bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2022‒05‒01
thirteen papers selected by
Maria-Virginia Giolito

  1. Pathol Res Pract. 2022 Apr 12. pii: S0344-0338(22)00139-X. [Epub ahead of print]234 153895
      SPOCK1 is an extracellular proteoglycan and involved in tumor growth and metastasis in various cancers. 5-fluorouracil (5-FU) is commonly used for the treatment of colorectal cancer (CRC) in patients who receive concurrent chemoradiotherapy. However, the relationship between development of resistance to 5-FU and SPOCK1 remain unclear. In this study, we established two 5-fluorouracil (5-FU)-resistant CRC cell lines, HCT116/FU and LOVO/FU, and found that SPOCK1 is upregulated in 5-FU-resistance CRC cells compared with its parental cell line. knockdown of SPOCK1 in 5-FU-resistant CRC cells increases their sensitivity to 5-FU. In contrast, transient transfection of SPOCK1 enhanced HCT116 and LOVO cell resistance to 5-FU and reduced cell apoptosis. Mechanistically, SPOCK1 promoted 5-FU resistance by regulating PRRX1 expression and the downstream apoptosis signaling pathway. Taken together, our results revealed for the first time that SPOCK1 plays a crucial role in the resistance of CRC cells to 5-FU and indicated that targeting SPOCK1 may be a promising therapeutic strategy to overcome 5-FU resistance in CRC.
    Keywords:  5-fluorouracil; Apoptosis; Drug resistance; PRRX1; SPOCK1
  2. Cancer Res. 2022 Apr 26. pii: canres.4128.2021. [Epub ahead of print]
      Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDOs) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically-expanded Lgr5+-intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.
  3. DNA Repair (Amst). 2022 Apr 16. pii: S1568-7864(22)00064-7. [Epub ahead of print]115 103331
      The proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC), where it has been shown to enhance tumour cell survival. However, although increased expression correlates with poor patient prognosis, the role of BCL-3 in determining therapeutic response remains largely unknown. In this study, we use combined approaches in multiple cell lines and pre-clinical mouse models to investigate the function of BCL-3 in the DNA damage response. We show that suppression of BCL-3 increases γH2AX foci formation and decreases homologous recombination in CRC cells, resulting in reduced RAD51 foci number and increased sensitivity to PARP inhibition. Importantly, a similar phenotype is seen in Bcl3-/- mice, where Bcl3-/- mouse crypts also exhibit sensitivity to DNA damage with increased γH2AX foci compared to wild type mice. Additionally, Apc.Kras-mutant x Bcl3-/- mice are more sensitive to cisplatin chemotherapy compared to wild type mice. Taken together, our results identify BCL-3 as a regulator of the cellular response to DNA damage and suggests that elevated BCL-3 expression, as observed in CRC, could increase resistance of tumour cells to DNA damaging agents including radiotherapy. These findings offer a rationale for targeting BCL-3 in CRC as an adjunct to conventional therapies and suggest that BCL-3 expression in tumours could be a useful biomarker in stratification of rectal cancer patients for neo-adjuvant chemoradiotherapy.
    Keywords:  Colorectal cancer/DNA Damage response/Therapy response/Chemoradiotherapy/Homologous recombination
  4. J Recept Signal Transduct Res. 2022 Apr 27. 1-8
      OBJECTIVE: The effect of thyroid hormone (TH) on cancers was proposed more than 100 years ago; however, conclusions are conflicting. THs are precisely regulated at tissue and cellular levels. It seems that this regulation is altered in cancers. Thyroid hormone receptor beta (TRβ) has anti-proliferative and tumor-suppressive effects in many cancer cells. Therefore, we decided to investigate thyroid hormone receptor beta (THRB) expression and activation by the selective agonist, GC-1, on tumor growth in a syngeneic mouse model of colorectal cancer (CRC) and colon cell lines.METHODS: In vitro cell viability assay using MTT analysis, cell cycle analysis by PI staining, and FACS analysis were performed. In vivo tumor growth measurements were carried out by caliper and [18F] Fluoro-2-deoxy-2-D-glucose (FDG) - PET imaging. Gene expressions were determined using quantitative-PCR.
    RESULTS: Some concentrations of GC-1 had a marked negative effect on the cell viability of colorectal cell lines. Cell cycle analysis showed that the anti-proliferative effect of GC-1 may not result from cell cycle arrest or apoptosis. Tumor growth analysis in mice harboring colorectal tumor showed that GC-1 treatment for 8 d profoundly inhibited tumor growth and 18FDG uptake. THRB expression was decreased in mice tumor; however, it was upregulated following GC-1 administration.
    CONCLUSIONS: Our results showed that specific activation of TRβ by GC-1 had negative effect on tumor growth and restored its gene expression in tumors of CRC mice model.
    Keywords:  GC-1; Thyroid hormone receptor beta; colorectal cancer; tumor growth; tumor suppressor
  5. Med Oncol. 2022 Apr 28. 39(5): 80
      BACKGROUND: Colorectal cancer (CRC) is among the leading cause of cancer-related morbidity and mortality worldwide. Aerobic glycolysis, as a metabolic hallmark of cancer, plays an important role in CRC progression. Enolase 3 (ENO3) is a glycolytic enzyme that catalyzes 2-phosphoglycerate into phosphoenolpyruvate, while its role in CRC is still unknown.METHODS: Bioinformatics analysis was performed to examine the expression changes and roles of ENO3 in CRC patients from public databases. Then, ENO3 expression was validated in CRC tissues using Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) analysis, and western blot. Overexpression and silencing models were constructed using plasmid and lentivirus transfection. Cell viability, proliferation, and migration in vitro were applied to evaluate the protumoral effects of ENO3 on CRC. RNA sequencing and GO enrichment analysis of differentially expressed genes (DEGs) were performed to explore the underlying molecular mechanisms of ENO3 in CRC progression. The ATP and lactate production level were detected to assess cell glycolysis.
    RESULTS: ENO3 was significantly up-regulated in CRC. High ENO3 expression was positively correlated with poor prognosis and higher clinical stages of CRC patients. ROC curve demonstrated the diagnostic value of ENO3 for CRC with the AUC of 0.802. Gain- and loss-of function experiments demonstrated that ENO3 significantly enhanced the proliferation and migration ability of CRC cells in vitro. After ENO3 knockdown, RNA sequencing screened out a list of DEGs which were enriched in the regulation of the glycolytic process. The detection of lactate production and ATP level verified the role of ENO3 in the glycolytic process.
    CONCLUSION: Our findings illustrate that ENO3 could promote the progression of CRC by the enhancement of cell glycolysis, indicating the potential value of ENO3 as a novel biomarker and therapeutic target for CRC.
    Keywords:  Aerobic glycolysis; Biomarker; Cell proliferation; Colorectal cancer; Metastasis
  6. BMC Immunol. 2022 Apr 23. 23(1): 20
      BACKGROUND: Immunotherapy in colorectal cancer (CRC) regulates specific immune checkpoints and, when used in combination with chemotherapy, can improve patient prognosis. One specific immune checkpoint is the recruitment of circulating monocytes that differentiate into tumor-associated macrophages (TAMs) and promote tumor angiogenesis. Changes in vascularization can be non-invasively assessed via diffuse reflectance spectroscopy using hemoglobin concentrations and oxygenation in a localized tumor volume. In this study, we examine whether blockade of monocyte recruitment via CCL2 (macrophage chemoattractant protein-1) leads to enhanced sensitivity of 5-fluorouracil (5-FU) in a CT26-Balb/c mouse model of CRC. It was hypothesized that the blockade of TAMs will alter tumor perfusion, increasing chemotherapy response. A subcutaneous tumor model using Balb/c mice injected with CT26 colon carcinoma cells received either a saline or isotype control, anti-CCL2, 5-FU, or a combination of anti-CCL2 and 5-FU.RESULTS: Findings show that 12 days post-treatment, monocyte recruitment was significantly reduced by approximately 61% in the combination group. This shows that the addition of anti-CCL2 to 5-FU slowed the fold-change (change from the original measurement to the final measurement) in tumor volume from Day 0 to Day 12 (~ 5 fold). Modest improvements in oxygen saturation (~ 30%) were observed in the combination group.
    CONCLUSION: The findings in this work suggest that the blockade of CCL2 is sufficient in the reduction of TAMs that are recruited into the tumor microenvironment and has the ability to modestly alter tumor perfusion during early-tumor response to treatment even though the overall benefit is relatively modest.
    Keywords:  Colorectal cancer; Diffuse reflectance spectroscopy; Immunomodulation; Tumor-associated macrophages
  7. Front Oncol. 2022 ;12 852927
      Colorectal cancer (CRC), a leading cause of cancer-related mortalities globally, results from the accumulation of multiple genetic and epigenetic alterations in the normal colonic and rectum epithelium, leading to the progression from colorectal adenomas to invasive carcinomas. Almost half of CRC patients will develop metastases in the course of the disease and most patients with metastatic CRC are incurable. Particularly, the 5-year survival rate of patients with stage 4 CRC at diagnosis is less than 10%. Although genetic understanding of these CRC tumors and paired metastases has led to major advances in elucidating early driver genes responsible for carcinogenesis and metastasis, the pathophysiological contribution of transcriptional and epigenetic aberrations in this malignancy which influence many central signaling pathways have attracted attention recently. Therefore, treatments that could affect several different molecular pathways may have pivotal implications for their efficacy. In this review, we summarize our current knowledge on the molecular network of CRC, including cellular signaling pathways, CRC microenvironment modulation, epigenetic changes, and CRC biomarkers for diagnosis and predictive/prognostic use. We also provide an overview of opportunities for the treatment and prevention strategies in this field.
    Keywords:  biomarkers; cellular signaling; colorectal cancer; epigenetic changes; microenvironment modulation
  8. Front Pharmacol. 2022 ;13 879751
      Background: Tumor dormancy is an important way to develop drug resistance. This study aimed to identify the characteristics of colorectal cancer (CRC) cell dormancy. Methods: Based on the CRC cohorts, a total of 1,044 CRC patients were included in this study, and divided into a dormant subgroup and proliferous subgroup. Non-negative matrix factorization (NMF) was used to distinguish the dormant subgroup of CRC via transcriptome data of cancer tissues. Gene Set Enrichment Analysis (GSEA) was used to explore the characteristics of dormant CRC. The characteristics were verified in the cell model, which was used to predict key factors driving CRC dormancy. Potential treatments for CRC dormancy were also examined. Results: The dormant subgroup had a poor prognosis and was more likely to relapse. GSEA analysis showed two defining characteristics of the dormant subgroup, a difference in energy metabolism and synergistic effects of cancer-associated fibroblasts (CAFs), which were verified in a dormant cell model. Transcriptome and clinical data identified LMOD1, MAB21L2, and ASPN as important factors associated with cell dormancy and verified that erlotinib, and CB-839 were potential treatment options. Conclusion: Dormant CRC is associated with high glutamine metabolism and synergizes with CAFs in 5-FU resistance, and the key effectors are LMOD1, MAB21L2, and ASPN. Austocystin D, erlotinib, and CB-839 may be useful for dormant CRC.
    Keywords:  cancer-associated fibroblasts; colorectal cancer; metabolomics; transcriptomics; tumor dormancy
  9. Nature. 2022 Apr 27.
      Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.
  10. Nat Cancer. 2022 Apr;3(4): 418-436
      Patient-derived organoids (PDOs) recapitulate tumor architecture, contain cancer stem cells and have predictive value supporting personalized medicine. Here we describe a large-scale functional screen of dual-targeting bispecific antibodies (bAbs) on a heterogeneous colorectal cancer PDO biobank and paired healthy colonic mucosa samples. More than 500 therapeutic bAbs generated against Wingless-related integration site (WNT) and receptor tyrosine kinase (RTK) targets were functionally evaluated by high-content imaging to capture the complexity of PDO responses. Our drug discovery strategy resulted in the generation of MCLA-158, a bAb that specifically triggers epidermal growth factor receptor degradation in leucine-rich repeat-containing G-protein-coupled receptor 5-positive (LGR5+) cancer stem cells but shows minimal toxicity toward healthy LGR5+ colon stem cells. MCLA-158 exhibits therapeutic properties such as growth inhibition of KRAS-mutant colorectal cancers, blockade of metastasis initiation and suppression of tumor outgrowth in preclinical models for several epithelial cancer types.
  11. Science. 2022 Apr 29. 376(6592): 476-483
      Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.
  12. CA Cancer J Clin. 2022 Apr 26.
      Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000-000.
    Keywords:  immunotherapy; metastatic colorectal cancer; molecular target therapy; precision medicine; tumor molecular profiling
  13. Comput Biol Med. 2022 Apr 18. pii: S0010-4825(22)00308-0. [Epub ahead of print]146 105516
      BACKGROUND: Colorectal cancer (CRC), the 3rd most universal cancer globally, accounts for approximately 10% of newly diagnosed cancer incidences each year. Identifying biomarkers associated with CRC survival and predicting the survival of CRC patients are critical for personalized therapy. Existing studies on CRC survival are mainly based on single omics, studies using multi-omics to predict CRC survival are still vacant. To fill in this gap, we aim to identify biomarkers associated with CRC survival at mRNA, miRNA and tissue microbiome levels, and to evaluate the accuracy of potential biomarkers in predicting CRC survival.METHODS: First, we collected 31 short-term survival (ST, less than 3 years) and 47 long-term survival (LT, longer than 3 years) CRC samples from the database, was named The Cancer Genome Atlas (TCGA). Then, we carried out bioinformatics analysis with collected multi-omics data: (1) comparing the bacterial community structures between ST and LT, (2) identifying differentially expressed mRNAs and miRNAs between ST and LT, and (3) exploring the relationship between bacteria and genes. Finally, we trained models based on multi-omics data to evaluate the performance of several omics data in predicting CRC survival.
    RESULTS: Among the compared omics data, microbiome of CRC tissue had the best predictive power on the three-year survival of CRC patients, the area under the receiver operating characteristic curve (AUC) is 0.755 with 10-fold Cross-Validation (CV). In addition, we screened out 26 differential microbial communities and 13 differential expression genes (DEGs) between ST and LT. Thermoanaerobacterium, Parabacteroides, Oceanicaulis, and Acetonema were more abundant in the ST, while Methylotenera, Candidatus_Riesia and Aquamicrobium were enriched in the LT. We also found that up-regulated genes were significantly enriched in ST group, but the down-regulated genes were enriched in the LT group.
    CONCLUSION: The tissue bacterial communities of CRC patients with different survival periods show significant differences, and the bacteria in tumour tissue of CRC are potential biomarkers for predicting the three-year survival of CRC patients.
    Keywords:  Colorectal cancer; Microbial community; Multi-omics; Random forest; Survival