Search Results (1,054)

Background and Objectives: Serrated adenocarcinoma (SAC) is a distinctive neoplasm that is histopathologically characterized by the presence of epithelial serration, an eosinophilic cytoplasm, and a vesicular nucleus. However, the literature data concerning somatic mutations in SACs remain extremely limited. Materials and Methods: A total of 159 colon resection cases diagnosed with adenocarcinoma whose DNA mutations were analyzed by next-generation sequencing (NGS) were retrospectively reviewed. In 23 cases, the SAC area exceeded 50%. A chi-square test was used to evaluate histopathologic characteristics and somatic mutations in SACs and non-serrated adenocarcinomas (non-SACs). Results: A significant difference was found in histological grade (p = 0.019) between SACs and non-SACs. TP53, KRAS, and PIK3CA genes have been identified as the most frequently mutated genes in both SACs and non-SACs. No statistically significant difference in somatic mutations was observed between the two groups (p > 0.05). Conclusions: In the present study, a higher prevalence of KRAS mutations was observed in SACs compared to BRAF mutations (KRAS: 39.1%, BRAF: 4.3%). This finding is consistent with the recent literature reporting a higher prevalence of KRAS mutations in colorectal SACs, in contrast to previous studies. The somatic mutation results of our study and the previous literature data suggest the potential importance of epigenetic alterations documented in the literature in the development of SACs. Full article

Background/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds—incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and 1,2,3-oxadiazole scaffolds, as well as N-(1-(4-hydroxy-3-methoxyphenyl)-3-oxo-3-(2-(phenylcarbamothioyl)hydrazineyl) prop-1-en-2-yl)benzamide—was evaluated for antioxidant activity (DPPH assay), PDK-1 and LDHA inhibition, cytotoxic effects against LoVo and HCT-116 colon carcinoma cells, with parallel assessment of safety profiles on normal HUVECs. The underlying anticancer mechanism of the most active compound was investigated through analysis of cell cycle distribution, apoptosis induction, intracellular reactive oxygen species levels, mitochondrial membrane potential disruption, and expression levels of apoptosis-related genes. Molecular docking assessed binding interactions within LDHA and PDK-1 active sites. The physicochemical, drug-likeness, and ADMET properties of the multi-bioactive candidates were predicted in silico. Results: Among the synthesized compounds, thiophenes 3b and 3d exhibited superior PDK-1/LDHA and DPPH/LDHA inhibitions along with significant cytotoxic effects on LoVo and HCT-116 cells (IC₅₀ in µM: 190.3/170.2 and 161.0/156.6), respectively, and minimal cytotoxicity toward HUVECs. Molecular docking revealed favorable interactions with key amino acid residues within the LDHA and/or PDK-1 active sites. Compound 3d notably induced G2/M (LoVo) and G1 (HCT-116) arrest and promoted apoptosis via enhancing ROS generation, modulating Bax/Bcl-2 expressions, disrupting mitochondrial membrane potential, and ultimately activating caspses-3. In silico predictions indicated their promising drug-likeness and pharmacokinetics, though high lipophilicity, poor solubility (especially for 3b), and potential toxicity risks were identified as limitations. Conclusions: Thiophenes 3b and 3d emerged as promising multi-target candidates; however, structural optimization is warranted to enhance their solubility, bioavailability, and safety to support further development as lead anti-colon cancer agents. Full article

Background: A glioblastoma (GBM) is a type of tumor originating from the glial brain cells, the astrocytes, and thus belongs to the astrocytoma group. Bevacizumab (BV) is a treatment for GBM. BV is the active ingredient in the drugs Avastin^®, Alymsys^®, Mvasi^® and ZiraBev^®. It is currently approved as second-line treatment for GBM recurrence in combination with radiotherapy, and as first-line treatment for other cancers, including advanced colorectal cancer, metastatic breast cancer and advanced non-small-cell lung cancer. The objective of this systematic review was to analyze the scientific evidence from the science-based literature on the therapeutic effect and adverse effects of the drug BV in patients with GBM or GBM multiforme. Methods: We systematically searched electronic databases for the literature search, including the MEDLINE (via PubMed), SCOPUS, Google Scholar, the Cumulative Index to Nursing and Allied Health Literature and Web of Science databases, covering records from their earliest data to December 2024. Randomized or controlled clinical trials that were published in English or Spanish were included. The following keywords were used in different combinations: “Bevacizumab therapy”, “Bevacizumab pharmaceutical”, “Glioblastoma”, “Glioma” and “multiform glioblastoma”. Results: The use of Bevacizumab has been extensively studied in the scientific literature, with beneficial effects in symptom control. However, the adverse effects of BV vary across different types of carcinomas, which is why it has already been established that these adverse effects must be taken into consideration. In our meta-analysis of adverse effects, we found 14 adverse effects and estimated their prevalence, with an average of 19% (CI: 4 to 44%). The most significant vascular adverse effect was thromboembolism, which led to a greater number of complications for patients with GBM. Finally, the most common adverse effects were nausea, vomiting, fatigue and hypertension. Conclusions: While the beneficial properties of this pharmacological therapy have been observed, its adverse effect profile requires constant evaluation, as it includes vascular, blood and symptomatic adverse effects, which must be analyzed on a case-by-case basis and with great attention, especially in the case of more serious complications such as thromboembolic events. Full article

T40214 (STAT) and its recently investigated analogue STATB are G-quadruplex (G4) forming aptamers characterized by an unusually high percentage of C. The therapeutic potential of T40214 relies on its ability to inhibit the signalling pathway of STAT3, a protein frequently overexpressed in tumor cells. STAT adopts a dimeric 5′-5′ end-stacked quadruplex structure, characterized by parallel strands, three G-tetrads and three propeller-shaped loops formed by a cytidine residue. STATB folds in a very similar structure, apart from an additional cytidine bulge loop. Many studies suggest that thermal stability and topology of G4 can be significantly affected by C methylation, thus resulting in altered interaction of G4-binding proteins with these structures. Considering this, two series of STAT and STATB analogues containing a single 5-methyl-2′-deoxycytidine (mC) residue instead of canonical C nucleotide in the loop have been prepared and investigated by a combination of spectroscopic and electrophoretic techniques. CD, NMR and PAGE data clearly indicate that all derivatives adopt dimeric G4 strictly similar to that assumed by parent aptamers, but with higher stabilities. Furthermore, the resistance to nucleases and the antiproliferative activity of these mC-containing derivatives against HCT116 (human colorectal carcinoma) and T24 (human bladder carcinoma) cell lines have been evaluated. In most of the cases, STAT and STATB derivatives inhibit cell proliferation to different extents, although to a lesser degree than the unmodified parent sequences. All the data highlight the key role of the loops and indicate mC as a useful tool to contribute favorably to the stability of G4-forming aptamers without alteration of their topology, required for the biological activity. Full article

Background: 3-Lup-20(29)-ene-3β,28-diol (betulin, BN) is a natural bioactive compound with significant synthetic and pharmacological potential. A growing body of research highlights the increasing interest in BN and its derivatives, driven by their broad biological activities (anticancer, antibacterial, anti-inflammatory, antiretroviral). However, poor bioavailability and low intracellular accumulation limit its pharmaceutical application. Methods: A promising strategy to enhance BN’s therapeutic potential is glycoconjugation. This approach improves drug bioavailability, solubility, and selectivity, particularly in cancer therapy, by leveraging cancer cells’ heightened glucose demand and overexpression of glucose transporters. Incorporating an N-heterocyclic linker, such as a 1,2,3-triazole ring, further enhances biological activity. Results: We developed an efficient method for modifying the betulin backbone at position C28 with sugar units via a (CO)CH₂CH₂COOH linker, based on CuAAC, yielding ten new betulin glycoconjugates with good yields and purity confirmed by spectroscopic analysis (NMR, HRMS). The potential for inhibition of cancer cell proliferation (HCT-116 human colorectal carcinoma cell line and MCF-7 human breast cancer cell line) and cytotoxicity toward normal human dermal fibroblasts (NHDF-Neo) was assessed. Conclusions: The obtained glycoconjugates exhibited higher activity against MCF-7, indicating the selectivity of their action. The development of glycoconjugates based on increased glucose demand and overexpression of its transporters could be an interesting strategy for acquiring anticancer agents, combining innovative chemical solutions with biological complexity. Such an approach may be crucial in the effective fight against cancer diseases. Full article

Double-hydrolyzed collagen, a key structural protein, has gained increasing attention for its role in cancer progression and its potential therapeutic applications. This study aims to investigate the effects of double-hydrolyzed collagen (Type I and III peptides) on HCT116 colon carcinoma cells and CCD-18Co fibroblasts as a normal control. Cells were treated with 0.5 µg/mL, 1 µg/mL, and 1.5 µg/mL of collagen peptide solution. HCT116 and CCD-18Co cells were cultured under standard conditions and treated with 1 µg/mL collagen. Cell viability (MTT assay), migration (scratch assay), oxidative stress (TAS/TOS kits), TNF-α expression (qRT-PCR), and tumor marker levels (CA19-9, CEA, CA72-4, and CYFRA 21-1; CLIA) were evaluated. Cell viability, proliferation, migration, oxidative stress, and tumor marker levels were assessed. Statistical analyses were performed to determine significance. Double-hydrolyzed collagen treatment significantly increased CCD-18Co fibroblast proliferation (p = 0.0143), while HCT116 cancer cell numbers significantly decreased (p = 0.0045). Migration of HCT116 cells was markedly reduced (p < 0.0001), whereas no significant effect was observed in CCD-18Co fibroblasts (p = 0.559). Oxidative stress analysis showed decreased total oxidative status (TOS) and increased total antioxidant status (TAS) in HCT116 cells (p = 0.0075 and p = 0.0095, respectively), with no significant changes in normal fibroblasts. Among tumor markers, CA19-9 levels were significantly reduced in HCT116 cells (p = 0.013), while CEA, CA72-4, and CYFRA 21-1 remained unchanged. TNF-α gene expression analysis confirmed the absence of inflammatory or adverse effects in normal fibroblasts. These findings suggest that double-hydrolyzed collagen selectively inhibits colon cancer cell proliferation and migration, modulates oxidative stress, and reduces CA19-9 levels while promoting fibroblast growth. The differential effects between cancerous and normal cells highlight collagen’s potential as a complementary therapeutic approach for colorectal cancer. Further research is needed to elucidate the underlying mechanisms and assess its clinical applicability. Double-hydrolyzed collagen appears to be a safe and beneficial dietary component with promising biological effects and therapeutic potential. Full article

Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times (e.g., AAAAA or TTTTT). Only recently have mutations in such STR regions been seen in colorectal cancer, where microsatellite instability (MSI) is common. In non-melanoma skin cancer (NMSC), MSI is rare. In this study, we focus on somatic mutations in such homopolymeric regions in NMSC and their functional implications. Methods: We performed targeted DNA sequencing (paired tissue and blood from the same individual), using more than 400 cancer-related genes from 32 NMSC patients as cases and non-lesional skin tissue from 16 independent individuals as controls. Results: We identified NMSC-associated STR somatic mutations. These are associated with the dysregulation of DNA damage and repair mechanisms. In artificial intelligence (AI) predictive modeling, these markers could successfully differentiate basal cell carcinoma (BCC) and non-lesional skin tissue. To our knowledge, we present the first study focusing on STR somatic mutations in multiple cancer-related genes in NMSC found only in tumor tissue and not in non-lesional skin tissue. Some of them (APC, BRAF) are associated with more pronounced dysregulation of relevant gene pathways (hedgehog, Notch signaling, and Wnt signaling). Conclusions: Our findings suggest that this STR somatic mutation status might potentially be used to select BCC patients who could benefit from certain precision therapy including hedgehog inhibitors, gamma-secretase inhibitors, anti-Vasuclar endothelial growth factor (VEGF), proteasome inhibitors, and immune check-point inhibitors. Full article

Disease progression and treatment resistance in colorectal and other cancers are driven by a subset of cells within the tumor that have stem-cell-like properties and long-term tumorigenic potential. These stem-cell-like cells express the leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) and have characteristics similar to tissue-resident stem cells in normal adult tissues such as the colon. Organoid models of murine and human colorectal and other cancers contain LGR5-expressing (LGR5+) stem-cell-like cells and can be used to investigate the underlying mechanisms of cancer development, progression, therapy vulnerability, and resistance. A large biobank of organoids derived from colorectal cancer or adjacent normal tissue was developed. We performed a large-scale unbiased functional screen to identify bispecific antibodies (BsAbs) that preferentially inhibit the growth of colon tumor-derived, as compared to normal tissue-derived, organoids. We identified the most potent BsAb in the screen as petosemtamab, a Biclonics^® BsAb targeting both LGR5 and the epidermal growth factor receptor (EGFR). Petosemtamab employs three distinct mechanisms of action: EGFR ligand blocking, EGFR receptor internalization and degradation in LGR5+ cells, and Fc-mediated activation of the innate immune system by antibody-dependent cellular phagocytosis (ADCP) and enhanced antibody-dependent cellular cytotoxicity (ADCC) (see graphical abstract). Petosemtamab has demonstrated substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). The safety profile is generally favorable, with low rates of skin and gastrointestinal toxicity. Phase 3 trials are ongoing in both first-line programmed death-ligand 1-positive (PD-L1+) and second/third-line r/m HNSCC. Full article

PEIG-1/GPRC5A (phorbol ester induced gene-1/G-protein Coupled Receptor Class C Group 5 Member A) was the first identified member of the orphan G protein-coupled receptor family GPRC5. Deregulation of its expression is associated with the development and progression of various types of tumours, particularly colon carcinoma. In this work, we study the effects of vitamin D (VD, cholecalciferol) and retinoic acid (RA) on GPRC5A mRNA expression in the colorectal cancer cell lines Caco-2 and T84. Both VD (10 µM) and all-trans retinoic acid (ATRA, atRA, RA) (10 µM) increased GPRC5A mRNA levels. Protein kinase C (PKC) inhibition with Gö6983 (10 µM) completely abolished the effects of VD and RA on GPRC5A expression. In parallel, VD and RA increased cytosolic and mitochondrial ROS levels (cROS and mtROS). However, the antioxidants NAC (10 mM) and MitoTEMPO (10 µM) raised GPRC5A gene expression levels in the presence of VD or RA, suggesting that elevated ROS may inhibit GPRC5A expression. In conclusion, both VD and RA stimulate GPRC5A expression. The mechanisms involve a common and essential PKC signalling pathway, as Gö6983 inhibited both VD- and RA-induced signalling. Full article

Today, endoscopy plays a crucial role not only in the detection of precancerous and malignant colorectal lesions, but also in the treatment of even widespread adenomas and T1 early cancers. In addition to classic polypectomy and endoscopic mucosal resection (EMR) using a snare, in recent years, endoscopic submucosal dissection (ESD) has become increasingly important. Marking, submucosal injection, circumferential incision of the mucosa around the lesion, tunneling, and submucosal dissection using a short diathermic knife facilitate the ‘en bloc’ resection of lesions larger than 3 cm, difficult to resect in one piece using a snare. Lesions with high-grade dysplasia or mucosal carcinoma are other good candidates aside from widespread adenomata with a high risk of recurrence after piecemeal resection. ESD allows R0 resection rates of more than 90% in specialized centers. Lesions of 20 cm have been removed ‘en bloc’ by expert endoscopists. ESD provides an optimal histopathologic yield and has a risk of recurrence as low as 3%. Endoscopic full-thickness resection using a special device (eFTRD) is another addition to the resection armamentarium. It is especially suitable for circumscribed lesions up to 2 cm in the middle and upper rectum. Endoscopic intermuscular dissection (EID) is a recent modification of ESD primarily in the rectum, including the inner, circular muscular layer into the resection specimen. In this way, it allows a histopathologic analysis of the entire submucosa beyond the mucosal and upper submucosal layer such as in ESD. This is especially important for T1 cancers invading the submucosa without any other risk factors of invasion. Full article

Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies that could improve outcomes among CRC patients. This case series was conducted to assess the efficacy and safety of regorafenib plus 5-fluorouracil (5-FU) in patients with refractory metastatic CRC (mCRC). Methods: We conducted a retrospective analysis of data from adult patients aged 18 and above who were diagnosed with refractory mCRC and received regorafenib plus 5-FU combination therapy at Houston Methodist Hospital between November 2017 and October 2023. Our study focuses on assessing key outcomes, including Overall Survival [OS], Progression-Free Survival [PFS], and safety. Results: Among the 12 patients we included in this study who underwent regorafenib plus 5-FU combination therapy for refractory mCRC after receiving at least three prior lines of treatment, the best response for six patients (50%) was successfully achieved, with disease control within 7–12 weeks from therapy initiation. Patients had an overall good tolerance for this treatment regimen and reported only the most common adverse events, including Hand-Foot Syndrome (HFS), mucositis, and hypertension (HTN), which were mostly resolved with dose adjustment of medications. Conclusions: This study highlights that using a combination of regorafenib plus 5-FU can be a potential treatment option for patients with refractory mCRC. Additional research, including prospective clinical trials, is required to assess the effectiveness and safety of regorafenib and 5-FU combination therapy in comparison to other currently limited treatment options. Full article

Colorectal cancer (CRC) progression occurs through three stages: adenoma (pre-cancerous lesion), carcinoma in situ (CIS) and adenocarcinoma, with tumor stage playing a pivotal role in the prognosis and treatment outcomes. Despite therapeutic advancements, the lack of stage-specific biomarkers hinders the development of accurate diagnostic tools and effective therapeutic strategies. This study aims to identify stage-specific gene expression profiles and key molecular mechanisms in CRC providing insights into molecular alterations across disease progression. Our methodological approach integrates the use of absolute gene set enrichment analysis (absGSEA) on formalin-fixed paraffin-embedded (FFPE)-derived transcriptomic data, combined with large-scale clinical validation and experimental confirmation. A comparative whole transcriptomic analysis (RNA-seq) was performed on FFPE samples including adenoma (n = 10), carcinoma in situ (CIS) (n = 8) and adenocarcinoma (n = 11) samples. Using absGSEA, we identified significant cellular pathways and putative molecular biomarkers associated with each stage of CRC progression. Key findings were then validated in a large independent CRC patient cohort (n = 1926), with survival analysis conducted from 1336 patients to assess the prognostic relevance of the candidate biomarkers. The key differentially expressed genes were experimentally validated using real-time PCR (RT-qPCR). Pathway analysis revealed that in CIS, apoptotic processes and Wnt signaling pathways were more prominent than in adenoma samples, while in adenocarcinoma, transcriptional co-regulatory mechanisms and protein kinase activity, which are critical for tumor growth and metastasis, were significantly enriched compared to adenoma. Additionally, extracellular matrix organization pathways were significantly enriched in adenocarcinoma compared to CIS. Distinct gene signatures were identified across CRC stages that differentiate between adenoma, CIS and adenocarcinoma. In adenoma, ARRB1, CTBP1 and CTBP2 were overexpressed, suggesting their involvement in early tumorigenesis, whereas in CIS, RPS3A and COL4A5 were overexpressed, suggesting their involvement in the transition from benign to malignant stage. In adenocarcinoma, COL1A2, CEBPZ, MED10 and PAWR were overexpressed, suggesting their involvement in advanced disease progression. Functional analysis confirmed that ARRB1 and CTBP1/2 were associated with early tumor development, while COL1A2 and CEBPZ were involved in extracellular matrix remodeling and transcriptional regulation, respectively. Experimental validation with RT-qPCR confirmed the differential expression of the candidate biomarkers (ARRB1, RPS3A, COL4A5, COL1A2 and MED10) across the three CRC stages reinforcing their potential as stage-specific biomarkers in CRC progression. These findings provide a foundation to distinguish between the CRC stages and for the development of accurate stage-specific diagnostic and prognostic biomarkers, which helps in the development of more effective therapeutic strategies for CRC. Full article

Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320’s absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1. Full article

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic condition marked by persistent intestinal inflammation of unknown etiology. Disease onset involves genetic predisposition and environmental factors that disrupt the intestinal immune homeostasis. The intestinal microbiome and immune response play pivotal roles in disease progression. Advances in molecular therapies and early interventions have reduced surgery rates; however, colorectal cancer (CRC) remains a significant concern, driven by chronic inflammation. In UC, the risk of UC-associated neoplasia (UCAN) increases with disease duration, while CD patients face elevated risks of small intestine, anal fistula, and anal canal cancers. Endoscopic surveillance is advised for UCAN, but optimal screening intervals remain undefined, and no established guidelines exist for CD-associated cancers. UCAN morphology often complicates detection due to its flat, inflammation-blended appearance, which differs pathologically from sporadic CRC (sCRC). UCAN is frequently surrounded by dysplasia, with p53 mutations evident at the dysplasia stage. IBD-associated gastrointestinal cancers exemplify inflammation-driven carcinogenesis with distinct molecular mechanisms from the adenoma-carcinoma sequence. This review explores the epidemiology, risk factors, clinical and pathological features, current surveillance practices, and molecular pathways underlying inflammation-associated cancers in IBD. Full article

Research undertaken over the past few years has brought attention to the role of oxidative stress in the development of neoplasms by damaging nucleic acids, lipids, and proteins, thereby altering their normal function. In general, the levels of antioxidant enzymes are low in patients with neoplasms, and the biomarkers used to quantify oxidative stress have increased levels. Elevated levels of 8-hydroxy-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), as well as decreased levels of antioxidant enzymes, have been observed in patients diagnosed with colorectal cancer (CRC) at various stages of evolution, but further research is needed on the correlation between these biomarkers and disease progression. Inflammation enhances the production of reactive oxygen species and plays an important role in CRC development. Studies in the field of metabolomics have suggested that changes in serum metabolites might be indicators of the progression from adenoma to colorectal carcinoma, particularly those resulting from lipid metabolism. The role of lipidomics in the pathogenesis of CRC warrants further investigation, as these combinations of metabolites (metabolic fingerprints) may have the potential to become clinically useful markers. In this article, we review our current understanding of the interplay between oxidative stress, inflammatory markers and lipidomic products in the pathogenesis of CRC. Full article