TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in <i>KRAS</i>-mutated colorectal cancer cells: A potential novel approach to the treatment of metastatic colorectal cancer

Tarpgaard, Line Schmidt; Ørum-Madsen, Maj Sofie; Christensen, Ib Jarle; Nordgaard, Cathrine; Noer, Julie B.; Guren, Tormod Kyrre; Glimelius, Bengt; Sørbye, Halfdan; Ikdahl, Tone; Kure, Elin H.; Nielsen, Hans Jørgen; Pfeiffer, Per; Brünner, Nils; Moreira, José M.A.

doi:10.18632/oncotarget.11118

Cited by 7 publications

(11 citation statements)

References 48 publications

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“…MMP-14, on the other hand, degrades other basement membrane components, such as collagen type I [14]. TIMP-1, associated with MMPs, has been described as a predictive factor of survival and might predict recurrence in certain types of cancer [15,16]. In contrast, TIMP-2 is the only TIMP protein that can inhibit the mitogenic response independently of MMP [17].…”

Section: Introductionmentioning

confidence: 99%

Tumoral and stromal expression of MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2, and VEGF-A in cervical cancer patient survival: a competing risk analysis

et al. 2020

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Background: Expression of matrix metalloproteases 2, 9 and 14 (MMP-2, MMP-9, MMP-14), tissue inhibitors of metalloprotease 1 and 2 (TIMP-1, TIMP-2) and vascular endothelial growth factor A (VEGF-A) is involved in tumor invasion and metastasis via extracellular matrix degradation and angiogenesis. This study aimed to assess whether the expression of MMP-2, MMP-9, MMP-14, TIMP-1, and TIMP-2 in tumors and in the adjacent stroma is associated with cervical cancer prognosis. Methods: This study analyzed a retrospective cohort of 64 patients. Protein expression was previously obtained by immunohistochemistry from biopsies containing both tumor and stroma. The expression and percentage of stained cells were categorized as high or low according to the cutoff points by using ROC curves. The follow-up data was collected from diagnosis to the last clinical visit. Clinical status categorized as alive without disease, alive with disease, death due to other causes, and death from the disease. The relative risk of death from the disease was evaluated according to the proteins expression using a cause-specific Cox regression model with a 95% confidence interval (95%CI). For the significant associations (p < 0.05), survival curves of patients with low and high expression were plotted for the competing risk survival curve analyses. Results: High expression levels of stromal MMP-2 (RR; 95%CI: 3.91; 1.17-13.02) and stromal TIMP-2 (RR, 95%CI: 8.67; 1.15-65.27) were associated with a greater relative risk of death from the disease and with lower survival (p = 0.03; p = 0.04) than lower expression levels. Low expression levels of stromal MMP-9 (RR, 95%CI: 0.19; 0.05-0.65) and tumoral MMP-9 (HR, 95%CI: 0.19; 0.04-0.90) were protective factors against death from the disease and were associated with poorer survival.

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Section: Introductionmentioning

confidence: 99%

Tumoral and stromal expression of MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2, and VEGF-A in cervical cancer patient survival: a competing risk analysis

et al. 2020

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“…Recently, we found that TIMP‐1 plasma levels predicted benefit from EGFR‐inhibition therapy in KRAS ‐mutated metastatic colorectal cancer patients. These results were supported by data from cellular models showing that exposure of colorectal cancer (CRC) cells to exogenously added recombinant TIMP‐1 promoted a more aggressive behavior in these cells, specifically in KRAS ‐mutated cells (Tarpgaard et al , ). We added recombinant TIMP‐1 to a matched set of isogenic DLD‐1 CRC cell clones, in which either the endogenous KRAS wt allele (from here on referred to as DLD‐1 G13D cell line) or the KRAS (G13D) mutant allele (from here on referred to as DLD‐1 wt cell line) has been inactivated by targeted homologous recombination (Yun et al , ), respectively.…”

Section: Introductionmentioning

confidence: 79%

“…Although TIMP‐1 expression is up‐regulated in colorectal tumor tissue (Lu et al , ), the molecular mechanisms underlying the prognostic effect of TIMP‐1 in CRC remain unclear. We previously reported a differential cellular effect of TIMP‐1 on CRC cell invasion, dependent on KRAS status (Tarpgaard et al , ). A similar observation has also been reported for pancreatic ductal adenocarcinoma, where exogenous addition of human recombinant TIMP‐1 significantly increased proliferation of pancreatic ductal cells, but only in KRAS ‐transformed cells (Botta et al , ).…”

Section: Discussionmentioning

confidence: 98%

“…We added recombinant TIMP‐1 to a matched set of isogenic DLD‐1 CRC cell clones, in which either the endogenous KRAS wt allele (from here on referred to as DLD‐1 G13D cell line) or the KRAS (G13D) mutant allele (from here on referred to as DLD‐1 wt cell line) has been inactivated by targeted homologous recombination (Yun et al , ), respectively. Whereas the DLD‐1 wt cells showed no significant difference in invasive potential, DLD‐1 G13D cells responded to the presence of TIMP‐1 in the growth medium by becoming significantly more invasive (Tarpgaard et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Metallopeptidase inhibitor 1 (TIMP‐1) promotes receptor tyrosine kinase c‐Kit signaling in colorectal cancer

et al. 2019

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Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700 000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer, including targeted biological agents, such as cetuximab, a monoclonal antibody that targets EGFR. We have previously reported a study indicating multiple levels of interaction between metallopeptidase inhibitor 1 (TIMP‐1) and the epidermal growth factor (EGF) signaling axis, which could explain how TIMP‐1 levels can affect the antitumor effects of EGFR inhibitors. We also reported an association between TIMP‐1‐mediated cell invasive behavior and KRAS status. To gain insight into the molecular mechanisms underlying the effects of TIMP‐1 in CRC, we examined by transcriptomics, proteomics, and kinase activity profiling a matched pair of isogenic human CRC isogenic DLD‐1 CRC cell clones, bearing either an hemizygous KRAS wild‐type allele or KRAS G13D mutant allele, exposed, or not, to TIMP‐1. Omics analysis of the two cell lines identified the receptor tyrosine kinase c‐Kit, a proto‐oncogene that can modulate cell proliferation and invasion in CRC, as a target for TIMP‐1. We found that exposure of DLD‐1 CRC cells to exogenously added TIMP‐1 promoted phosphorylation of c‐Kit, indicative of a stimulatory effect of TIMP‐1 on the c‐Kit signaling axis. In addition, TIMP‐1 inhibited c‐Kit shedding in CRC cells grown in the presence of exogenous TIMP‐1. Given the regulatory roles that c‐Kit plays in cell proliferation and migration, and the realization that c‐Kit is an important oncogene in CRC, it is likely that some of the biological effects of TIMP‐1 overexpression in CRC may be exerted through its effect on c‐Kit signaling.

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“…As such, inhibitors of the EGFR signaling pathway have received attention as potential therapeutic agents (49). Moreover, EGF-induced activation of EGFR increases MMP-9 expression levels through the activation of the PI3K/Akt pathway in patients with glioblastoma (50).…”

Section: Discussionmentioning

confidence: 99%

Identification of potential hub genes associated with the pathogenesis and prognosis of pancreatic duct adenocarcinoma using bioinformatics meta‑analysis of multi‑platform datasets

et al. 2019

Oncol Lett

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Pancreatic duct adenocarcinoma (PDAC) is a highly malignant type of cancer with a low five-year survival rate. Gene alterations are crucial to the molecular pathogenesis of PDAC. Therefore, the present study analyzed gene expression profiles to reveal genes involved in the tumorigenesis of PDAC. A total of eight gene expression profiles (GSE15471, GSE16515, GSE41368, GSE62165, GSE62452, GSE71729, GSE71989 and GSE91035) and a PDAC dataset were acquired from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database, respectively. Differentially expressed genes (DEGs) were screened using functional annotation, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network construction. A Cox proportional hazards model was then constructed and used to analyze the data. A total of 136 DEGs (67 up- and 69 downregulated genes) were identified between PDAC tissues and normal tissues. The ‘extracellular matrix-related’ genes were the most enriched in the GO term analysis. ‘Pancreatic secretion’, ‘phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-Akt) signaling pathway’, ‘protein digestion and absorption’ and ‘ECM-receptor interaction’ were the most enriched categories in KEGG pathway analysis. Following PPI network construction, the 10 most significant genes [albumin, epidermal growth factor, matrix metalloproteinase (MMP) 9, epidermal growth factor receptor, fibronectin 1, MMP1, plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase 1, plasminogen activator urokinase (PLAU) and PLAU receptor) exhibiting a high degree of connectivity, were identified as the hub genes likely to be associated with the pathogenesis of PDAC. In addition, a prognostic predictive system for PDAC, composed of five genes (laminin subunit γ 2, laminin subunit β 3, serpin family B member 5, amphiregulin and secreted frizzled related protein 4), was constructed. This was validated in the GSE62452 dataset (using 66 PDAC samples with outcome data) and TCGA PDAC dataset (using 146 PDAC samples with outcome data). In conclusion, the present study revealed potential hub genes involved in PDAC progression, providing directive significance for individualized clinical decision-making and molecular-targeting therapy in patients with PDAC.

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TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells: A potential novel approach to the treatment of metastatic colorectal cancer

Cited by 7 publications

References 48 publications

Tumoral and stromal expression of MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2, and VEGF-A in cervical cancer patient survival: a competing risk analysis

Tumoral and stromal expression of MMP-2, MMP-9, MMP-14, TIMP-1, TIMP-2, and VEGF-A in cervical cancer patient survival: a competing risk analysis

Metallopeptidase inhibitor 1 (TIMP‐1) promotes receptor tyrosine kinase c‐Kit signaling in colorectal cancer

Identification of potential hub genes associated with the pathogenesis and prognosis of pancreatic duct adenocarcinoma using bioinformatics meta‑analysis of multi‑platform datasets

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