Abstract
Simple SummaryDietary restriction regimens, such as caloric restriction (CR), in the initiation and development of cancers has been studied using biological models and traditionally considers CR as anti-cancerogenic. However, the experimental, clinical facts and conclusions are controversial. CR-induced molecular and cellular mechanisms and pro-oncogenic pathways have not been systematically studied, leaving therapeutic benefits unclear. Here, using systems biology and deep data analysis approach, we study the CR-induced molecular pathway switches and cell-type context-specific responses known to underly early pre-malignant states in mouse and human mucosa. We identify the genes and energy-restricted networks associated with pre-malignant state metabolic reprogramming in normal stem cells and epithelial cell cycle activation, leading to telomere ends misbalance and immune response depletion. We define the changes in tumor suppressor and oncogenic pathways which may precede intestinal mucosa lesion development. This work will aid in the near future to define critical biomarkers for earlier detection and risk of adenomas and colorectal cancer.Systems cancer biology analysis of calorie restriction (CR) mechanisms and pathways has not been carried out, leaving therapeutic benefits unclear. Using metadata analysis, we studied gene expression changes in normal mouse duodenum mucosa (DM) response to short-term (2-weeks) 25% CR as a biological model. Our results indicate cancer-associated genes consist of 26% of 467 CR responding differential expressed genes (DEGs). The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest telomeric maintenance misbalance and metabolic pathway activation playing dual (anti-cancer and pro-oncogenic) roles. The aberrant DEG profile of DM epithelial cells is found within CR-induced overexpression of Paneth cells and is coordinated significantly across GI tract tissues mucosa. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor-immune surveillance. CR induces metabolic reprogramming, suppressing immune mechanics and activating oncogenic pathways. We introduce and argue for our network pro-oncogenic model of the mucosa multicellular tissue response to CR leading to aberrant transcription and pre-malignant states. These findings change the paradigm regarding CR’s anti-cancer role, initiating specific treatment target development. This will aid future work to define critical oncogenic pathways preceding intestinal lesion development and biomarkers for earlier adenoma and colorectal cancer detection.
Highlights
Calorie restriction (CR), where test animals receive a reduced energy diet, is one of the most broadly acting regimens for preventing or reversing weight gain and inhibiting cancer in experimental tumor models [1,2]
We carried out gene microarray expression profiling and its experimental validation for CR-responded differential expressed genes (DEGs) in mouse duodenum mucosa (DM) [15]
A gene of a human or mouse dataset was considered expressed with a mean log signal intensity value larger than the cut-off value of three. (B) GO functional enrichment analysis of mouse DM DEGs with human orthologs responding to CR were analyzed using the STRING v11 tools at enrichment false discovery rate (FDR) < 0.05
Summary
Calorie restriction (CR), where test animals receive a reduced energy diet, is one of the most broadly acting regimens for preventing or reversing weight gain and inhibiting cancer in experimental tumor models [1,2]. Chronic reduction of dietary energy intake without malnutrition decreases adiposity, inflammation, and improves metabolic profiles [3,4]. CR was shown to increase tumor latency and have protective effects in some experimental mammary carcinogenesis models [5,6]. Upon CR, metabolic alterations foster healthpromoting characteristics including increased insulin sensitivity, decreased blood glucose and growth factors (IGF-1), and angiogenesis [4]. Reducing IGF-1 and glucose levels may decrease tumor progression [2,3,4,7]. Mice small intestinal response had a highly-dispersal trend decreasing large polyps (>2 mm) but increasing small polyp (≤2 mm) numbers [8]
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