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

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

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

10.21203/rs.3.rs-56319/v2 ◽

2020 ◽

Author(s):

Luciana Petti ◽

Giulia Rizzo ◽

Federica Rubbino ◽

Sudharshan Elangovan ◽

Piergiuseppe Colombo ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Normal Mucosa ◽

Colorectal Carcinogenesis ◽

Intestinal Stem Cells ◽

Cancer Information ◽

Intestinal Epithelial ◽

Epithelial Stem Cells ◽

Mucosal Regeneration ◽

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.

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

10.21203/rs.3.rs-56319/v1 ◽

2020 ◽

Author(s):

Luciana Petti ◽

Giulia Rizzo ◽

Federica Rubbino ◽

Sudharshan Elangovan ◽

Piergiuseppe Colombo ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Normal Mucosa ◽

Genetically Engineered ◽

Colorectal Carcinogenesis ◽

Intestinal Stem Cells ◽

Cancer Information ◽

Intestinal Epithelial ◽

Epithelial Stem Cells ◽

Mucosal Regeneration

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Toll-like receptor 4 (TLR4) is expressed on intestinal stem cells and inhibits stem cell proliferation in the pathogenesis of intestinal inflammation

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2011.06.201 ◽

2011 ◽

Vol 213 (3) ◽

pp. S85 ◽

Cited By ~ 2

Author(s):

Matthew D. Neal ◽

Chhinder P. Sodhi ◽

Ibrahim Yazji ◽

Anthony M. Russo ◽

Richard Siggers ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Stem Cell ◽

Intestinal Inflammation ◽

Intestinal Stem Cells ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Stem Cell Proliferation

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Cancer-Preventive Role of Bone Marrow-Derived Mesenchymal Stem Cells on Colitis-Associated Colorectal Cancer: Roles of Gut Microbiota Involved

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.642948 ◽

2021 ◽

Vol 9 ◽

Author(s):

Ruohang He ◽

Chaoqun Han ◽

Ying Li ◽

Wei Qian ◽

Xiaohua Hou

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

Tumor Cell ◽

Rna Sequencing ◽

Ribosomal Rna ◽

Tumor Cell Proliferation

BackgroundMesenchymal stem cells (MSCs) treatment showed promising results in inflammatory bowel disease in both rodent models and patients. Nevertheless, previous studies conducted conflicting results on preclinical tumor models treated with MSCs concerning their influence on tumor initiation and progression. This study is designed to demonstrate the role of bone marrow-derived MSCs and the potential mechanism in the colitis-associated colon cancer (CAC) model.MethodsBone marrow-derived MSCs were isolated from green fluorescent protein-transgenic mice, cultured, and identified by flow cytometry. Azoxymethane and dextran sulfate sodium were administrated to establish the CAC mouse model, and MSCs were infused intraperitoneally once per week. The mice were weighed weekly, and colon length, tumor number, and average tumor size were assessed after the mice were killed. MSC localization was detected by immunofluorescence staining; tumor cell proliferation and apoptosis were measured by immunohistochemistry staining of Ki-67 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay, respectively. The colonic tumor tissues were isolated for RNA-seq, and fecal samples were collected for 16S ribosomal RNA sequencing of the microbiome.ResultsAfter injection intraperitoneally, MSCs migrated to the intestine and inhibited the initiation of colitis-associated colorectal cancer. This inhibition effect was marked by less weight loss, longer colon length, and reduced tumor numbers. Moreover, MSCs reduced tumor cell proliferation and induced tumor cell apoptosis. Furthermore, MSCs could inhibit chronic inflammation assessed by RNA-sequencing and promote gut microbiome normalization detected by 16S ribosomal RNA sequencing.ConclusionThe results proved that MSCs could migrate to the colon, inhibit chronic inflammation, and regulate gut microbiome dysbiosis to suppress the development of CAC.

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The murine intestinal stem cells are highly sensitive to the modulation of the T3/TRα1-dependent pathway

Development ◽

10.1242/dev.194357 ◽

2021 ◽

pp. dev.194357

Author(s):

Matthias Godart ◽

Carla Frau ◽

Diana Farhat ◽

Maria Virginia Giolito ◽

Catherine Jamard ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Stem Cell ◽

Ex Vivo ◽

Cell Activity ◽

Crypt Cell ◽

Intestinal Stem Cells ◽

Gut Development ◽

Crypt Cell Proliferation ◽

Depth Analysis

The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation. Despite increasing data, in depth analysis on their specific action on intestinal stem cells is lacking.By using ex vivo 3D organoid cultures and molecular approaches we observed early responses to T3 involving the T3-metabolizing enzyme Dio1 and the transporter Mct10, accompanied by a complex response of stem cell- and progenitor-enriched genes. Interestingly, specific TRα1 loss-of-function (inducible or constitutive) was responsible for low ex vivo organoid development and impaired stem cell activity. T3-treatment of animals in vivo not only confirmed the positive action of this hormone on crypt cell proliferation but also demonstrated its key action in modulating i) the number of the stem cells, ii) the expression of their specific markers and iii) the commitment of progenitors into lineage-specific differentiation.In conclusion, T3 treatment or TRα1 modulation has a rapid and strong effect on intestinal stem cells, broadening our perspectives in the study of T3/TRα1-dependent signaling in these cells.

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PTBP1/HNRNP I controls intestinal epithelial cell regeneration by maintaining stem cell survival and stemness

10.1101/2021.11.03.466345 ◽

2021 ◽

Author(s):

Wesley Tung ◽

Ullas Valiya Chembazhi ◽

Jing Yang ◽

Ka Lam Nguyen ◽

Aryan Lalwani ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Epithelial Cell ◽

Cell Survival ◽

Intestinal Epithelial Cell ◽

Intestinal Stem Cells ◽

Intestinal Stem Cell ◽

Cell Regeneration ◽

Intestinal Epithelial ◽

Stem Cell Survival

Properly controlled intestinal epithelial cell regeneration is not only vital for protection against insults from environmental hazards but also crucial for preventing intestinal cancer. Intestinal stem cells located in the crypt region provide the driving force for epithelial regeneration, and thus their survival and death must be precisely regulated. We show here that polypyrimidine tract binding protein 1 (PTBP1, also called heterogeneous nuclear ribonucleoprotein I, or HNRNP I), an RNA-binding protein that post-transcriptionally regulates gene expression, is critical for intestinal stem cell survival and stemness. Mechanistically, we show that PTBP1 inhibits the expression of PHLDA3, an AKT repressor, and thereby maintains AKT activity in the intestinal stem cell compartment to promote stem cell survival and proliferation. Furthermore, we show that PTBP1 inhibits the expression of PTBP2, a paralog of PTBP1 that is known to induce neuron differentiation, through repressing inclusion of alternative exon 10 to Ptbp2 transcript. Loss of PTBP1 results in a significant upregulation of PTBP2, which is accompanied by splicing changes in genes that are important for neuron cell development. This finding suggests that PTBP1 prevents aberrant differentiation of intestinal stem cells into neuronal cells through inhibiting PTBP2. Our results thus reveal a novel mechanism whereby PTBP1 maintains intestinal stem cell survival and stemness through the control of gene function post-transcriptionally.

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Glycolipids Recognized by A2B5 Antibody Promote Proliferation, Migration, and Clonogenicity in Glioblastoma Cells

Cancers ◽

10.3390/cancers11091267 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1267 ◽

Cited By ~ 4

Author(s):

Baeza-Kallee ◽

Bergès ◽

Soubéran ◽

Colin ◽

Denicolaï ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Stem Cell ◽

Cell Growth ◽

Self Renewal ◽

Neuraminidase Treatment ◽

Attractive Therapeutic Target ◽

And Migration

A2B5+ cells isolated from human glioblastomas exhibit cancer stem cell properties. The A2B5 epitope belongs to the sialoganglioside family and is synthetized by the ST8 alpha-N-acetyl-neuraminidase α-2,8-sialyltransferase 3 (ST8SIA3) enzyme. Glycolipids represent attractive targets for solid tumors; therefore, the aim of this study was to decipher A2B5 function in glioblastomas. To this end, we developed cell lines expressing various levels of A2B5 either by genetically manipulating ST8SIA3 or by using neuraminidase. The overexpression of ST8SIA3 in low-A2B5-expressing cells resulted in a dramatic increase of A2B5 immunoreactivity. ST8SIA3 overexpression increased cell proliferation, migration, and clonogenicity in vitro and tumor growth when cells were intracranially grafted. Conversely, lentiviral ST8SIA3 inactivation in low-A2B5-expressing cells resulted in reduced proliferation, migration, and clonogenicity in vitro and extended mouse survival. Furthermore, in the shST8SIA3 cells, we found an active apoptotic phenotype. In high-A2B5-expressing cancer stem cells, lentiviral delivery of shST8SIA3 stopped cell growth. Neuraminidase treatment, which modifies the A2B5 epitope, impaired cell survival, proliferation, self-renewal, and migration. Our findings prove the crucial role of the A2B5 epitope in the promotion of proliferation, migration, clonogenicity, and tumorigenesis, pointing at A2B5 as an attractive therapeutic target for glioblastomas.

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Mitochondria deliver a gut check to intestinal stem cells

The Journal of Cell Biology ◽

10.1083/jcb.201707076 ◽

2017 ◽

Vol 216 (8) ◽

pp. 2231-2231

Author(s):

Ben Short

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Stem Cell ◽

Tissue Homeostasis ◽

Intestinal Stem Cells ◽

Stem Cell Proliferation ◽

Mitochondrial Turnover

Mitochondrial turnover regulates stem cell proliferation and tissue homeostasis in Drosophila intestines.

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Role of Stem Cells in Colorectal Cancer Progression and Prognostic and Predictive Characteristics of Stem Cell Markers in Colorectal Cancer

Current Stem Cell Research & Therapy ◽

10.2174/1574888x11666160905092938 ◽

2016 ◽

Vol 12 (1) ◽

pp. 19-30 ◽

Cited By ~ 3

Author(s):

Mikhail Fedyanin ◽

Popova Anna ◽

Polyanskaya Elizaveta ◽

Tjulandin Sergei

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Progression ◽

Stem Cell Markers ◽

Cell Markers ◽

Colorectal Cancer Progression

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

Cancers ◽

10.3390/cancers13050996 ◽

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.

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