Disease Modeling on Tumor Organoids Implicates AURKA as a Therapeutic Target in Liver Metastatic Colorectal Cancer (2024)

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BMC Cancer

SMAD4 - Molecular gladiator of the TGF-β signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene

2010 •

A Syed Sameer

Background The development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the SMAD4 gene mutations with KRAS mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of SMAD4 gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and KRAS mutant genotype. Methods We examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of SMAD4 and exon 1 of KRAS by PCR-SSCP and/or PCR-Direct sequencing. Results The overall mutation rate of mutation cluster region (MCR) region of SMAD4 gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the SMAD4 gene mutants were found to have mutations in KRAS gene as well. The association between the KRAS mutant genotype with SMAD4 mutants was found to be significant (P =< 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the SMAD4 gene (P =< 0.05). Conclusion Our study suggests that SMAD4 gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the KRAS mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.

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International Journal of Colorectal Disease

Role of TGF-β1, its receptor TGFβRII, and Smad proteins in the progression of colorectal cancer

2010 •

Katya G Peeva

Aim In the current study, we investigated the expression of TGF-β1, its receptor TGFβRII, and the signaling proteins Smad4 and Smad7 in colorectal cancer tissue in relation to infiltration with antigen-presenting cells and some clinical and pathologic parameters of disease progression in patients with colorectal cancer (CRC). Materials and methods: The immunohistochemical expression of TGF-β1, TGFβRII, Smad4, Smad7, HLA-DR antigen, CD1a, CD83, and CD68 was evaluated in 142 patients (50 females and 92 males) with CRC, followed-up for 6–8 years period. Results In our study, 127 (89.4%) out of 142 colorectal cancers displayed cytoplasmic TGF-β1 immunoreactivity. Common-mediator Smad4 was detected in the tumor cytoplasm in 124 cancers (79.5%) and inhibitory Smad7 immunostaining was observed in 110 (77.4%) tumor specimens. TGFβRII was expressed on tumor cell membranes in 119 (76.3%) of the cancers. The increased TGF-β1 expression in tumor cytoplasm was related to low CD68+- and CD83+-cell infiltration in tumor tissues. Patients with TGF-β1 overexpression had worse prognosis after surgical therapy compared to those with low expression of TGF-β1. The observed association was more pronounced for the patients in T1–T2 stage (p = 0.0015). Conclusions: The expression of TGF-β1, its receptor TGFβRII, and signaling proteins Smad4 and Smad7 was observed in the majority of colorectal cancer specimens. Our results suggest that TGF-β1 production by tumor cells may affect the tumor environment via suppression of tumor-infiltrating immune cells and probably contributes to tumor cells aggressiveness through autocrine activation of Smad signaling.

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Cancer Research

Smad2 and Smad3 Phosphorylated at Both Linker and COOH-Terminal Regions Transmit Malignant TGF-β Signal in Later Stages of Human Colorectal Cancer

2009 •

Jun-ichi Fujisawa

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Biochemical Journal

Molecular and functional consequences of Smad4C-terminal missense mutations in colorectal tumour cells

2004 •

FRANCISCO JOSE NICOLAS

Smad4 is an essential signal transducer of the transforming growth factor β (TGF-β) signalling pathway and has been identified as a tumour suppressor, being mutated in approx. 50% of pancreatic cancers and approx. 15% of colorectal cancers. Two missense mutations in the C-terminal domain of Smad4, D351H (Asp351→His) and D537Y (Asp537→Tyr), have been described recently in the human colorectal cancer cell lines CACO-2 and SW948 respectively [Woodford-Richens, Rowan, Gorman, Halford, Bicknell, Wasan, Roylance, Bodmer and Tomlinson (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 9719–9723]. Previous work in vitro suggested that only Asp-351 was required for interaction with Smad2 [Wu, Fairman, Penry and Shi (2001) J. Biol. Chem. 276, 20688–20694]. In the present study, we investigate the functional consequences of these point mutations in vivo. We demonstrate that neither of these colorectal cancer cells undergo growth arrest in response to TGF-β, which can be explained, at least in part, by t...

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Oncogene

Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis

1999 •

登志夫 黒木黒木

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Molecular …

Frequent loss of SMAD4/DPC4 protein in colorectal cancers

2002 •

Egle Avizienyte

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Cancer Research

Enhancement of TGF- Signaling Responses by the E3 Ubiquitin Ligase Arkadia Provides Tumor Suppression in Colorectal Cancer

2011 •

Vasiliki Bravou

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Molecular pathology

Frequent loss of SMAD4/DPC4 protein in colorectal cancer

2007 •

Egle Avizienyte

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International Journal of Cancer

Expression of Smad proteins in human colorectal cancer

1999 •

Maréne Landström

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Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin

Role of transforming growth factor-beta pathway in progressiveness of colorectal cancer

Katya G Peeva

Background: Most of all epithelial-derived tumors become resistant to the growth inhibitory effect of TGF-beta.The aim of the present study was to evaluate TGF-beta1, TGFbetaRII, Smad4 and Smad7 expression in tumor tissue of colorectal cancer (CRC) patients and to determine their relationship survival. TGF-beta expression in tumor cell cytoplasm was correlated with HLA-DR expression, with macrophages and dendritic cells. Methods: The expression of TGF-beta1, TGF-betaRII, Smad4 and Smad7 and of HLA-DR antigen, CD1a, CD83 and CD68 was evaluated immunohistochemically in 142 CRC patients (50 females and 92 males), followed-up for 6–8 years period. Results: The TGF-beta1 expression in tumor cytoplasm was observed in 127 patients (89,4%) and of Smad4 expression - in 83,8% patients. Smad4 expression in tumor nuclei correlated with TGF- beta1 expression in tumor cytoplasm (χ2=38.88; p=0,0001) whereas cytoplasmic Smad4 expression correlated with TGF- betaRII on the tumor cell membrane (χ2=23...

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Disease Modeling on Tumor Organoids Implicates AURKA as a Therapeutic Target in Liver Metastatic Colorectal Cancer (2024)

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