Dataset Information

Expression data from Apcmin/+ mice treated with BAMLET

ABSTRACT: Tumor surveillance is essential to stop tumor progenitors in their tracks. Clearly, endogenous protective mechanisms other than immune surveillance are important, but their molecular nature and mechanisms of action remain unclear. In the newborn intestine, the immature cells need to be surveilled to promote differentiation and tumor development prevented. This study addressed if molecules in milk may be relevant for tumor surveillance. Alpha-lactalbumin, which is the most abundant protein in human milk and crucial for the survival of mammals, due to its role in lactose synthesis, also forms tumoricidal oleic-acid complexes with documented therapeutic efficacy. This study identifies BAMLET, a complex formed by bovine alpha-lactalbumin and oleic acid, as a tumor surveillance molecule. BAMLET substitution of the drinking water protected tumor-prone ApcMin/+ mice from developing intestinal cancer and prolonged their survival, with pronounced inhibition of genes regulating the tumor environment, metastasis, Wnt/β-catenin signaling and cancer related gene networks. Unexpected extra-intestinal effects on lungs, livers, kidneys and spleens further suggested a protective effect of BAMLET beyond the intestine. These effects were specific for the cancer-prone ApcMin/+ mice. Healthy C57BL/6 mice were largely unaffected by peroral BAMLET administration, except for improved metabolic functions such as lipid and glucose metabolism and insulin resistance and there was no evidence of toxicity. The results suggest that molecules, which have evolved to support tissue differentiation, may identify and remove tumor progenitors. The findings support the potential of BAMLET as a tumor surveillance molecule with potential for clinical use in cancer-prone patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE235766 | GEO | 2024/02/12

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:To identify the precise molecular mechanisms that could contribute to the increase in colon carcinogenesis, microarray gene expression analysis was performed on colon RNA isolated from 5-week-old VhlF/F and VhlΔIE, VhlΔIE/Apcmin/+ and VhlF/F/Apcmin/+ mice. Hypoxia-inducible factor (HIF) is a key modulator of the transcriptional response to hypoxia and is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. Intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apcmin/+ intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and Hif-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue, however tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, BrdU incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis demonstrated that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α-mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings demonstrate that a chronic increase in HIF-2α in the colon initiates pro-tumorigenic signaling which may have important implications in developing preventive and therapeutic strategies for colon cancer. Global gene expression profiling in colon RNAs isolated from 5-week-old VhlF/F (n=4, Shah 001), VhlF/F/Apcmin/+(n=3, Shah 003), VhlΔIE (n=3, Shah 002) and VhlΔIE/Apcmin/+ mice (n=5, Shah 004).

Project description:Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of carcinogenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2positive), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of carcinogenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes regulated by PRC2 and associated with the intestinal stem cell signature. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+mice, but at lower levels than advanced cancers. Taking into account the parallelisms between human and mouse intestinal carcinogenesis, this study provides a reference framework to interpret the alterations found in human cancer. We have analyzed ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Samples were in triplicates, except for tissue adjacent to adenoma (in duplicates).

Dataset Information

Expression data from Apcmin/+ mice treated with BAMLET

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets