New insights from animal models of colon cancer: inflammation control as a new facet on the tumor suppressor APC gem

Zeineldin, Maged; Neufeld, Kristi L.

doi:10.2147/gictt.s51386

Cited by 3 publications

(4 citation statements)

References 189 publications

(218 reference statements)

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“…The precise function of APC in these APC high goblet cells has yet to be determined. We and others have reported that APC promotes goblet cell differentiation and mucosal barrier integrity (van de Wetering et al, 2002;Zeineldin & Neufeld et al, 2015). In terms of goblet cell differentiation, APC has been shown to target CtBP1 for degradation (Nadauld et al, 2006) and CtBP1 is a transcriptional co-repressor of a goblet cell-specific differentiation factor, KLF4 (Katz et al, 2008;Liu, Zheng, & Ai, 2009).…”

Section: Discussionmentioning

confidence: 97%

Elevated adenomatous polyposis coli in goblet cells is associated with inflammation in mouse and human colon

Gomez

Neufeld

2020

Experimental Physiology

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Adenomatous polyposis coli (APC) serves as a gatekeeper of intestinal homeostasis by promoting cellular differentiation and maintaining crypt architecture. Although appreciated as a critical colon tumour suppressor, roles for APC in disease states such as inflammation have yet to be fully delineated. This study aimed to characterize the localization of APC protein in gastrointestinal tissues from human patients with active inflammatory bowel disease and mice with dextran sodium sulfate (DSS)-induced colitis. Fluorescence immunohistochemistry revealed a subset of goblet cells with elevated Apc staining intensity in the small intestines and proximal/medial colons of mice. Upon induction of colitis with DSS, these 'APC high ' goblet cells remained in the proximal and medial colon, but now were also observed in the distal colon. This phenotype was recapitulated in humans, with APC high goblet cells observed only in the descending colons of patients with active ulcerative colitis. In cultured human colon cells derived from normal tissue, APC depletion reduced expression of mRNAs encoding the interleukin 1 (IL1) signalling pathway components IL1β and interleukin-1 receptor (IL1R), known regulators of Muc2 expression. Treating cancer cells lacking wild-type APC with IL1β, or induction of full-length APC in these cells led to increases in IL1R and MUC2 expression. Combining IL1β treatment with APC induction led to an increase of MUC2 expression greater than expected for additive affects, suggesting that APC sensitizes cells to IL1 signalling. These findings suggest that APC has novel roles in maintaining proper goblet cell function, thus providing further evidence for APC as an important factor in intestinal tissue homeostasis and disease.

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Section: Discussionmentioning

confidence: 97%

Elevated adenomatous polyposis coli in goblet cells is associated with inflammation in mouse and human colon

Gomez

Neufeld

2020

Experimental Physiology

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“…AvrA also activates STAT3 pathways which are promoting inflammation-associated colonic tumorigenesis [25]. Inflammation activates many pathways including the NF-kB pathway that synergize with Wnt signal activation which maintains stemness and activates cancer stem cells [26], [27].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Acute and Chronic Infection-Induced by AvrA Protein of Salmonella typhimurium on Radical Oxygen Species, Phosphatase and Tensin Homolog, and Cellular Homolog Expression During the Development of Colon Cancer

Satuman

Sari

Rachmi

et al. 2021

Open Access Maced J Med Sci

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AIM. The aim of the study was to analyze Avra's effector in inducing cancer stem cells into colon cancer through increased radical oxygen species (ROS), PTEN expression and c-myC as markers of tumorigenesis in mice model of the colorectal cancer infected with S. typhimurium. METHODS. The study used balb c mice induced once a week by 10 mg / mL / day of AOM for 1-week and 12-week treatment period. Isolation of S. typhimurium specific protein had been carried out before being induced to mice in intraperitoneal manner in the amount of 40 mL / 50 mL. Propagation of S. typhimurium ATCC bacteria with MacConkey media and isolation of S. typhimurium protein were administered. The sample was divided into 4 groups, positive control group (group that was only exposed to azoxymethane (AOM), group exposed to both AOM and AvrA (AOM + AvrA), and group exposed to both AOM and S. typhimurium (AOM + S. typhimurium). Blood flow cytometry and soft tissue sampling for IHC and data analysis were then conducted. RESULTS. The results of the study showed that there was an increase in the expression of ROS, PTEN and c-Myc. Increased ROS expression was found in the 12-week treatment period group and it was known that such increase was due to AOM + S. typhimurium (45.78 Â± 2.93) induction compared to AOM, AOM + AvrA and control (p <0.05). PTEN and C-myc expression increased at the 12th week compared to the negative control. CONCLUSION. Inflammation is the triggering factor for colorectal cancer, in which the expression of ROS, PTEN and c-Myc as the colorectal cancer markers increases in both the acute and chronic phases.

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“…The protein sequence and domain structure in APC are evolutionary conserved between murine and humans with 89% identity and 91.9% similarity shared at the amino acid level [ 144 ]. This high conservation made murine widely used models investigate the role of Apc in colorectal cancer—at least 43 different mouse models and 3 rat models have been established [ 173 , 174 , 175 , 176 ] ( Figure 3 ). The first genetically engineered mouse model, known as Apc Min (for multiple intestinal neoplasia), contains a nonsense point mutation in the codon 850 that behaves as autosomal dominant loss of Apc function [ 177 , 178 ] and promotes intestinal adenomas (polyps).…”

Section: Apc Functional Domain Analysis and Animal Models For Invementioning

confidence: 99%

“…New animal models to design selective Apc deletions, e.g., use of the LoxP-Cre system or CRISPR genome-editing would help dissect the precise contributions of Wnt and cytoskeletal activities to gut homeostasis. Further, such mutants will shed light into the long-standing question of whether both of these APC activities are mechanistically connected [ 173 , 174 , 175 ].…”

Section: Apc Functional Domain Analysis and Animal Models For Invementioning

confidence: 99%

Cytoskeletal Control and Wnt Signaling—APC’s Dual Contributions in Stem Cell Division and Colorectal Cancer

Juanes

2020

Cancers

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Intestinal epithelium architecture is sustained by stem cell division. In principle, stem cells can divide symmetrically to generate two identical copies of themselves or asymmetrically to sustain tissue renewal in a balanced manner. The choice between the two helps preserve stem cell and progeny pools and is crucial for tissue homeostasis. Control of spindle orientation is a prime contributor to the specification of symmetric versus asymmetric cell division. Competition for space within the niche may be another factor limiting the stem cell pool. An integrative view of the multiple links between intracellular and extracellular signals and molecular determinants at play remains a challenge. One outstanding question is the precise molecular roles of the tumour suppressor Adenomatous polyposis coli (APC) for sustaining gut homeostasis through its respective functions as a cytoskeletal hub and a down regulator in Wnt signalling. Here, we review our current understanding of APC inherent activities and partners in order to explore novel avenues by which APC may act as a gatekeeper in colorectal cancer and as a therapeutic target.

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New insights from animal models of colon cancer: inflammation control as a new facet on the tumor suppressor APC gem

Cited by 3 publications

References 189 publications

Elevated adenomatous polyposis coli in goblet cells is associated with inflammation in mouse and human colon

Elevated adenomatous polyposis coli in goblet cells is associated with inflammation in mouse and human colon

The Effect of Acute and Chronic Infection-Induced by AvrA Protein of Salmonella typhimurium on Radical Oxygen Species, Phosphatase and Tensin Homolog, and Cellular Homolog Expression During the Development of Colon Cancer

Cytoskeletal Control and Wnt Signaling—APC’s Dual Contributions in Stem Cell Division and Colorectal Cancer

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