bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2021‒09‒12
twelve papers selected by
Maria-Virginia Giolito

  1. Biochim Biophys Acta Rev Cancer. 2021 Sep 01. pii: S0304-419X(21)00121-9. [Epub ahead of print]1876(2): 188623
      Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Despite significant progress that has been made in therapies against CRC over the past decades, drug resistance is still a major limitation in CRC treatment. Numerous investigations have unequivocally shown that epigenetic regulation plays an important role in CRC drug resistance because of the high rate of epigenetic alterations in multiple genes during cancer development or drug treatment. Furthermore, the reversibility of epigenetic alterations provides novel therapeutic strategies to overcome drug resistance using small molecules, which can target non-coding RNAs or reverse histone modification and DNA methylation. In this review, we discuss epigenetic regulation in CRC drug resistance and the possible role of preventing or reversing CRC drug resistance using epigenetic therapy in CRC treatment.
    Keywords:  Colorectal cancer; DNA methylation; Drug resistance; Histone modification; Noncoding RNA
  2. Int J Mol Sci. 2021 Aug 27. pii: 9286. [Epub ahead of print]22(17):
      Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.
    Keywords:  5-Fluorouracil; P-glycoprotein; S-Adenosylmethionine; colorectal cancer; combination therapy; multidrug resistance
  3. Int J Mol Sci. 2021 Aug 31. pii: 9487. [Epub ahead of print]22(17):
      The monoamine serotonin, 5-hydroxytryptamine (5-HT), is a remarkable molecule with conserved production in prokaryotes and eukaryotes and a wide range of functions. In the gastrointestinal tract, enterochromaffin cells are the most important source for 5-HT production. Some intestinal bacterial species are also able to produce 5-HT. Besides its role as a neurotransmitter, 5-HT acts on immune cells to regulate their activation. Several lines of evidence indicate that intestinal 5-HT signaling is altered in patients with inflammatory bowel disease. In this review, we discuss the current knowledge on the production, secretion, and signaling of 5-HT in the intestine. We present an inventory of intestinal immune and epithelial cells that respond to 5-HT and describe the effects of these signaling processes on intestinal homeostasis. Further, we detail the mechanisms by which 5-HT could affect inflammatory bowel disease course and describe the effects of interventions that target intestinal 5-HT signaling.
    Keywords:  inflammatory bowel disease; intestine; microbiome; tryptophan
  4. Cell Mol Gastroenterol Hepatol. 2021 Sep 07. pii: S2352-345X(21)00180-6. [Epub ahead of print]
      The gastrointestinal (GI) tract is home to a complex and dynamic community of microorganisms, comprising bacteria, archaea, viruses, yeast and fungi. It is widely accepted that human health is shaped by these microbes and their collective microbial genome. This so-called "second genome" plays an important role in normal functioning of the host, contributing to processes involved in metabolism and immune modulation. Furthermore, the gut microbiota is also capable of generating energy and nutrients (e.g. short chain fatty acids and vitamins), which are otherwise inaccessible to the host, and are essential for mucosal barrier homeostasis. In recent years, numerous studies have pointed towards microbial dysbiosis as a key driver in many GI conditions, including cancers. Yet comprehensive mechanistic insights on how collectively gut microbes influence carcinogenesis remains limited. In addition to their role in carcinogenesis, the gut microbiota has now been demonstrated to play a key role in influencing clinical outcomes to cancer immunotherapy making them valuable targets in the treatment of cancer. It is also becoming apparent that, besides the gut microbiota's impact on therapeutic outcomes, cancer treatment may in turn influence GI microbiota composition. This review provides a comprehensive overview of microbial dysbiosis in GI cancers, specifically oesophageal, gastric and colorectal cancers, potential mechanisms of microbiota in carcinogenesis and their implications in diagnostics and cancer treatment.
    Keywords:  Gastrointestinal cancer; diagnostics; gut microbiota; therapeutics
  5. Int J Mol Sci. 2021 Sep 03. pii: 9589. [Epub ahead of print]22(17):
      The epithelial-mesenchymal transition (EMT) comprises an important biological mechanism not only for cancer progression but also in the therapeutic resistance of cancer cells. While the importance of the protein abundance of EMT-inducers, such as Snail (SNAI1) and Zeb1 (ZEB1), during EMT progression is clear, the reciprocal interactions between the untranslated regions (UTRs) of EMT-inducers via a competing endogenous RNA (ceRNA) network have received little attention. In this study, we found a synchronized transcript abundance of Snail and Zeb1 mediated by a non-coding RNA network in colorectal cancer (CRC). Importantly, the trans-regulatory ceRNA network in the UTRs of EMT inducers is mediated by competition between tumor suppressive miRNA-34 (miR-34) and miRNA-200 (miR-200). Furthermore, the ceRNA network consisting of the UTRs of EMT inducers and tumor suppressive miRs is functional in the EMT phenotype and therapeutic resistance of colon cancer. In The Cancer Genome Atlas (TCGA) samples, we also found genome-wide ceRNA gene sets regulated by miR-34a and miR-200 in colorectal cancer. These results indicate that the ceRNA networks regulated by the reciprocal interaction between EMT gene UTRs and tumor suppressive miRs are functional in CRC progression and therapeutic resistance.
    Keywords:  Snail; ZEB1; ceRNA; colorectal cancer; epithelial mesenchymal transition; therapeutic resistance
  6. Cell Death Dis. 2021 Sep 06. 12(9): 837
      Mitochondrial retrograde signaling (mito-RTG) triggered by mitochondrial dysfunction plays a potential role in regulating tumor metabolic reprogramming and cellular sensitivity to radiation. Our previous studies showed phos-pyruvate dehydrogenase (p-PDH) and PDK1, which involved in aerobic glycolysis, were positively correlated with radioresistance, but how they initiate and work in the mito-RTG pathway is still unknown. Our further genomics analysis revealed that complex I components were widely downregulated in mitochondrial dysfunction model. In the present study, high expression of p-PDH was found in the complex I deficient cells and induced radioresistance. Mechanistically, complex I defects led to a decreased PDH both in cytoplasm and nucleus through [Ca2+]m-PDP1-PDH axis, and decreased PDH in nucleus promote DNA damage repair (DDR) response via reducing histone acetylation. Meanwhile, NDUFS1 (an important component of the complex I) overexpression could enhance the complex I activity, reverse glycolysis and resensitize cancer cells to radiation in vivo and in vitro. Furthermore, low NDUFS1 and PDH expression were validated to be correlated with poor tumor regression grading (TRG) in local advanced colorectal cancer (CRC) patients underwent neoadjuvant radiotherapy. Here, we propose that the [Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling activated by mitochondrial complex I defects contribute to cancer cell radioresistance, which provides new insight in the understanding of the mito-RTG. For the first time, we reveal that NDUFS1 could be served as a promising predictor of radiosensitivity and modification of complex I function may improve clinical benefits of radiotherapy in CRC.
  7. Pharmacol Ther. 2021 Sep 01. pii: S0163-7258(21)00187-X. [Epub ahead of print] 107985
      Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a privotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments. This poses major hindrances for CSC-targeting anti-cancer therapies: cell plasticity maintains stemness in CSCs and renders tumor cells to acquire stem-like phenotypes, contributing to tumor heterogeneity and CSC generation; cellular senescence induces genetic reprogramming and stemness activation, leading to CSC-mediated tumor progression and metastasis; cell quienscence facilitates CSC to overcome their intrinsic vulnerabilities and therapeutic stress, inducing tumor relapse and therapy resistance. These mechanisms are subjected to spatiotemporal regulation by hypoxia, CSC niche, and extracellular matrix in the tumor microenvironment. Here we integrate the recent advances and current knowledge to elucidate the mechanisms involved in the regulation of plasticity, senescence and quiescence of CSCs and the potential therapeutic implications for the future.
    Keywords:  Cancer stem cells; Plasticity; Quiescence; Senescence; Therapy resistance; Tumor microenvironment
  8. Nat Rev Mol Cell Biol. 2021 Sep 10.
      Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division, however, create increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell viability. New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment.
  9. Aging (Albany NY). 2021 Sep 07. 13(undefined):
      Therapy-induced senescence (TIS) is a major cellular response to anticancer therapies. While induction of a persistent growth arrest would be a desirable outcome in cancer therapy, it has been shown that, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, likely contributing to tumor relapse. Notably, cells that escape from TIS acquire a plastic, stem cell-like phenotype. The metabolic dependencies of cells that evade senescence have not been thoroughly studied. In this study, we show that glutamine depletion inhibits escape from TIS in all cell lines studied, and reduces the stem cell subpopulation. In line with a metabolic reliance on glutamine, escaped clones overexpress the glutamine transporter SLC1A5. We also demonstrate a central role of glutamine synthetase that mediates resistance to glutamine deprivation, conferring independence from exogenous glutamine. Finally, rescue experiments demonstrate that glutamine provides nitrogen for nucleotides biosynthesis in cells that escape from TIS, but also suggest a critical involvement of glutamine in other metabolic and non-metabolic pathways. On the whole, these results reveal a metabolic vulnerability of cancer stem cells that recover proliferation after exposure to anticancer therapies, which could be exploited to prevent tumor recurrence.
    Keywords:  cancer stem cells; escape; glutamine; glutamine synthetase; therapy-induced senescence
  10. Biochim Biophys Acta Mol Basis Dis. 2021 Sep 03. pii: S0925-4439(21)00198-8. [Epub ahead of print] 166265
      Autophagy is an intracellular lysosomal degradation process involved in multiple facets of cancer biology. Various dimensions of autophagy are associated with tumor growth and cancer progression, and here we focus on the dimensions involved in regulation of cell survival/cell death, cell proliferation and tumor dormancy. The first dimension of autophagy supports cell survival under stress within tumors and under certain contexts drives cell death, impacting tumor growth. The second dimension of autophagy promotes proliferation through directly regulating cell cycle or indirectly maintaining metabolism, increasing tumor growth. The third dimension of autophagy facilitates tumor cell dormancy, contributing to cancer treatment resistance and cancer recurrence. The intricate relationship between these three dimensions of autophagy influences the extent of tumor growth and cancer progression. In this review, we summarize the roles of the three dimensions of autophagy in tumor growth and cancer progression, and discuss unanswered questions in these fields.
    Keywords:  Autophagy; Cell death; Cell survival; Proliferation; Tumor dormacy; Tumor growth
  11. Tumour Biol. 2021 ;43(1): 209-223
      OBJECTIVE: The microenvironment of colon cancer (CC) is heterogeneous including cells of myeloid lineage affecting tumor growth and metastasis. Two functional subtypes of myeloid cells have been identified; one (M1) is tumor-inhibitory and the other one (M2) is tumor-promoting. Whether the three myeloid markers EMR1, CD206 and CD86 are expressed only in the infiltrating myeloid cells or also in the tumor cells was investigated.METHODS: Expression of the myeloid markers was investigated in CC at the mRNA and protein levels in primary tumors and lymph nodes. mRNA expression was also determined in 5 CC cell lines. Protein expression was investigated by two-color immunofluorescence and consecutive-sections-immune-staining combined with morphometry using specific antibodies for the myeloid cell markers and the epithelial cell markers CEACAM5 and EpCAM.
    RESULTS: EMR1 and CD86, but not CD206, mRNA levels were significantly higher in CC primary tumors compared to apparently normal colon tissue (P <  0.0001). EMR1 mRNA levels were significantly higher in both hematoxylin-eosin positive (H&E(+)) and H&E(-) lymph nodes of CC patients compared to control nodes (P = 0.03 and P = 0.01, respectively). EMR1 and CD206 mRNAs were expressed in 4/5 and 5/5 CC cell lines, respectively, while CD86 mRNA was not expressed. Immuno-morphometry revealed that about 20% of the tumor cells expressed EMR1 and CD206. Positive cells were tumor cells as revealed by anti-CEACAM5 and anti-EpCAM staining. The number of EMR1, CD206 and CD86 positive cells were significantly increased in CC primary tumors compared to normal colon tissue (P <  0.0001). However, CD206 was also expressed in normal colonocytes. Only EMR1 showed significantly increased numbers of positive tumor cells in H&E(+) nodes compared to H&E(-) nodes (P = 0.001). EMR1 expression in CC tumor cells correlated with CXCL17 expressing tumor cells.
    CONCLUSION: EMR1, like the chemokine CXCL17, is ectopically expressed in colon cancer possibly in the same cancer cells.
    Keywords:  CD206; CD86; EMR1; chemokines; epithelial cell markers
  12. Cancers (Basel). 2021 Sep 03. pii: 4448. [Epub ahead of print]13(17):
      One of the major problems of traditional anti-cancer treatments is that they lead to the emergence of treatment-resistant cells, which results in treatment failure. To avoid or delay this phenomenon, it is relevant to take into account the eco-evolutionary dynamics of tumors. Designing evolution-based treatment strategies may help overcoming the problem of drug resistance. In particular, a promising candidate is adaptive therapy, a containment strategy which adjusts treatment cycles to the evolution of the tumors in order to keep the population of treatment-resistant cells under control. Mathematical modeling is a crucial tool to understand the dynamics of cancer in response to treatments, and to make predictions about the outcomes of these treatments. In this review, we highlight the benefits of in silico modeling to design adaptive therapy strategies, and to assess whether they could effectively improve treatment outcomes. Specifically, we review how two main types of models (i.e., mathematical models based on Lotka-Volterra equations and agent-based models) have been used to model tumor dynamics in response to adaptive therapy. We give examples of the advances they permitted in the field of adaptive therapy and discuss about how these models can be integrated in experimental approaches and clinical trial design.
    Keywords:  Lotka–Volterra models; adaptive therapy; agent-based models; cancer evolution