Involvement of trefoil factor family 2 in the enlargement of intestinal tumors in ApcMin/+ mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE329550 | GEO | 2026/04/29
REPOSITORIES: GEO
Similar Datasets
Project description:Trefoil factor family member 2 (Tff2) is significantly involved in intestinal tumor growth in ApcMin/+ mice, which can be used as a human colon cancer model. TFF2, which encodes TFF2 (spasmolytic protein 1) is highly expressed in human cancer tissues, including the pancreas, colon and bile ducts, as well as in normal gastric and duodenum tissues. By contrast, TFF2 exhibits low expression levels in other normal tissues, including the small and large intestine. Furthermore, TFF2 expression has not been detected in DLD-1 cells, a cell line derived from human colon cancer. The trigger of TFF2 expression in normal and tumor cells remains unknown. Highly malignant tumor tissues are characterized by higher temperatures and lower pH (6.2-6.9) than in normal tissues, where the normal pH ranges from 7.2 to 7.4. This microenvironment exacerbates malignancy by promoting the acquisition of cell death resistance, drug resistance and immune escape. Therefore, the present study examined how TFF2 expression is affected in cultured cells that imitate the tumor tissue microenvironment. The incubation temperature was increased from 37 to 40˚C, but no expression of TFF2 was induced. Subsequently, a culture solution with an acidic pH was prepared to simulate the Warburg effect in tumors. TFF2 expression was increased by 42.8- and 5.8-fold in cells cultured in acidic medium at pH 6.5 and 6.8 compared with at pH 7.4, respectively, as determined using the relative quantification method following quantitative polymerase chain reaction. The present study also analyzed fluctuations in the expression levels of genes other than TFF2, under acidic conditions. Acidic conditions upregulated the expression of genes related to cell membranes and glycoproteins, based on the Database for Annotation, Visualization, and Integrated Discovery. In conclusion, TFF2 was highly expressed under acidic conditions, implying that it may have an important function in protecting the plasma membrane from acidic environments in both normal and cancer cells. These findings warrant further investigation of TFF2 as a target of cancer therapy and diagnosis.
2024-02-16 | GSE246091 | GEO
Project description:Exocrine-to-endocrine crosstalk in the pancreas is crucial to maintain beta cell function. However, the molecular mechanisms underlying this crosstalk are largely undefined. Trefoil factor 2 (Tff2) is a secreted factor known to promote the proliferation of beta cells in vitro, but its physiological role in vivo in the pancreas is unknown. Also, it remains unclear which pancreatic cell type expresses Tff2 protein. We therefore created a mouse model with a conditional knockout of Tff2 in the murine pancreas. We find that the Tff2 protein is preferentially expressed in acinar but not ductal or endocrine cells. Tff2 deficiency in the pancreas reduces beta cell mass on embryonic day 16.5. However, homozygous mutant mice are born without a reduction of beta cells and with acinar Tff3 compensation by day 7. When mice are aged to 1 year, both male and female homozygous and male heterozygous mutants develop impaired glucose tolerance without affected insulin sensitivity. Perifusion analysis reveals that the second phase of glucose-stimulated insulin secretion from islets is reduced in aged homozygous mutant compared to controls. Collectively, these results demonstrate a previously unknown role of Tff2 as an exocrine acinar cell-derived protein required for maintaining functional endocrine beta cells in mice.
2024-05-13 | GSE267036 | GEO
Project description:Involvement of trefoil factor family 2 in the enlargement of intestinal tumors in ApcMin/+ mice
| PRJNA1459486 | ENA
Project description:The aim of the study was to investigate whether the trefoil peptide genes, in concerted action with a miRNA regulatory network, were contributing to nutritional maintrenance. Using a Tff2 knock-out mouse model, 48 specific miRNAs were noted to be significantly deregulated when compared to the wild type strain.
2012-01-01 | GSE25815 | GEO
Project description:The gene expression of murine splenic myeloid derived suppressor cells treated with Tff2 is characterized. The motivation of the study originates in the fact that Gr1+Cd11b+ myeloid-derived suppressor cells (MDSCs), which resemble immature myeloid cells (IMCs), expand during cancer in response to inflammatory cytokines and accumulate in the spleen. MDSCs promote neoplastic progression through their suppression of anti-tumourigenic cytotoxic T-cells. MDSCs are also rapidly expanded following acute insults, but in cancer as opposed to acute inflammation, MDSCs persist. It is now recognized that a vagally-mediated, anti-inflammatory reflex arc promoting acetylcholine secretion by Cd4+ (Cd44hiSelllo) T cells, is necessary for a return to homeostasis after an acute insult. Failure of this restorative neural circuit might contribute to unabated procarcinogenic inflammation, with the chronic expansion of MDSCs driving carcinogenesis. Trefoil factor 2 (Tff2) is a secreted anti-inflammatory peptide produced by both epithelial cells and a small subset of splenic T cell. In this study, we show that splenic Tff2 is induced in vagally-modulated memory T cells to suppress the expansion of MDSCs in response to chemical and carcinogenic injury. Deletion of Tff2 interrupts this anti-inflammatory neural arc and leads to expanded MDSCs and a dramatically increased incidence of colorectal cancer. Tff2 directly suppresses proliferation of myeloid progenitors, in a large part through upregulation of cell-bound Apolipoprotein E (ApoE), which has previously been shown to suppress proliferation of haematopoietic stem and progenitor cells. The predisposition to inflammation-associated cancer can be rescued through transgenic overexpression of splenic Tff2, adenoviral transfer of Tff2 expression or transplantation of Tff2-expressing haematopoietic cells. Thus, Tff2 production in memory T cells, is regulated by the vagus nerve, plays a central role in arresting procarcinogenic MDSC proliferation, and offers a novel approach to the prevention and treatment. A. Gr1+Cd11b+ splenic cells from Tff2-/- mice treated with Csf2 (n=4). B. Gr1+Cd11b+ splenic cells from Tff2-/- mice treated with Tff2 and Csf2 (n=4).
2016-05-30 | E-GEOD-47596 | biostudies-arrayexpress
Project description:The aim of the study was to investigate whether the trefoil peptide genes, in concerted action with a miRNA regulatory network, were contributing to nutritional maintrenance. Using a Tff2 knock-out mouse model, 48 specific miRNAs were noted to be significantly deregulated when compared to the wild type strain. n = 6 mus musculus wild type samples and n = 6 knock-down experiments have been screened for a currently known mus musculus miRNAs and validated by TaqMan
2012-01-01 | E-GEOD-25815 | biostudies-arrayexpress
Project description:The gene expression of murine splenic myeloid derived suppressor cells treated with Tff2 is characterized. The motivation of the study originates in the fact that Gr1+Cd11b+ myeloid-derived suppressor cells (MDSCs), which resemble immature myeloid cells (IMCs), expand during cancer in response to inflammatory cytokines and accumulate in the spleen. MDSCs promote neoplastic progression through their suppression of anti-tumourigenic cytotoxic T-cells. MDSCs are also rapidly expanded following acute insults, but in cancer as opposed to acute inflammation, MDSCs persist. It is now recognized that a vagally-mediated, anti-inflammatory reflex arc promoting acetylcholine secretion by Cd4+ (Cd44hiSelllo) T cells, is necessary for a return to homeostasis after an acute insult. Failure of this restorative neural circuit might contribute to unabated procarcinogenic inflammation, with the chronic expansion of MDSCs driving carcinogenesis. Trefoil factor 2 (Tff2) is a secreted anti-inflammatory peptide produced by both epithelial cells and a small subset of splenic T cell. In this study, we show that splenic Tff2 is induced in vagally-modulated memory T cells to suppress the expansion of MDSCs in response to chemical and carcinogenic injury. Deletion of Tff2 interrupts this anti-inflammatory neural arc and leads to expanded MDSCs and a dramatically increased incidence of colorectal cancer. Tff2 directly suppresses proliferation of myeloid progenitors, in a large part through upregulation of cell-bound Apolipoprotein E (ApoE), which has previously been shown to suppress proliferation of haematopoietic stem and progenitor cells. The predisposition to inflammation-associated cancer can be rescued through transgenic overexpression of splenic Tff2, adenoviral transfer of Tff2 expression or transplantation of Tff2-expressing haematopoietic cells. Thus, Tff2 production in memory T cells, is regulated by the vagus nerve, plays a central role in arresting procarcinogenic MDSC proliferation, and offers a novel approach to the prevention and treatment.
2016-05-30 | GSE47596 | GEO
Project description:Murphy2016 - Differences in predictions of
ODE models of tumor growth
Comparison of 7 ODE models for tumour
size. This models have been compared to experimental data.
This model is described in the article:
Differences in predictions
of ODE models of tumor growth: a cautionary example.
Murphy H, Jaafari H, Dobrovolny
HM.
BMC Cancer 2016 Feb; 16: 163
Abstract:
While mathematical models are often used to predict
progression of cancer and treatment outcomes, there is still
uncertainty over how to best model tumor growth. Seven ordinary
differential equation (ODE) models of tumor growth
(exponential, Mendelsohn, logistic, linear, surface, Gompertz,
and Bertalanffy) have been proposed, but there is no clear
guidance on how to choose the most appropriate model for a
particular cancer.We examined all seven of the previously
proposed ODE models in the presence and absence of
chemotherapy. We derived equations for the maximum tumor size,
doubling time, and the minimum amount of chemotherapy needed to
suppress the tumor and used a sample data set to compare how
these quantities differ based on choice of growth model.We find
that there is a 12-fold difference in predicting doubling times
and a 6-fold difference in the predicted amount of chemotherapy
needed for suppression depending on which growth model was
used.Our results highlight the need for careful consideration
of model assumptions when developing mathematical models for
use in cancer treatment planning.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000671.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000671 | BioModels
Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer. 18 tumor tissue samples were analysed, no replicates
2013-12-18 | E-GEOD-53127 | biostudies-arrayexpress
Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer.
2013-12-18 | GSE53127 | GEO