scholarly journals Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yeji Kim ◽  
Yong-Soo Lee ◽  
Sung Wan Kang ◽  
Seungil Kim ◽  
Tae-Young Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Intestinal Stem Cells

scholarly journals Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Luciana Petti ◽  
Giulia Rizzo ◽  
Federica Rubbino ◽  
Sudharshan Elangovan ◽  
Piergiuseppe Colombo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Normal Mucosa ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Sphingosine 1 Phosphate

Abstract Background Sphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap. Methods We screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2+/+) and S1PR2 deficient (S1PR2−/−) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked the ablation of S1PR2 in normal mucosa by treating S1PR2+/+ organoids with JTE013 and characterized intestinal epithelial stem cells isolated from S1PR2−/−Lgr5-EGFP- mice. Results S1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc+/min mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2−/− mice compared to S1PR2+/+ controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN. Conclusions In normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5. Graphical Abstract. Schematic drawing of the role of S1PR2 in normal mucosa and colorectal cancer. In the normal mucosa, S1PR2 is highly expressed by differentiated cells at the upper region of both colon and intestinal crypts (S1PR2 ON), but not by the undifferentiated stem cell at the base of the crypts (S1PR2 OFF), in which acts as a negative proliferative regulator promoting epithelial differentiation. Its loss leads to the expansion of stem cells and reduced levels of PTEN and Axin-2, two negative regulators respectively of PI3K/AKT and Wnt signaling that control β-catenin signaling. The translocation of β-catenin into the nucleus promotes the transcription of target genes involved in the proliferation and malignant transformation. Thereby, S1PR2 works in the intestine as a tumor suppressor

scholarly journals Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yuhua Tian ◽  
Xianghui Ma ◽  
Cong Lv ◽  
Xiaole Sheng ◽  
Xiang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Radiation Injury ◽  
Intestinal Stem Cells ◽  
Potential Therapeutic Target ◽  
Intestinal Homeostasis ◽  
Intestinal Tumorigenesis ◽  
Stat3 Signaling ◽  
Coordinate Control ◽  
Stat3 Signaling Pathway

Intestinal regeneration and tumorigenesis are believed to be driven by intestinal stem cells (ISCs). Elucidating mechanisms underlying ISC activation during regeneration and tumorigenesis can help uncover the underlying principles of intestinal homeostasis and disease including colorectal cancer. Here we show that miR-31 drives ISC proliferation, and protects ISCs against apoptosis, both during homeostasis and regeneration in response to ionizing radiation injury. Furthermore, miR-31 has oncogenic properties, promoting intestinal tumorigenesis. Mechanistically, miR-31 acts to balance input from Wnt, BMP, TGFβ signals to coordinate control of intestinal homeostasis, regeneration and tumorigenesis. We further find that miR-31 is regulated by the STAT3 signaling pathway in response to radiation injury. These findings identify miR-31 as a critical modulator of ISC biology, and a potential therapeutic target for a broad range of intestinal regenerative disorders and cancers.

Host–microbiota interaction and intestinal stem cells in chronic inflammation and colorectal cancer

2013 ◽  
Vol 9 (5) ◽  
pp. 409-422 ◽  
Author(s):  
Shirin Moossavi ◽  
Hongyu Zhang ◽  
Jun Sun ◽  
Nima Rezaei
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Chronic Inflammation ◽  
Intestinal Stem Cells

Expression of Lgr5, a marker of intestinal stem cells, in colorectal cancer and its clinicopathological significance

2014 ◽  
Vol 68 (5) ◽  
pp. 507-513 ◽  
Author(s):  
Songbing He ◽  
Hao Zhou ◽  
Xinguo Zhu ◽  
Shuiqing Hu ◽  
Min Fei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Intestinal Stem Cells ◽  
Clinicopathological Significance

scholarly journals Stem Cell Impairment at the Host-Microbiota Interface in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 996
Author(s):  
Marinella Marzano ◽  
Bruno Fosso ◽  
Elisabetta Piancone ◽  
Giuseppe Defazio ◽  
Graziano Pesole ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Gut Microbiota ◽  
The Body ◽  
Intestinal Stem Cells ◽  
Epigenetic Alterations ◽  
Tumor Initiating Cells ◽  
Diverse Community ◽  
The Relationship

Colorectal cancer (CRC) initiation is believed to result from the conversion of normal intestinal stem cells (ISCs) into cancer stem cells (CSCs), also known as tumor-initiating cells (TICs). Hence, CRC evolves through the multiple acquisition of well-established genetic and epigenetic alterations with an adenoma-carcinoma sequence progression. Unlike other stem cells elsewhere in the body, ISCs cohabit with the intestinal microbiota, which consists of a diverse community of microorganisms, including bacteria, fungi, and viruses. The gut microbiota communicates closely with ISCs and mounting evidence suggests that there is significant crosstalk between host and microbiota at the ISC niche level. Metagenomic analyses have demonstrated that the host-microbiota mutually beneficial symbiosis existing under physiologic conditions is lost during a state of pathological microbial imbalance due to the alteration of microbiota composition (dysbiosis) and/or the genetic susceptibility of the host. The complex interaction between CRC and microbiota is at the forefront of the current CRC research, and there is growing attention on a possible role of the gut microbiome in the pathogenesis of CRC through ISC niche impairment. Here we primarily review the most recent findings on the molecular mechanism underlying the complex interplay between gut microbiota and ISCs, revealing a possible key role of microbiota in the aberrant reprogramming of CSCs in the initiation of CRC. We also discuss recent advances in OMICS approaches and single-cell analyses to explore the relationship between gut microbiota and ISC/CSC niche biology leading to a desirable implementation of the current precision medicine approaches.

scholarly journals Dietary Factors in the Control of Gut Homeostasis, Intestinal Stem Cells, and Colorectal Cancer

Nutrients ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2936 ◽  
Author(s):  
Federica Francescangeli ◽  
Maria Laura De Angelis ◽  
Ann Zeuner
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Low Income ◽  
Dietary Factors ◽  
Intestinal Stem Cells ◽  
Intestinal Homeostasis ◽  
Increased Risk ◽  
Incidence And Mortality

Colorectal cancer (CRC) is the third commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Global CRC burden is expected to increase by 60% in the next decade, with low-income countries experiencing an escalation of CRC incidence and mortality in parallel to the adoption of western lifestyles. CRC incidence is also sharply increasing in individuals younger than 50 years, often presenting at advanced stages and with aggressive features. Both genetic and environmental factors have been recognized as major contributors for the development of CRC, the latter including diet-related conditions such as chronic inflammation and obesity. In particular, a diet rich in fat and sugars (Western-style diet, WSD) has been shown to induce multiple pathophysiological changes in the intestine linked to an increased risk of CRC. In this scenario, dietary factors have been recently shown to play novel unexpected roles in the regulation of intestinal stem cells (ISCs) and of the gut microbiota, which represent the two main biological systems responsible for intestinal homeostasis. Furthermore, diet is increasingly recognized to play a key role in the neoplastic transformation of ISCs and in the metabolic regulation of colorectal cancer stem cells. This review illustrates novel discoveries on the role of dietary components in regulating intestinal homeostasis and colorectal tumorigenesis. Particular focus is dedicated to new areas of research with potential clinical relevance including the effect of food components on ISCs and cancer stem cells (CSCs), the existence of CRC-specific microbial signatures and the alterations of intestinal homeostasis potentially involved in early-onset CRC. New insights on the role of dietary factors in intestinal regulation will provide new tools not only for the prevention and early diagnosis of CRC but also for improving the effectiveness of current CRC therapies.

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