bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–09–01
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. The intestinal stem cell as a target: A review.
  2. Bottom-up or Top-down: Inflammation Reprograms Paneth Cells to Develop Bowel Cancers.
  3. Villification of the intestinal epithelium is driven by Foxl1.
  4. Single-cell atlas defines distinct immune escape mechanisms in colorectal cancer.
  5. Differential Regulation of Wingless-Wnt/c-Jun N-Terminal Kinase Crosstalk via Oxidative Eustress in Primary and Metastatic Colorectal Cancer Cells.
  6. Targeting Bmi1 for Enhancing Anoikis Sensitivity and Inhibiting Metastasis in Colorectal Cancer.
  7. ETHE1 dampens colorectal cancer angiogenesis by promoting TC45 Dephosphorylation of STAT3 to inhibit VEGF-A expression.
  8. Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion.
  1. Medicine (Baltimore). 2024 Aug 23. 103(34): e39456
    The intestinal stem cell as a target: A review.
    Nisreen Lutfi Faizo.
      Human intestinal epithelium handles several events that may affect health. It is composed of villi and crypts, which contain different types of cells. Each cell type plays an essential role in intestinal functions, including absorption, defense, self-renewal, and regeneration. Intestinal stem cells (ISCs), located at the base of intestinal crypts, play an important role in intestinal homeostasis and renewal. Any disruption in intestinal homeostasis, in which ISCs alter their function, may result in tumor growth. As Wnt and Notch signaling pathways are essential for ISCs homeostasis and for maintaining self-renewal, any defects in these pathways could increase the risk of developing colorectal cancer (CRC). Lgr5+ cells have been identified as intestinal stem cells expressing a leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), which is involved in the regulation of Wnt signaling. Several studies have reported upregulated expression of LGR5 in CRC. Hence, in this review, we discuss the relationship between LGR5, Wnt signaling, and Notch signaling and the development of CRC, as well as recent therapeutic strategies targeting LGR5, cancer stem cells (CSCs), and the aforementioned signaling pathways.
    DOI:  https://doi.org/10.1097/MD.0000000000039456
  2. Cancer Res. 2024 Aug 26.
    Bottom-up or Top-down: Inflammation Reprograms Paneth Cells to Develop Bowel Cancers.
    Julian Chua, Alex Gregorieff, Arshad Ayyaz.
      The origins of colorectal cancer (CRC) have long been a subject of intense debate. Early observations noted cancer formation in the human gut slightly above the base of crypts, the structural and functional units of the regenerative compartment of the intestinal epithelium. This suggested that the cells of origin for CRC reside close to the crypt-villus junction, where more differentiated cells are located. However, the specific induction of early cancer-initiating mutations within differentiated cells failed to initiate cancer. The subsequent identification of long-lived Lgr5+ intestinal stem cells and investigations into their role in cancer development further shifted the earlier views, leading to the widely accepted theory that CRC arises from stem cells and progenitors located at the base of crypts. A recent study published in Nature Genetics by Mathijs P. Verhagen and colleagues challenges this paradigm, providing compelling evidence that differentiated non-stem cell lineages, particularly Paneth cells, can serve as a source of intestinal tumorigenesis, especially in the context of inflammation and the consumption of a Western-style diet. This work significantly advances our understanding of the CRC initiation process and provides a new paradigm that may explain the increasingly higher incidence of CRC in younger people.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3073
  3. Res Sq. 2024 Aug 16. pii: rs.3.rs-4882679. [Epub ahead of print]
    Villification of the intestinal epithelium is driven by Foxl1.
    Klaus Kaestner, Guoli Zhu, Deeksha Lahori, Jonathan Schug.
      The primitive gut tube of mammals initially forms as a simple cylinder consisting of the endoderm-derived, pseudostratified epithelium and the mesoderm-derived surrounding mesenchyme. During mid-gestation a dramatic transformation occurs in which the epithelium is both restructured into its final cuboidal form and simultaneously folded and refolded to create intestinal villi and intervillus regions, the incipient crypts. Here we show that the mesenchymal winged helix transcription factor Foxl1, itself induced by epithelial hedgehog signaling, controls villification by activating BMP and PDGFRa as well as planar cell polarity genes in epithelial-adjacent telocyte progenitors, both directly and in a feed- forward loop with Foxo3. In the absence of Foxl1-dependent mesenchymal signaling, villus formation is delayed, the separation of epithelial cells into mitotic intervillus and postmitotic villus cells impaired, and the differentiation of secretory progenitors blocked. Thus, Foxl1 orchestrates key events during the epithelial transition of the fetal mammalian gut.
    DOI:  https://doi.org/10.21203/rs.3.rs-4882679/v1
  4. Nat Cancer. 2024 Aug 23.
    Single-cell atlas defines distinct immune escape mechanisms in colorectal cancer.
      
    DOI:  https://doi.org/10.1038/s43018-024-00809-x
  5. Biomedicines. 2024 Aug 09. pii: 1816. [Epub ahead of print]12(8):
    Differential Regulation of Wingless-Wnt/c-Jun N-Terminal Kinase Crosstalk via Oxidative Eustress in Primary and Metastatic Colorectal Cancer Cells.
    Gitana Maria Aceto, Sara Pagotto, Francesco Domenico Del Pizzo, Concetta Saoca, Federico Selvaggi, Rosa Visone, Roberto Cotellese, M'hammed Aguennouz, Rossano Lattanzio, Teresa Catalano.
      In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H2O2-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/β-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H2O2 concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/β-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H2O2 eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H2O2 alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, β-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential.
    Keywords:  H2O2; JNK; Wnt/β-catenin; adenomatous polyposis coli; colorectal cancer progression; metastasis; oxidative stress; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines12081816
  6. Cancer Genomics Proteomics. 2024 Sep-Oct;21(5):21(5): 523-532
    Targeting Bmi1 for Enhancing Anoikis Sensitivity and Inhibiting Metastasis in Colorectal Cancer.
    Yin-Chou Hsu, Chi-Wen Luo, Shu-Jyuan Chang, Chiao-Ying Lai, Yu-Tzu Yang, Yi-Zi Chen, Wang-Ta Liu, Chun-Chieh Wu, Cheuk-Kwan Sun, Ming-Feng Hou, Mei-Ren Pan.
       BACKGROUND/AIM: Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario.
    MATERIALS AND METHODS: We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis.
    RESULTS: Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis.
    CONCLUSION: Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC.
    Keywords:  Bmi1; Colorectal cancers; anoikis resistance; metastasis; midkine
    DOI:  https://doi.org/10.21873/cgp.20469
  7. Cell Death Dis. 2024 Aug 28. 15(8): 631
    ETHE1 dampens colorectal cancer angiogenesis by promoting TC45 Dephosphorylation of STAT3 to inhibit VEGF-A expression.
    Xiaowei She, Jialu Xu, Haokun Zhang, Chengxin Yu, Zejun Rao, Jiakun Zhang, Wenli Zhan, Fuqing Hu, Da Song, Haijie Li, Xuelai Luo, Guihua Wang, Junbo Hu, Senyan Lai.
      Angiogenesis is critical for colorectal cancer (CRC) progression, but its mechanisms remain unclear. Here, we reveal that ethylmalonic encephalopathy protein 1 (ETHE1), an essential enzyme in hydrogen sulfide catabolism, inhibits VEGF-A expression and tumor angiogenesis in vitro and in vivo. Moreover, we find that this biological function of ETHE1 depends on the STAT3/VEGF-A pathway. Further investigation demonstrates that ETHE1 promotes the interaction between T cell protein tyrosine phosphatase (TC45) and STAT3, resulting in decreased STAT3 phosphorylation and inhibition of the STAT3 signaling pathway. In clinical samples, we find that ETHE1 is downregulated in CRC and positively correlates with survival outcomes of CRC patients. Meanwhile, the negative correlation of ETHE1 and VEGF-A expression is verified in CRC specimens, and the patients with low ETHE1 and high VEGF-A expression exhibits poorer prognosis. Collectively, our study identifies ETHE1 as a novel regulator of tumor angiogenesis, implying its potential as a prognostic biomarker and promising antiangiogenic target for CRC patients.
    DOI:  https://doi.org/10.1038/s41419-024-07021-w
  8. Life Sci. 2024 Aug 23. pii: S0024-3205(24)00605-2. [Epub ahead of print]355 123015
    Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion.
    Miguel Angel Sarabia-Sánchez, José Manuel Tinajero-Rodríguez, Elizabeth Ortiz-Sánchez, Eduardo Alvarado-Ortiz.
      Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review-CD44, CD133, ICAM1/CD54, and LGR5-provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.
    Keywords:  CD133; CD44; CD54; Cancer stem cell; Chemoresistance; Immune evasion; LGR5
    DOI:  https://doi.org/10.1016/j.lfs.2024.123015
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