2 uptake to levels comparable to those observed in control cells.”
- Also stated in: § 2.3. Increase in Cell Surface MT1-MMP Catalytic Activity Downregulates An2 Internalization · boosted
“Interestingly, Ilomastat eliminated the effect of recombinant MT1-MMP, confirming that the catalytic activity of MT1-MMP was required to alter An2 internalization (Figure 4B).”
Quote in the paperSubstantial claim - Also stated in: § 2.3. Increase in Cell Surface MT1-MMP Catalytic Activity Downregulates An2 Internalization · boosted
- Findingown data
LRP-1 transcript levels inversely correlate with increasing brain tumor grade.
“we found that membrane type-1 (MT1)-MMP expression increased from grade 1 to 4 brain tumors, while that of LRP-1 decreased inversely.”
- Also stated in: § 2.1. LRP-1 and MT1-MMP Gene Expression Profiling in Grade 1–4 Brain Tumor Tissues · hedged
“LRP-1 transcript levels appeared to inversely correlate with increasing brain tumor gradation (Figure 1A, right panel).”
- Also stated in: § 3. Discussion · plain
“Here, we provide evidence for differential genotypic MT1-MMP and LRP-1 biomarker expression between tissues from grade 1 to 4 brain tumors.”
Quote in the paperSubstantial claim - Also stated in: § 2.1. LRP-1 and MT1-MMP Gene Expression Profiling in Grade 1–4 Brain Tumor Tissues · hedged
- Findingown data
Overexpression of recombinant MT1-MMP reduced An2 internalization in U87 glioblastoma cells.
“recombinant MT1-MMP overexpression reduced both cell surface LRP-1 expression as well as An2 internalization.”
- Also stated in: § 2.3. Increase in Cell Surface MT1-MMP Catalytic Activity Downregulates An2 Internalization · plain
“Visualization of Wt-MT1-MMP-GFP-positive cells was performed by fluorescent microscopy (Figure 4A) and it was observed that these cells demonstrated less internalization of Alexa568-An2 (Figure 4B).”
Quote in the paperSubstantial claim - Also stated in: § 2.3. Increase in Cell Surface MT1-MMP Catalytic Activity Downregulates An2 Internalization · plain
- Findingown data
Flow cytometry analysis indicated that the binding and uptake of Alexa568-An2 were unaffected in cells overexpressing MT1-MMP whether treated or not with Ilomastat.
“Interestingly, flow cytometry analysis indicated that the binding and uptake of Alexa568-An2 were unaffected in cells overexpressing MT1-MMP whether treated or not with Ilomastat (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of recombinant MT1-MMP reduced cell surface LRP-1 expression in U87 glioblastoma cells.
“recombinant MT1-MMP overexpression reduced both cell surface LRP-1 expression as well as An2 internalization.”
- Also stated in: § 2.4. MT1-MMP Catalytic Activity Is Required for Cell Surface Shedding of LRP-1 · plain
“LRP-1 cell surface immunolabelling was performed (Figure 5A, red) and, when quantified in green, fluorescent cells, found to be decreased in cells overexpressing Wt-MT1-MMP-GFP (Figure 5B, white bars).”
Quote in the paperSubstantial claim - Also stated in: § 2.4. MT1-MMP Catalytic Activity Is Required for Cell Surface Shedding of LRP-1 · plain
- Findingown data
siRNA-mediated MT1-MMP gene silencing increased basal An2 cell surface binding in U87 glioblastoma cells.
“Transient siRNA-mediated MT1-MMP gene silencing resulted in increased basal An2 cell surface binding and intracellular uptake”
- Also stated in: § 2.2. An2 Internalization in U87 Glioblastoma Cells Is Increased upon MT1-MMP Gene Silencing · plain
“Effective silencing of MT1-MMP expression was confirmed by RT-qPCR (Figure 2A) and was correlated with significant increases in both An2 binding and uptake processes (Figure 2B).”
Quote in the paperSubstantial claim - Also stated in: § 2.2. An2 Internalization in U87 Glioblastoma Cells Is Increased upon MT1-MMP Gene Silencing · plain
- Findingown data
Ilomastat restored cell surface LRP-1 expression in MT1-MMP-overexpressing U87 cells to levels comparable to control cells.
“The addition of Ilomastat to cells overexpressing recombinant MT1-MMP restored LRP-1 expression at the cell surface and An2 uptake to levels comparable to those observed in control cells.”
- Also stated in: § 2.4. MT1-MMP Catalytic Activity Is Required for Cell Surface Shedding of LRP-1 · plain
“Ilomastat significantly prevented that decrease and was also found to increase LRP-1 cell surface expression by 37% in control GFP-transfected cells (Figure 5B, black bars).”
Quote in the paperSubstantial claim - Also stated in: § 2.4. MT1-MMP Catalytic Activity Is Required for Cell Surface Shedding of LRP-1 · plain
- Findingown data
MT1-MMP expression increased with brain tumor grade from 1 to 4.
“we found that membrane type-1 (MT1)-MMP expression increased from grade 1 to 4 brain tumors, while that of LRP-1 decreased inversely.”
- Also stated in: § 2.1. LRP-1 and MT1-MMP Gene Expression Profiling in Grade 1–4 Brain Tumor Tissues · plain
“Conversely, MT1-MMP expression increased with the tumor grade in accordance with previous observations which reported high MT1-MMP expression as correlating with poor survival in human GBM patients (Figure 1A, left panel) [40].”
- Also stated in: § 3. Discussion · plain
“Here, we provide evidence for differential genotypic MT1-MMP and LRP-1 biomarker expression between tissues from grade 1 to 4 brain tumors.”
Quote in the paperSubstantial claim - Also stated in: § 2.1. LRP-1 and MT1-MMP Gene Expression Profiling in Grade 1–4 Brain Tumor Tissues · plain
- Findingown data
Ilomastat increased LRP-1 cell surface expression by 37% in control GFP-transfected U87 cells.
“Ilomastat significantly prevented that decrease and was also found to increase LRP-1 cell surface expression by 37% in control GFP-transfected cells (Figure 5B, black bars).”
Quote in the paperSubstantial claim - Findingown data
siRNA-mediated MT1-MMP gene silencing increased intracellular uptake of An2 in U87 glioblastoma cells.
“Transient siRNA-mediated MT1-MMP gene silencing resulted in increased basal An2 cell surface binding and intracellular uptake”
- Also stated in: § 2.2. An2 Internalization in U87 Glioblastoma Cells Is Increased upon MT1-MMP Gene Silencing · boosted
“The increased An2 internalization in siMT1-MMP-transfected cells was further confirmed by confocal microscopy (Figure 2C) as fluorescence quantification shows that suppressing MT1-MMP significantly improved the basal uptake of Alexa488-An2 (Figure 2D).”
Quote in the paperSubstantial claim - Also stated in: § 2.2. An2 Internalization in U87 Glioblastoma Cells Is Increased upon MT1-MMP Gene Silencing · boosted
- Findingown data
MMP inhibitors Ilomastat, Doxycycline, and Actinonin increased in vitro An2 internalization by up to 2.5 fold in U87 glioblastoma cells.
“MMP pharmacological inhibitors such as Ilomastat, Doxycycline and Actinonin increased in vitro An2 internalization by up to 2.5 fold within a human grade IV-derived U87 glioblastoma cell model.”
- Also stated in: § 2.3. Increase in Cell Surface MT1-MMP Catalytic Activity Downregulates An2 Internalization · plain
“Using fluorescent microscopy (Figure 3A), we found that all three MMP inhibitors significantly increased Alexa488-An2 internalization (Figure 3B).”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of the pharmacological MMP inhibitors Ilomastat, Doxycycline, and Actinonin on An2 internalization are attributable to inhibition of MT1-MMP rather than to other MMPs or off-target effects.
- Also stated in: § 2.3. Increase in Cell Surface MT1-MMP Catalytic Activity Downregulates An2 Internalization · plain
- Interpretationown data
The catalytic activity of MT1-MMP was required to alter An2 internalization.
“Interestingly, Ilomastat eliminated the effect of recombinant MT1-MMP, confirming that the catalytic activity of MT1-MMP was required to alter An2 internalization (Figure 4B).”
Quote in the paperSubstantial claim - Interpretationown data
MT1-MMP expression status dictates An2-mediated internalization processes in part by regulating cell surface LRP-1 functions.
“Collectively, our data suggest that MT1-MMP expression status dictates An2-mediated internalization processes in part by regulating cell surface LRP-1 functions.”
Quote in the paperSubstantial claim - Interpretationown data
The extent of LRP-1 expression appears to correlate with ligand internalization functions.
“This suggests that the extent of LRP-1 expression appears to correlate with ligand internalization functions.”
Quote in the paperSubstantial claim - Study design and conductown data
Functional inhibition of MT1-MMP catalytic functions was validated by zymography as MT1-MMP-mediated proMMP-2 activation in Concanavalin-A-treated cells was abrogated.
“Efficient functional inhibition of MT1-MMP catalytic functions was validated by zymography as MT1-MMP-mediated proMMP-2 activation in Concanavalin-A-treated cells was abrogated (Figure 3C).”
Quote in the paperSubstantial claim - Interpretationown data
MT1-MMP cell surface expression/function status may reduce the efficacy of LRP-1-mediated An2 internalization in brain cancer cells.
“These results in part explain how MT1-MMP cell surface expression/function status may reduce the efficacy of LRP-1-mediated An2 internalization in brain cancer cells.”
Quote in the paperSubstantial claim - Interpretationown data
MT1-MMP exerts a suppressive role in An2 internalization processes.
“These suggest that MT1-MMP exerts a suppressive role in An2 internalization processes and that its inhibition could relieve that suppressive function and possibly lead to improved An2–drug conjugate accumulation within brain tumors.”
Quote in the paperSubstantial claim - Interpretationnone given
This study strengthens the involvement of LRP-1 in An2-mediated internalization processes taking place in brain cancer cells.
“This study strengthens the involvement of LRP-1 in An2-mediated internalization processes taking place in brain cancer cells.”
Quote in the paperSubstantial claim- Rests on an assumption: U87 glioblastoma cells are representative of brain cancer cells for An2-mediated internalization processes.
- It may state two separate claims as one. 11
- Probably not a substantial claim. 14
- The quote only partly states this claim. 1
It may state two separate claims as one.
Findingown dataCells overexpressing recombinant Wt-MT1-MMP led to efficient activation of latent proMMP-2 and this was abrogated by Ilomastat.
“As demonstrated, cells overexpressing recombinant Wt-MT1-MMP led to efficient activation of latent proMMP-2 and this was abrogated by Ilomastat (Figure 4D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataLRP-1 protein expression in U87 glioblastoma cells was comparable to brain tumor tissue homogenate, whereas DAOY medulloblastoma cells expressed very low levels.
“In parallel, LRP-1 protein expression was compared between adult U87 glioblastoma cells and pediatric DAOY medulloblastoma cells and was found expressed as much as in a sample of brain tumor tissue homogenate, whereas DAOY cells expressed very low levels of LRP-1 (Figure 1B).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe expression and function of LRP-1 correlates with glioblastoma cell invasion.
“In addition, the expression and function of receptor low-density lipoprotein receptor-related protein-1 (LRP-1) was shown to correlate with glioblastoma cell invasion [15,16,17].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [15] Blakely, 2000, Human glioblastoma cell lines: Levels of low-density lipoprotein receptor and low-density lipoprotein receptor-related protein, Cancer Res.
- cites [16] Lopes, 1994, Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein is increased in reactive and neoplastic glial cells, FEBS Lett. source
- cites [17] Song, 2009, Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9, Cancer Res. source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
InterpretationreasoningA given MT1-MMP expression status may possibly dictate either intracellular LRP-1 trafficking to the cell surface or efficient cell surface LRP-1 functions.
“our observations imply that, first, a pool of LRP-1 may be inducible or mobilized to contribute to efficient cell surface LRP-1-mediated An2 brain cancer cell internalization and, second, that a given MT1-MMP expression status may possibly dictate either intracellular LRP-1 trafficking to the cell surface or efficient cell surface LRP-1 functions.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenTissue cDNAs in the arrays were normalized and validated with β-actin in two sequential qPCR analyses.
“normalized and validated with β-actin in two sequential qPCR analyses”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may be too vague to check against evidence.
InterpretationreasoningRegulation of LRP-1 cell surface expression and function, through gene silencing or pharmacological inhibition of catalytic MMP activity, might become very useful in enhancing the chemotherapeutic effects of An2-drug conjugates by promoting their internalization in both low-grade- and high-grade gliomas.
“Our study further suggests that regulation of LRP-1 cell surface expression and function, through gene silencing or pharmacological inhibition of catalytic MMP activity, might become very useful in enhancing the chemotherapeutic effects of An2–drug conjugates [46,68,69] by promoting their internalization in both low-grade- and high-grade gliomas.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [46] Drappatz, 2013, Phase I study of GRN1005 in recurrent malignant glioma, Clin. Cancer Res. source
- cites [68] Kurzrock, 2012, Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors, Mol. Cancer Ther. source
- cites [69] Regina, 2015, ANG4043, a novel brain-penetrant peptide-mAb conjugate, is efficacious against HER2-positive intracranial tumors in mice, Mol. Cancer Ther. source
- Rests on an assumption: Findings in U87 glioblastoma cells apply to low-grade gliomas.
Probably not a substantial claim.
Study design and conductnone givenMT1-MMP-specific gene silencing efficacy was assessed by RT-qPCR.
“MT1-MMP-specific gene silencing efficacy was assessed by RT-qPCR as described above.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationLRP-1 is highly expressed in most gliomas, and its silencing significantly decreases An2 uptake in vitro in a U87 glioma cell model.
“LRP-1 has been reported to be highly expressed in most gliomas, and its silencing found to significantly decrease An2 uptake in vitro in a U87 glioma cell model [21].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Bertrand, 2011, Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1, Br. J. Cancer source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationConjugation of An2 to small therapeutic molecules significantly increased their internalization across the BBTB upon systemic administration.
“Conjugation of this peptide to small therapeutic molecules such as paclitaxel, doxorubicin or etoposide significantly increased their internalization across the BBTB upon systemic administration [20,21].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [20] Che, 2010, New Angiopep-modified doxorubicin (ANG1007) and etoposide (ANG1009) chemotherapeutics with increased brain penetration, J. Med. Chem. source
- cites [21] Bertrand, 2011, Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1, Br. J. Cancer source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
InterpretationreasoningInhibiting MT1-MMP cell surface functions may increase the LRP-1-mediated An2 internalization mechanism and ultimately that of An2-drug conjugates.
“Inhibiting MT1-MMP cell surface functions may therefore increase the LRP-1-mediated An2 internalization mechanism and, ultimately, that of An2–drug conjugates.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationPharmacological inhibition or gene silencing of MT1-MMP potentiates antiglioma therapies using either combined temozolomide/radiation therapy or glioma virotherapy.
“Interestingly, pharmacological inhibition or gene silencing of MT1-MMP has been shown to potentiate antiglioma therapies using either combined temozolomide/radiation therapy [47] or glioma virotherapy [48].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [47] Ulasov, 2013, Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas, Cancer Med. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [48] Ulasov, 2015, MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo, Cancer Lett. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationANG1005 has shown clinical activity for treatment of leptomeningeal carcinomatosis and recurrent brain metastases in breast cancer patients.
“ANG1005, a brain-penetrant Angiopep–paclitaxel bioconjugate, has recently shown clinical activity for the treatment of leptomeningeal carcinomatosis and recurrent brain metastases in breast cancer patients [22].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Kumthekar, 2020, ANG1005, a brain-penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases, Clin. Cancer Res. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationHigh MT1-MMP expression/function is often correlated with poor cancer survival prognosis.
“Accordingly, high MT1-MMP expression/function is often correlated with a poor cancer survival prognosis [30,31].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSeven glioblastoma cell lines had high LDLR expression.
“This adaptive molecular signature was documented in seven glioblastoma cell lines that showed that these cells had high LDLR expression [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Blakely, 2000, Human glioblastoma cell lines: Levels of low-density lipoprotein receptor and low-density lipoprotein receptor-related protein, Cancer Res.
It may state two separate claims as one.
Interpretationown dataMT1-MMP contributed to LRP-1 shedding and to reduced cell-surface availability to perform An2 internalization.
“In the current study, we found that MT1-MMP actually contributed to LRP-1 shedding and to reduced cell-surface availability to perform An2 internalization.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningThe soluble form of LRP-1 may function as a decoy receptor for An2 in conditioned media and reduce the efficacy of An2 internalization.
“Considering the binding nature of An2 against LRP-1 ectodomain, it is plausible that the soluble form of LRP-1 would function as the decoy receptor for An2 in the conditioned media and reduce the efficacy of An2 internalization.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenTissue cDNAs in the arrays were synthesized from high quality total RNAs of pathologist-verified tissues.
“Tissue cDNAs in each array were synthesized from high quality total RNAs of pathologist-verified tissues”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
InterpretationreasoningA potential pool of LRP-1 may be available in low-grade brain tumor tissues, which would still contribute to LRP-1-mediated An2 uptake.
“our observations imply that, first, a pool of LRP-1 may be inducible or mobilized to contribute to efficient cell surface LRP-1-mediated An2 brain cancer cell internalization”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataInhibition of MT1-MMP could relieve its suppressive function and possibly lead to improved An2-drug conjugate accumulation within brain tumors.
“These suggest that MT1-MMP exerts a suppressive role in An2 internalization processes and that its inhibition could relieve that suppressive function and possibly lead to improved An2–drug conjugate accumulation within brain tumors.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Study design and conductnone givenValidation of MT1-MMP overexpression was performed upon monitoring of proMMP-2 activation by gelatin zymography.
“Validation of MT1-MMP overexpression was performed upon monitoring of proMMP-2 activation by gelatin zymography.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationLRP-1 activity/expression at the cell surface is controlled through intracellular trafficking mechanisms and by shedding processes involving proteolytic cleavage of LRP-1's extracellular domain.
“Interestingly, LRP-1 activity/expression at the cell surface is controlled through intracellular trafficking mechanisms [33] and by shedding processes that involve proteolytic cleavage of LRP-1′s extracellular domain.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Nanni, 2016, Impact of Concanavalin-A-mediated cytoskeleton disruption on low-density lipoprotein receptor-related protein-1 internalization and cell surface expression in glioblastomas, Biomark. Cancer source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenData are representative of triplicate measurements of two to three independent experiments, and represented as the means +/− SEM.
“Data are representative of triplicate measurements of two to three independent experiments, and represented as the means +/− SEM.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The effects of the pharmacological MMP inhibitors Ilomastat, Doxycycline, and Actinonin on An2 internalization are attributable to inhibition of MT1-MMP rather than to other MMPs or off-target effects.
“Pharmacological MMP inhibition using Ilomastat (GM6001), Doxycycline, or Actinonin as well as transient transfection of cells with a cDNA encoding recombinant Wt-MT1-MMP were performed [41].”
“Using fluorescent microscopy (Figure 3A), we found that all three MMP inhibitors significantly increased Alexa488-An2 internalization (Figure 3B).”
The paper relies on this without support.
Transcript levels measured by the brain cancer tissue scan cDNA array reflect functional LRP-1 and MT1-MMP protein expression in grade 1–4 brain tumor tissues.
“A brain cancer tissue scan cDNA array was used to assess their respective transcript levels.”
“LRP-1 transcript levels appeared to inversely correlate with increasing brain tumor gradation (Figure 1A, right panel).”
The paper relies on this without support.
U87 glioblastoma cells are representative of brain cancer cells for An2-mediated internalization processes.
“This study strengthens the involvement of LRP-1 in An2-mediated internalization processes taking place in brain cancer cells.”
The paper relies on this without support.
Findings in U87 glioblastoma cells apply to low-grade gliomas.
“Our study further suggests that regulation of LRP-1 cell surface expression and function, through gene silencing or pharmacological inhibition of catalytic MMP activity, might become very useful in enhancing the chemotherapeutic effects of An2–drug conjugates [46,68,69] by promoting their internalization in both low-grade- and high-grade gliomas.”
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Immunotherapy of Diffuse Gliomas: Biological Background, Current Status and Future Developments
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Metadata
- Authors
- Pratt, J., Haidara, K., & Annabi, B.
- Affiliations
- Université du Québec à Montréal (CA)
- Laboratoire d’Oncologie Moléculaire, Centre de Recherche CERMO-FC, Département de Chimie, Université du Québec à Montréal, Montréal, QC H3C 3P8, Canada
- Corresponding author
- Annabi, Borhane
- ORCID
- Annabi, Borhane
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2022-11-17
- Volume
- 23
- Issue
- 22
- Pages
- 14214
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC9692856
- OpenAlex
- W4309455496
- Cited by
- 8
- References
- 71
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2
- FWCI
- 0.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Sciences and Engineering Research Council (RDCPJ 445033-12)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Keywords
- MT1-MMP, LDL receptor-related protein 1, Angiopep-2, receptor internalization, glioblastoma, matrix metalloproteinases, matrix metalloproteinase inhibitors, ilomastat, doxycycline, actinonin, blood-brain tumor barrier, drug conjugates, U87 cells
- MeSH terms
- Brain Neoplasms, Glioblastoma, Humans, Hydroxamic Acids, Indoles, Ligands, Peptides, Low Density Lipoprotein Receptor-Related Protein-1, Cell Line, Tumor, Matrix Metalloproteinase 14, Matrix Metalloproteinase Inhibitors
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