-
British Journal of Cancer Feb 2021Most cancer cells employ the Warburg effect to support anabolic growth and tumorigenesis. Here, we discovered a key link between Warburg effect and aberrantly activated...
BACKGROUND
Most cancer cells employ the Warburg effect to support anabolic growth and tumorigenesis. Here, we discovered a key link between Warburg effect and aberrantly activated Wnt/β-catenin signalling, especially by pathologically significant APC loss, in CRC.
METHODS
Proteomic analyses were performed to evaluate the global effects of KYA1797K, Wnt/β-catenin signalling inhibitor, on cellular proteins in CRC. The effects of APC-loss or Wnt ligand on the identified enzymes, PKM2 and LDHA, as well as Warburg effects were investigated. A linkage between activation of Wnt/β-catenin signalling and cancer metabolism was analysed in tumour of Apc mice and CRC patients. The roles of PKM2 in cancer metabolism, which depends on Wnt/β-catenin signalling, were assessed in xenograft-tumours.
RESULTS
By proteomic analysis, PKM2 and LDHA were identified as key molecules regulated by Wnt/β-catenin signalling. APC-loss caused the increased expression of metabolic genes including PKM2 and LDHA, and increased glucose consumption and lactate secretion. Pathological significance of this linkage was indicated by increased expression of glycolytic genes with Wnt target genes in tumour of Apc mice and CRC patients. Warburg effect and growth of xenografted tumours-induced by APC-mutated-CRC cells were suppressed by PKM2-depletion.
CONCLUSIONS
The β-catenin-PKM2 regulatory axis induced by APC loss activates the Warburg effect in CRC.
Topics: Animals; Carrier Proteins; Colorectal Neoplasms; Genes, APC; Heterografts; Humans; L-Lactate Dehydrogenase; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondrial Proton-Translocating ATPases; Neoplasm Proteins; Proteomics; Thiazolidines; Thyroid Hormones; Tissue Array Analysis; Warburg Effect, Oncologic; Wnt Signaling Pathway; beta Catenin; Thyroid Hormone-Binding Proteins
PubMed: 33071283
DOI: 10.1038/s41416-020-01118-7 -
Journal of Industrial Microbiology &... Jan 2020The impact of the global secondary metabolite regulators LaeA and VeA on echinocandin B production and morphological development was evaluated in the industrial...
The impact of the global secondary metabolite regulators LaeA and VeA on echinocandin B production and morphological development was evaluated in the industrial production strain Aspergillus pachycristatus NRRL 11440. Other representative secondary metabolites were examined as well to determine if the velvet complex functions as in A. nidulans and other species of fungi. Genetic methods used for gene manipulations in A. nidulans were applied to A. pachycristatus. Separate deletions of genes Apc.laeA and Apc.veA resulted in similar yet differing phenotypes in strain NRRL 11440. Disruption of Apc.laeA and Apc.veA significantly reduced, but did not eliminate, the production of echinocandin B. Similar to what has been observed in A. nidulans, the production of sterigmatocystin was nearly eliminated in both mutants. Quantitative reverse transcription PCR analyses confirmed that selected genes of both the echinocandin B and sterigmatocystin gene clusters were down-regulated in both mutant types. The two mutants differed with respect to growth of aerial hyphae, pigmentation, development of conidiophores, conidial germination rate, and ascospore maturation. Further functional annotation of key regulatory genes in A. pachycristatus and related Aspergillus species will improve our understanding of regulation of echinocandin production and co-produced metabolites.
Topics: Aspergillus; Echinocandins; Fungal Proteins; Gene Expression Regulation, Fungal; Genome, Fungal; Multigene Family; Secondary Metabolism; Spores, Fungal
PubMed: 31758414
DOI: 10.1007/s10295-019-02250-x -
Neoplasma 2017Colorectal cancer is the 4th most common cause of cancer related deaths worldwide and new possibilities in accurate diagnosis and targeted treatment are highly required.... (Review)
Review
Colorectal cancer is the 4th most common cause of cancer related deaths worldwide and new possibilities in accurate diagnosis and targeted treatment are highly required. Mutations in adenomatous polyposis coli (APC) gene play a pivotal role in adenoma-carcinoma pathway of colorectal tumorigenesis. The quarter century from its´ first cloning, APC became one of the most frequently mutated, known driver genes in colorectal cancer. Intensive routine molecular testing of APC has brought the benefits for patients with family history of polyposis or colorectal cancer. Nevertheless, multiple mutational disease-causing mechanisms make the genetic testing still challenging. This minireview is focused on implementation of novel APC mutation screening diagnostic strategies for polyposis families according to the current findings. A further understanding and improved algorithms may help to increase the mutation detection rate. APC germline mutations achieve close to 100% penetrance, so more comprehensive approach followed by preventive and therapeutic strategies might reflect in decrease in burden of colorectal cancer.
Topics: Adenomatous Polyposis Coli Protein; Colorectal Neoplasms; DNA Mutational Analysis; Genes, APC; Germ-Line Mutation; Humans; Mutation
PubMed: 28253712
DOI: 10.4149/neo_2017_303 -
Asian Pacific Journal of Cancer... Dec 2021It is known that many genes are associated with colon cancer. We aimed to investigate the effect of gene mutations on metastasis and overall survival in metastatic and...
OBJECTIVE
It is known that many genes are associated with colon cancer. We aimed to investigate the effect of gene mutations on metastasis and overall survival in metastatic and non metastatic colon cancers.
METHODS
A total of 50 patients with metastatic (n=25) and non metastatic (n=25) diagnosed with colon cancer between 2010 and 2018 were included in the study. APC, MUTYH, RAD50, MEN1, ATM, PALB2, NSH2, BRCA1, BRCA2, MLH1, BRIP1, TP53, PTEN, BARD1, MSH6, PMS2, NBN, and FAM175A gene mutations were evaluated using the next generation sequencing method. The effect of gene mutations on metastasis and overall survival were evaluated.
RESULTS
The mean age of patients with colon cancer without distant metastasis was 48.64±14.72 years and for patients with distance metases was 56.68±11.65. The mean survival time of colon cancer patients with distant organ metastasis after the metastasis date was 104.36±58.59 weeks. The presence of APC, MUTYH, and TP53 genetic mutations was observed with a higher rate in metastatic colon cancer (p<0.05).
CONCLUSION
We showed that APC, MUTYH, and TP53 mutations are associated with distant organ metastasis.
Topics: Adolescent; Adult; Aged; Case-Control Studies; Colonic Neoplasms; DNA Glycosylases; Female; Genes, APC; Genes, p53; Genetic Predisposition to Disease; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Retrospective Studies; Survival Analysis; Young Adult
PubMed: 34967562
DOI: 10.31557/APJCP.2021.22.12.3839 -
Genes Jun 2018and genes are mutated in 70⁻90% and 10⁻30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP...
and genes are mutated in 70⁻90% and 10⁻30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine and mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel germline mutation, c.510_511insA. Overall, mutational analysis showed pathogenic mutations in 6/10 patients: 5/10 in and 1/10 in . Additionally, we found three variants of unknown significance in gene that showed no evidence of possible splicing defects by in silico analysis. Molecular analysis was also extended to family members of mutated patients. A genotype-phenotype correlation was observed for colonic signs whereas a variation of disease onset age was revealed for the same mutation. Moreover, we found an intrafamilial variability of FAP onset age. Regarding extracolonic manifestations, the development of desmoid tumors was related to surgery and not to mutation position, while a genotype-phenotype correspondence was observed for the onset of thyroid or gastric cancer. These findings can be useful in association to clinical data for early surveillance and suitable treatment of FAP patients.
PubMed: 29954149
DOI: 10.3390/genes9070322 -
Klinicka Onkologie : Casopis Ceske a... 2019It is estimated that 5-10% of colorectal cancers arise due to a known genetic syndrome. Individuals with these cancer syndromes are also at risk of extracolonic cancers.... (Review)
Review
BACKGROUND
It is estimated that 5-10% of colorectal cancers arise due to a known genetic syndrome. Individuals with these cancer syndromes are also at risk of extracolonic cancers. Polyposis and nonpolyposis hereditary syndromes are generally recognized. Inclusion of next-generation sequencing technology, especially multiple-gene panel testing, in routine laboratory practice has made identifying the causes of these diseases significantly easier.
PURPOSE
To summarize current knowledge of the causes, clinical manifestations, diagnostic criteria, and recommendations for presymptomatic screening of individuals at risk of hereditary gastrointestinal polyposis and colorectal cancer syndromes. We dicuss currently defined syndromes detected by multiple-gene panel next-generation sequencing; these include constitutional mismatch repair deficiency (biallelic MLH1, MSH2, MSH6, PMS2 gene mutations), gastric adenocarcinoma and proximal polyposis of the stomach (APC gene), NTHL1-associated polyposis, polymerase proofreading-associated polyposis (POLD1, POLE genes), juvenile polyposis (SMAD4, BMPR1A genes), and serrated polyposis syndromes. Another aim is to summarize recent knowledge about well-known syndromes, including hereditary nonpolyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, MUTYH-associated polyposis, and Peutz-Jeghers and Cowden/PTEN hamartoma tumor syndromes.
CONCLUSION
Awareness of hereditary polyposis/colon cancer syndromes enables early diagnosis and prevention of cancer in affected individuals and their relatives. Genetic counseling, presymptomatic testing of at-risk individuals, and efficient screening may be beneficial for affected families. Thank to Lenka Foretová, M.D., PhD, (Masaryk Memorial Cancer Institute, Brno) for a critical review of the manuscript and valuable advices. The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 6. 6. 2019.
Topics: Gastrointestinal Neoplasms; Genetic Testing; Humans; Neoplastic Syndromes, Hereditary
PubMed: 31409085
DOI: 10.14735/amko2019S97 -
International Journal of Clinical... Sep 2021Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC...
BACKGROUND
Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC gene. However, this variant is not detected in up to 30% of patients with the adenomatous polyposis phenotype.
METHODS
We performed next-generation sequencing (NGS) to identify the causative genes in FAP patients with 10 or more polyps. For patients in whom the APC germline variant was not able to be identified, we screened for APC mosaicism using high-coverage NGS of APC with DNA from leucocytes and/or frozen tissue.
RESULTS
The pathogenic APC germline variant was found in 93.3%, 71.6%, and 17.1% of patients with profuse-type polyposis, sparse-type polyposis, and oligo-polyposis, respectively. The APC germline variant detection rate in patients with FAP-related diseases was 69.7% for fundic gland polyposis, 79.7% for duodenal adenoma, 94.7% for desmoid tumor, and 71.4% for thyroid cancer, with increasing numbers of extracolonic lesions associated with an increasing APC germline variant detection rate. A mosaic test detected nine patients with APC mosaicism. A comparison of APC-associated polyposis with APC mosaicism showed that patients with APC mosaicism had a low frequency of duodenal adenoma and a family history of colonic polyposis.
CONCLUSIONS
We determined the detection rate of the APC germline variant by phenotype and identified APC mosaicism. Genetic testing of FAP patients is important because it can help with surgical decision-making, monitoring, and genetic counseling. Furthermore, genetic testing by NGS proved to be an effective method of detecting APC germline variants.
PubMed: 34106356
DOI: 10.1007/s10147-021-01946-4 -
Pharmacology & Therapeutics Dec 2015The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of... (Review)
Review
The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of the most notable findings is that the great majority of colorectal cancers (>80%) have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Loss of functional APC protein results in activation of canonical Wnt/β-catanin signaling and initiates intestinal carcinogenesis. Mutational inactivation of APC is the first genetic event, but colorectal cancer cells retain their dependency on constitutive Wnt signal activation even after accumulation of other genetic events. Accordingly, pharmacological blocking of Wnt signaling has been considered an attractive therapeutic approach for colorectal cancer. Several therapeutics targeting various molecular components of the Wnt signaling pathway, including porcupine, frizzled receptors and co-receptor, tankyrases, and cAMP response element binding protein (CREB)-binding protein (CBP), have been developed, and some of those are currently being evaluated in early-phase clinical trials. Traf2- and Nck-interacting protein kinase (TNIK) has been identified as a regulatory component of the T-cell factor-4 and β-catenin transcriptional complex independently by two research groups. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its inhibition is expected to block the signal even in colorectal cancer cells with APC gene mutation. Here we discuss some of the TNIK inhibitors under preclinical development.
Topics: ATP-Binding Cassette Transporters; Colorectal Neoplasms; Genes, APC; Humans; Intracellular Signaling Peptides and Proteins; Protein Serine-Threonine Kinases; TNF Receptor-Associated Factor 2; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 26542362
DOI: 10.1016/j.pharmthera.2015.10.009 -
Cancers Mar 2021Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10-15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is... (Review)
Review
Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10-15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the gene and mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-X, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.
PubMed: 33808549
DOI: 10.3390/cancers13061389 -
Journal of Comparative Pathology May 2023Cancers of the breast, prostate and intestinal tract account for most cancer-associated deaths in humans and represent several of the highest incidence human neoplasms.... (Review)
Review
Cancers of the breast, prostate and intestinal tract account for most cancer-associated deaths in humans and represent several of the highest incidence human neoplasms. Therefore, understanding the underlying pathophysiology, including the formation and propagation of these cancers, is key to designing potential treatments. Over the last 50 years or more, genetically engineered mouse models (GEMMs) have been instrumental platforms to our discovery of neoplastic disease as many follow near-identical molecular and histological progression as human tumours. In this mini review, we summarize three key preclinical models and focus on some of the major findings in relation to clinical care. We discuss the MMTV-PyMT (polyomavirus middle T antigen) mouse, TRAMP (transgenic adenocarcinoma mouse prostate) mouse and APC (multiple intestinal neoplasm mutation of APC gene) mouse, which mimic breast, prostate and intestinal cancers, respectively. We aim to describe the significant contributions these GEMMs have made to our collective understanding of high-incidence cancers as well as briefly discuss the limitations of each model as a device for therapeutic discovery.
Topics: Male; Mice; Humans; Animals; Mice, Transgenic; Disease Models, Animal; Prostatic Neoplasms; Genes, APC; Mutation
PubMed: 37236009
DOI: 10.1016/j.jcpa.2023.04.005