bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–06–11
eight papers selected by
Maria-Virginia Giolito, Free University of Brussels
  1. Interleukin-33 Potentiates TGF-β Signaling to Regulate Intestinal Stem Cell Regeneration After Radiation Injury.
  2. Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.
  3. Cbl and Cbl-b Ubiquitin Ligases are Essential for Intestinal Epithelial Stem Cell Maintenance.
  4. Patient-derived organoids as a platform for drug screening in metastatic colorectal cancer.
  5. Intestinal stem cells and their niches in homeostasis and disease.
  6. Differential Efficacy of Targeted Monoclonal Antibodies in Left-Sided Colon and Rectal Metastatic Cancers.
  7. Infant and Adult Human Intestinal Enteroids are Morphologically and Functionally Distinct.
  8. Wingless/It/β-catenin signaling in liver metastasis from colorectal cancer: A focus on biological mechanisms and therapeutic opportunities.
  1. Cell Transplant. 2023 Jan-Dec;32:32 9636897231177377
    Interleukin-33 Potentiates TGF-β Signaling to Regulate Intestinal Stem Cell Regeneration After Radiation Injury.
    Ruoyu Guan, Mengxue Pan, Xiaoya Xu, Lixia Du, Xinxin Rao, Guoxiang Fu, Tao Lv, Long Zhang, Yuanchuang Li, Peiyuan Tang, Yi Zhou, Yanqing Wang, Zhen Zhang, Jianjun Gao, Hong Zhou, Wenli Mi, Guoqiang Hua.
      Epithelial regeneration is critical for barrier maintenance and organ function after intestinal radiation injury. Accumulating evidence indicates that the interleukin family members play critical roles in intestinal stem-cell-mediated epithelial regeneration. However, little is known about the relationship between interleukin 33 (IL-33)/ST2 axis and intestinal regeneration after radiation injury. We demonstrate here that IL-33 expression significantly increased after radiation treatment. Deficiency of IL-33/ST2 promotes intestinal epithelial regeneration, resulting in a reduction of mortality during radiation-induced intestine injury. Using ex vivo organoid cultures, we show that recombinant IL-33 promotes intestinal stem cell differentiation. Mechanistically, the effects of IL-33 were mediated by activation of transforming growth factor-β signaling. Our findings reveal a fundamental mechanism by which IL-33 is able to regulate the intestinal crypt regeneration after tissue damage.
    Keywords:  GI syndrome; IL-33; intestinal stem cells; radiation; regeneration
    DOI:  https://doi.org/10.1177/09636897231177377
  2. Gastroenterology. 2023 Jun 02. pii: S0016-5085(23)00814-4. [Epub ahead of print]
    Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.
    Alain P Gobert, Thaddeus M Smith, Yvonne L Latour, Mohammad Asim, Daniel P Barry, Margaret M Allaman, Kamery J Williams, Kara M McNamara, Alberto G Delgado, Sarah P Short, Raghavendra G Mirmira, Kristie L Rose, Kevin L Schey, Irene Zagol-Ikapitte, Jeremy S Coleman, Olivier Boutaud, Shilin Zhao, M Blanca Piazuelo, M Kay Washington, Lori A Coburn, Keith T Wilson.
       BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis.
    METHODS: We utilized human colon tissue mRNA samples and publicly-available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis.
    RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS mRNA and DHPS protein, and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show downregulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis.
    CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have therapeutic impact.
    Keywords:  Colon cancer; Hypusine; Inflammation; Intestinal epithelial cells
    DOI:  https://doi.org/10.1053/j.gastro.2023.05.041
  3. bioRxiv. 2023 May 22. pii: 2023.05.17.541154. [Epub ahead of print]
    Cbl and Cbl-b Ubiquitin Ligases are Essential for Intestinal Epithelial Stem Cell Maintenance.
    Neha Zutshi, Bhopal C Mohapatra, Pinaki Mondal, Wei An, Benjamin T Goetz, Shuo Wang, Sicong Li, Matthew D Storck, David F Mercer, Adrian R Black, Sarah P Thayer, Jennifer D Black, Chi Lin, Vimla Band, Hamid Band.
      Among the signaling pathways that control the stem cell self-renewal and maintenance vs. acquisition of differentiated cell fates, those mediated by receptor tyrosine kinase (RTK) activation are well established as key players. CBL family ubiquitin ligases are negative regulators of RTKs but their physiological roles in regulating stem cell behaviors are unclear. While hematopoietic Cbl/Cblb knockout (KO) leads to a myeloproliferative disease due to expansion and reduced quiescence of hematopoietic stem cells, mammary epithelial KO led to stunted mammary gland development due to mammary stem cell depletion. Here, we examined the impact of inducible Cbl/Cblb double-KO (iDKO) selectively in the Lgr5-defined intestinal stem cell (ISC) compartment. Cbl/Cblb iDKO led to rapid loss of the Lgr5 Hi ISC pool with a concomitant transient expansion of the Lgr5 Lo transit amplifying population. LacZ reporter-based lineage tracing showed increased ISC commitment to differentiation, with propensity towards enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro , Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single cell RNAseq analysis of organoids revealed Akt-mTOR pathway hyperactivation in iDKO ISCs and progeny cells, and pharmacological inhibition of the Akt-mTOR axis rescued the organoid maintenance and propagation defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.
    DOI:  https://doi.org/10.1101/2023.05.17.541154
  4. Front Bioeng Biotechnol. 2023 ;11 1190637
    Patient-derived organoids as a platform for drug screening in metastatic colorectal cancer.
    Xingfeng He, Yan Jiang, Long Zhang, Yaqi Li, Xiang Hu, Guoqiang Hua, Sanjun Cai, Shaobo Mo, Junjie Peng.
      Introduction: Most advanced colorectal cancers are aggressive, and there is a lack of effective methods for selecting appropriate anticancer regimens. Patient-derived organoids (PDOs) have emerged as preclinical platforms for modeling clinical responses to cancer therapy. Methods: In this study, we successfully constructed a living biobank with 42 organoids derived from primary and metastatic lesions of metastatic colorectal cancer patients. Tumor tissue was obtained from patients undergoing surgical resection of the primary or metastatic lesion and then used to establish PDOs. Immunohistochemistry (IHC) and drug sensitivity assays were performed to analyze the properties of these organoids. Results: The mCRC organoids were successfully established with an 80% success rate. The PDOs maintained the genetic and phenotypic heterogeneity of their parental tumors. The IC50 values of5-fluorouracil (5-FU), oxaliplatin, and irinotecan (CPT11) were determined for mCRC organoids using drug sensitivity assays. The in vitro chemosensitivity data revealed the potential value of PDOs for clinical applications in predicting chemotherapy response and clinical outcomes in mCRC patients. Discussion: In summary, the PDO model is an effective platform for in vitro assessment of patient-specific drug sensitivity, which can guide personalized treatment decisions for patients with end-stage CRC.
    Keywords:  drug screening; metastatic colorectal cancer; patient-derived organoids; personalized therapy; preclinical model
    DOI:  https://doi.org/10.3389/fbioe.2023.1190637
  5. Cells Dev. 2023 Jun 02. pii: S2667-2901(23)00038-4. [Epub ahead of print] 203862
    Intestinal stem cells and their niches in homeostasis and disease.
    Jun Zhou, Michael Boutros.
      Tissues such as the intestine harbor stem cells that have remarkable functional plasticity in response to a dynamic environment. To adapt to the environment, stem cells constantly receive information from their surrounding microenvironment (also called the 'niche') that instructs them how to adapt to changes. The Drosophila midgut shows morphological and functional similarities to the mammalian small intestine and has been a useful model system to study signaling events in stem cells and tissue homeostasis. In this review, we summarize the current understanding of the Drosophila midgut regarding how stem cells communicate with microenvironmental niches including enteroblasts, enterocytes, enteroendocrine cells and visceral muscles to coordinate tissue regeneration and homeostasis. In addition, distant cells such as hemocytes or tracheal cells have been shown to interact with stem cells and influence the development of intestinal diseases. We discuss the contribution of stem cell niches in driving or counteracting disease progression, and review conceptual advances derived from the Drosophila intestine as a model for stem cell biology.
    Keywords:  Drosophila; Intestine; Niche; Signal transduction; Stem cells
    DOI:  https://doi.org/10.1016/j.cdev.2023.203862
  6. Clin Colorectal Cancer. 2023 May 11. pii: S1533-0028(23)00036-1. [Epub ahead of print]
    Differential Efficacy of Targeted Monoclonal Antibodies in Left-Sided Colon and Rectal Metastatic Cancers.
    Hiroyuki Kodama, Toshiki Masuishi, Munehiro Wakabayashi, Akinobu Nakata, Ryosuke Kumanishi, Taiko Nakazawa, Takatsugu Ogata, Yuki Matsubara, Kazunori Honda, Yukiya Narita, Hiroya Taniguchi, Shigenori Kadowaki, Masashi Ando, Kei Muro.
       BACKGROUND: The recommended first-line chemotherapy for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) is bevacizumab (BEV)-containing therapy for right-sided colon cancer (R) and antiepidermal growth factor receptor antibody (anti-EGFR)-containing therapy for left-sided colon cancer (L) or rectal cancer (RE). However, anatomical or biological heterogeneity reportedly exists between L and RE. Therefore, we aimed to compare the efficacies of anti-EGFR and BEV therapies for L and RE, respectively.
    METHODS: We retrospectively reviewed 265 patients with KRAS (RAS)/BRAF wild-type mCRC treated with fluoropyrimidine-based doublet chemotherapy plus anti-EGFR or BEV as the first-line treatment at a single institution. They were divided into 3 groups: R, L, and RE. Overall survival (OS), progression-free survival (PFS), objective response rate, and conversion surgery rate were analyzed.
    RESULTS: Forty-five patients had R (anti-EGFR/BEV: 6/39), 137 patients had L (45/92), and 83 patients had RE (25/58). In patients with R, both median (m) PFS and OS were superior with BEV therapy (mPFS, anti-EGFR vs. BEV: 8.7 vs. 13.0 months, hazard ratio [HR]: 3.90, P = .01; mOS, 17.1 vs. 33.9 months, HR: 1.54, P = .38). In patients with L, better mPFS and comparable mOS with anti-EGFR therapy were observed (mPFS, 20.0 vs. 13.4 months, HR: 0.68, P = .08; mOS, 44.8 vs. 36.0 months, HR: 0.87, P = .53), whereas, in patients with RE, comparable mPFS and worse mOS with anti-EGFR therapy were observed (mPFS, 17.2 vs. 17.8 months, HR: 1.08, P = .81; mOS, 29.1 vs. 42.2 months, HR: 1.53, P = .17).
    CONCLUSIONS: Efficacies of anti-EGFR and BEV therapies may differ between patients with L and RE.
    Keywords:  Anti-EGFR antibody; Bevacizumab; Overall survival; Progression-free survival; Tumor location
    DOI:  https://doi.org/10.1016/j.clcc.2023.05.002
  7. bioRxiv. 2023 May 20. pii: 2023.05.19.541350. [Epub ahead of print]
    Infant and Adult Human Intestinal Enteroids are Morphologically and Functionally Distinct.
    Grace O Adeniyi-Ipadeola, Julia D Hankins, Amal Kambal, Xi-Lei Zeng, Ketki Patil, Victoria Poplaski, Carolyn Bomidi, Hoa Nguyen-Phuc, Sandra L Grimm, Cristian Coarfa, Sue E Crawford, Sarah E Blutt, Allison L Speer, Mary K Estes, Sasirekha Ramani.
       Background & Aims: Human intestinal enteroids (HIEs) are gaining recognition as physiologically relevant models of the intestinal epithelium. While HIEs from adults are used extensively in biomedical research, few studies have used HIEs from infants. Considering the dramatic developmental changes that occur during infancy, it is important to establish models that represent the infant intestinal anatomy and physiological responses.
    Methods: We established jejunal HIEs from infant surgical samples and performed comparisons to jejunal HIEs from adults using RNA sequencing (RNA-Seq) and morphologic analyses. We validated differences in key pathways through functional studies and determined if these cultures recapitulate known features of the infant intestinal epithelium.
    Results: RNA-Seq analysis showed significant differences in the transcriptome of infant and adult HIEs, including differences in genes and pathways associated with cell differentiation and proliferation, tissue development, lipid metabolism, innate immunity, and biological adhesion. Validating these results, we observed as higher expression of enterocytes, goblet cells and enteroendocrine cells in differentiated infant HIEs, and greater numbers of proliferative cells in undifferentiated cultures. Compared to adult HIEs, infant HIEs portray characteristics of an immature gastrointestinal epithelium including significantly shorter cell height, lower epithelial barrier integrity, and lower innate immune responses to infection with an oral poliovirus vaccine.
    Conclusions: HIEs established from infant intestinal tissues reflect characteristics of the infant gut and are distinct from adult cultures. Our data support the use of infant HIEs as an ex-vivo model to advance studies of infant-specific diseases and drug discovery for this population.
    DOI:  https://doi.org/10.1101/2023.05.19.541350
  8. World J Gastroenterol. 2023 May 14. 29(18): 2764-2783
    Wingless/It/β-catenin signaling in liver metastasis from colorectal cancer: A focus on biological mechanisms and therapeutic opportunities.
    Federico Selvaggi, Teresa Catalano, Rossano Lattanzio, Roberto Cotellese, Gitana Maria Aceto.
      The liver is the most common site of metastases in patients with colorectal cancer. Colorectal liver metastases (CRLMs) are the result of molecular mechanisms that involve different cells of the liver microenvironment. The aberrant activation of Wingless/It (Wnt)/β-catenin signals downstream of Wnt ligands initially drives the oncogenic transformation of the colon epithelium, but also the progression of metastatization through the epithelial-mesenchymal transition/mesenchymal-epithelial transition interactions. In liver microenvironment, metastatic cells can also survive and adapt through dormancy, which makes them less susceptible to pro-apoptotic signals and therapies. Treatment of CRLMs is challenging due to its variability and heterogeneity. Advances in surgery and oncology have been made in the last decade and a pivotal role for Wnt/β-catenin pathway has been re-cognized in chemoresistance. At the state of art, there is a lack of clear understanding of why and how this occurs and thus where exactly the opportunities for developing anti-CRLMs therapies may lie. In this review, current knowledge on the involvement of Wnt signaling in the development of CRLMs was considered. In addition, an overview of useful biomarkers with a revision of surgical and non-surgical therapies currently accepted in the clinical practice for colorectal liver metastasis patients were provided.
    Keywords:  Colorectal cancer; Epithelial-mesenchymal transition/ mesenchymal-epithelial transition; Liver metastasis; Markers; Surgical and non-surgical therapies; Wingless/It/β-catenin signaling
    DOI:  https://doi.org/10.3748/wjg.v29.i18.2764
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