The intestinal epithelium, a rapidly renewing tissue, is characterized by a continuous cell turnover that occurs through a well-coordinated process of cell proliferation and differentiation. This dynamic is crucial for the long-term function of the gastrointestinal tract. Disruption of this process can lead to colorectal carcinoma, a common malignancy worldwide. The first part of the review focuses on the cellular composition of the epithelium and the molecular mechanisms that control its functions, and describes the pathways that lead to epithelial transformation and tumor progression. This forms the basis for understanding the development and progression of advanced colorectal cancer. The second part deals with current therapeutic approaches and presents the latest treatment options, ongoing clinical trials and new drugs. In addition, the biological and medical perspectives of the adverse effects of therapies and models of regeneration of the intestinal epithelium are highlighted and, finally, future treatment options are discussed.
- MeSH
- kolorektální nádory * terapie patologie MeSH
- lidé MeSH
- nádorová transformace buněk MeSH
- onkologové MeSH
- střevní sliznice patologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- chinoliny * terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- dospělí MeSH
- fenylmočovinové sloučeniny * aplikace a dávkování MeSH
- humanizované monoklonální protilátky * škodlivé účinky terapeutické užití aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom * farmakoterapie sekundární patologie MeSH
- nádory kůže * farmakoterapie patologie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- pozorovací studie MeSH
Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial-mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.
- Publikační typ
- časopisecké články MeSH
Systémová onkologická léčba metastazujícího kolorektálního karcinomu je v současnosti založena na chemoterapii kombinované s cílenou léčbou indikovanou podle přítomnosti aktivačních mutací v signální dráze EGFR-RAS-RAF, a to bez ohledu na histologickou podskupinu nádoru. V kazuistice popisujeme pacienta s mucinózní variantou kolorektálního karcinomu, který ve třetí linii léčby velmi dobře zareagoval na trifluridin/tipiracil. Ve stručném přehledu uvádíme základní charakteristiky tohoto histologického subtypu, který představuje 5-15 % všech případů, je charakterizován vysokou produkcí extracelulárního mucinu a je v souvislosti s nižší léčebnou odpovědí na chemoterapii spojován s horší prognózou. Dále poukazujeme na časný výskyt neutropenie jako potenciálního prediktivního ukazatele při léčbě trifluridinem/tipiracilem.
Systemic oncologic treatment of metastatic colorectal carcinoma is currently based on chemotherapy in combination with targeted therapy based on the presence of activating mutations in the EGFR-RAS-RAF pathway, regardless of the histological subgroup of the tumor. In this case report, we describe a patient with a mucinous variant of colorectal carcinoma who responded very well to trifluridine/tipiracil in the third-line treatment. We briefly review the basic features of this histologic subtype, which accounts for 5-15% of all cases, is characterized by high extracellular mucin production, and is associated with a poorer prognosis related to a lower response to chemotherapy. We also point to the early occurrence of neutropenia as a potential predictive marker in trifluridine/tipiracil treatment.
- Klíčová slova
- tipiracil,
- MeSH
- fixní kombinace léků MeSH
- kolorektální nádory * diagnóza farmakoterapie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- senioři MeSH
- trifluridin farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
- Publikační typ
- abstrakt z konference MeSH
A large proportion of colorectal carcinomas (CRC) evolve from colorectal adenomas. However, not all individuals with colonic adenomas have a risk of CRC substantially higher than those of the general population. The aim of the study was to determine the differences or similarities of mutation profile among low- and high-grade adenomas and in situ carcinoma with detailed follow up. We have investigated the mutation spectrum of well-known genes involved in CRC (such as APC, BRAF, EGFR, NRAS, KRAS, PIK3CA, POLE, POLD1, SMAD4, PTEN, and TP53) in a large, well-defined series of 96 adenomas and in situ carcinomas using a high-throughput genotyping technique. Besides, the microsatellite instability and APC and MLH1 promoter methylation were studied as well. We observed a high frequency of pathogenic variants in the studied genes. The APC, KRAS and TP53 mutation frequencies were slightly lower in adenoma samples than in in situ carcinoma samples. Further, when we stratified mutation frequency based on the grade, the frequency distribution was as follows: low-grade adenoma-high-grade adenomas-in situ carcinoma: APC gene 42.9-56.0-54.5%; KRAS gene 32.7-32.0-45.5%; TP53 gene 8.2-20.0-18.2%. The occurrence of KRAS mutation was associated with the presence of villous histology and methylation of the APC promoter was significantly associated with the presence of POLE genetic variations. However, no association was noticed with the presence of any singular mutation and occurrence of subsequent adenoma or CRC. Our data supports the multistep model of gradual accumulation of mutations, especially in the driver genes, such as APC, TP53 and KRAS.
- MeSH
- adenom genetika patologie MeSH
- karcinom in situ genetika patologie MeSH
- kolorektální nádory genetika patologie MeSH
- lidé MeSH
- metylace DNA MeSH
- mikrosatelitní nestabilita * MeSH
- mutace * MeSH
- nádorové biomarkery genetika MeSH
- následné studie MeSH
- prognóza MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- trifluridin/tipiracil,
- MeSH
- kolorektální nádory * diagnóza farmakoterapie patologie MeSH
- lidé MeSH
- mucinózní adenokarcinom patologie MeSH
- PET/CT metody MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování terapeutické užití MeSH
- pyrrolidiny aplikace a dávkování terapeutické užití MeSH
- senioři MeSH
- thymin aplikace a dávkování terapeutické užití MeSH
- trifluridin aplikace a dávkování terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
Radiation and chemotherapy represent standard-of-care cancer treatments. However, most patients eventually experience tumour recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate the molecular mechanisms of resistance to radio- and chemotherapy, we exposed human cancer cell lines (HeLa, MCF-7 and DU145) to clinically relevant doses of 5-azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations, including low-adherent stem-like cells. Stress-mobilized low-adherent cell fractions differed from other survivors in terms of deregulation of hundreds of genes, including those involved in interferon response. Exposure of cancer cells to interferon-gamma but not interferon-beta resulted in the development of a heterogeneous, low-adherent fraction comprising not only apoptotic/necrotic cells but also live cells exhibiting active Notch signalling and expressing stem-cell markers. Chemical inhibition of mitogen-activated protein kinase/ERK kinase (MEK) or siRNA-mediated knockdown of extracellular signal-regulated kinase 1/2 (Erk1/2) and interferon responsible factor 1 (IRF1) prevented mobilization of the surviving low-adherent population, indicating that interferon-gamma-mediated loss of adhesion and anoikis resistance required an active Erk pathway interlinked with interferon signalling by transcription factor IRF1. Notably, a skin-specific protein suprabasin (SBSN), a recently identified oncoprotein, was among the top scoring genes upregulated in surviving low-adherent cancer cells induced by 5-azacytidine or irradiation. SBSN expression required the activity of the MEK/Erk pathway, and siRNA-mediated knockdown of SBSN suppressed the low-adherent fraction in irradiated, interferon-gamma- and 5-azacytidine-treated cells, respectively, implicating SBSN in genotoxic stress-induced phenotypic plasticity and stress resistance. Importantly, SBSN expression was observed in human clinical specimens of colon and ovarian carcinomas, as well as in circulating tumour cells and metastases of the 4T1 mouse model. The association of SBSN expression with progressive stages of cancer development indicates its role in cancer evolution and therapy resistance.
- MeSH
- anoikis účinky léků účinky záření MeSH
- antitumorózní látky farmakologie MeSH
- azacytidin farmakologie MeSH
- chemorezistence MeSH
- diferenciační antigeny genetika MeSH
- interferony farmakologie MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky účinky léků metabolismus účinky záření MeSH
- nádorové proteiny genetika MeSH
- nádory farmakoterapie genetika radioterapie MeSH
- regulace genové exprese u nádorů účinky léků účinky záření MeSH
- upregulace účinky léků účinky záření MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
