Search Results (264)

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Colorectal cancer (CRC) is a major global health concern, with tumor progression closely influenced by inflammatory mechanisms and cytokine signaling. This study investigates the serum expression levels of interleukins IL-8, IL-17A, and IL-33 in patients with colon cancer, analyzing their association with tumor grade and depth of invasion. The cohort included 42 patients stratified by tumor differentiation (G1–G3) and various invasion types. ELISA assays revealed that IL-8 levels were highest in well-differentiated tumors and in cases of submucosal and serosal invasion, suggesting a key role in early stage inflammation and angiogenesis. IL-17A and IL-33 levels declined progressively with tumor dedifferentiation and increased invasion depth, indicating immune suppression in advanced stages. Multiple regression analyses highlighted a nonlinear, significant relationship between IL-8 and IL-17A, whereas IL-33 showed no direct correlation with other interleukins. A combined model incorporating IL-8, IL-17A, IL-33, and tumor grade accounted for over 70% of IL-17A variability, underscoring their interactive role in CRC biology. These findings support the potential utility of interleukins as biomarkers and therapeutic targets for stratified CRC management. Full article

Breast cancer is a leading cause of central nervous system (CNS) metastases in women, often associated with poor prognosis and limited therapeutic options. However, molecular differences between primary tumors and CNS metastases remain underexplored. We aimed to characterize transcriptomic differences between primary breast tumors and matched CNS metastases and identify immune-related biomarkers associated with metastatic progression and patient outcomes. Transcriptomic profiling was based on 11 matched FFPE sample pairs (primary tumor and CNS metastasis). Paired formalin-fixed paraffin-embedded (FFPE) samples from primary tumors (T1) and CNS metastases (T2) were analyzed using the NanoString nCounter^® platform and the PanCancer IO 360™ Gene Expression Panel. Differential gene expression, Z-score transformation, and heatmap visualization were performed in R. In silico survival analyses for overall survival (OS) and recurrence-free survival (RFS) were conducted using publicly available TCGA and GEO datasets. Forty-five genes were significantly differentially expressed between the T1 and T2 samples. Immune-related genes such as CXCL9, IL7R, CD79A, and CTSW showed consistent downregulation in CNS metastases. High expression of CXCL9 and CD79A was associated with improved OS and RFS, whereas high IL7R and CTSW expression correlated with worse outcomes. These findings indicate immune suppression as a hallmark of CNS colonization. Comparative transcriptomic analysis further underscored the distinct molecular landscapes between primary and metastatic tumors. This study highlights transcriptional signatures associated with breast cancer CNS metastases, emphasizing the role of immune modulation in metastatic progression. The identified genes have potential as prognostic biomarkers and therapeutic targets, supporting the need for site-specific molecular profiling in metastatic breast cancer management. Full article

Background/Objectives: The metastatic patterns of apical lymph node (ALN) in rectal and sigmoid colon cancer are currently unclear, and there is no consensus on the indications for dissection of ALN. This study aimed to analyze the impact of ALN metastasis on prognosis, determine the metastatic patterns of ALN and provide evidence for indications of ALN dissection in rectal and sigmoid colon cancer. Methods: In this multicenter, retrospective cohort study, patients from five centers with stage I-III rectal or sigmoid colon cancer who underwent laparoscopic radical surgery with ALN dissection without neoadjuvant treatment from January 2015 to December 2019 were enrolled. Results: Among 2809 patients, the positive rate of ALN was 1.9%. The 5-year overall survival and cancer-specific survival rate for patients with metastatic ALN were 37.5% and 41.0%, respectively. ALN metastasis was the independent risk factor for poor prognosis. Tumor size ≥5 cm (OR = 2.32, 95% CI: 1.30–4.13, p = 0.004), signet ring cell cancer/mucinous adenocarcinoma (vs. poor differentiated adenocarcinoma, OR = 0.19, 95% CI: 0.08–0.45, p < 0.001; vs. moderate to well differentiated adenocarcinoma, OR = 0.22, 95% CI: 0.11–0.42, p < 0.001), T4 stage (OR = 1.93, 95% CI: 1.05–3.55, p = 0.034), N2 stage (OR = 8.86, 95% CI: 4.45–17.65, p < 0.001) and radiologic evidence of extramural venous invasion (OR = 1.88, 95% CI: 1.03–3.42, p = 0.040) were independent risk factors for ALN metastasis. The nomogram model developed by these factors achieved a good predictive performance. Conclusions: This research offered insights into the incidence, risk factors, and prognostic significance of apical lymph node metastasis in cases of rectal and sigmoid colon cancer. Additionally, the study furnished empirical support for the criteria guiding ALN dissection. Furthermore, a pragmatic risk assessment model was developed to predict ALN metastasis. Full article

Background: PTEN is a tumor suppressor that controls many pathophysiological pathways, including cell proliferation, differentiation, apoptosis and invasiveness. Although PTEN down-modulation is a critical event in neoplastic progression, it becomes apparent that transient and local inhibition of PTEN activity might be beneficial for the healing process. Methods: In the present study, we investigated the impact of PTEN invalidation in mouse intestinal epithelium under a physiological condition and after dextran sulfate sodium (DSS) treatment to induce experimental colitis. PTEN conditional knockout was induced in intestinal epithelial cells after crossing villin-Cre and PTEN^flox/flox mice. Results: PTEN invalidation alleviates experimental colitis induced by DSS, as evidenced by decreased weight loss during the acute phase, the lower expression of inflammation markers, including the proinflammatory cytokines IFN-γ, CXCL1 and CXCL2, reduced mucosal lesions, and faster recovery after resolution of inflammation. This protective effect might result in part from the sustained proliferation of colonic epithelium, leading to hyperplasia and increased colonic crypt depth under physiological conditions, which was further exacerbated in the vicinity of mucosal injury induced by DSS treatment. Furthermore, PTEN knockout decreased paracellular permeability, thereby enhancing the intestinal barrier function. This process was associated with the reinforcement of claudin-3 immunostaining, especially on the surface epithelium of villin-Cre PTEN^flox/flox mice. Conclusions: PTEN inactivation exerts a protective effect on the onset of colitis, and the transient and local down-modulation of PTEN might constitute an approach to drive recovery following acute intestinal inflammation. Full article

Bone is a preferred site for disseminated tumor cells, yet the molecular mechanisms that prepare the skeletal microenvironment for metastatic colonization are only beginning to be understood. At the heart of this process are extracellular vesicles (EVs), nano-sized, lipid-encapsulated particles secreted by cancer cells and stromal components. This review consolidates current findings that position EVs as key architects of the bone-metastatic niche. We detail the biogenesis of EVs and their organotropic distribution, focusing on how integrin patterns and bone-specific ligands guide vesicle homing to mineralized tissues. We then outline the sequential establishment of the pre-metastatic niche, driven by EV-mediated processes including fibronectin deposition, stromal cell reprogramming, angiogenesis, neurogenesis, metabolic reconfiguration, and immune modulation, specifically, the expansion of myeloid-derived suppressor cells and impaired lymphocyte function. Within the bone microenvironment, tumor-derived EVs carrying microRNAs and proteins shift the balance toward osteoclastogenesis, inhibit osteoblast differentiation, and disrupt osteocyte signaling. These alterations promote osteolytic destruction or aberrant bone formation depending on tumor type. We also highlight cutting-edge imaging modalities and single-EV omics technologies that resolve EV heterogeneity and identify potential biomarkers detectable in plasma and urine. Finally, we explore therapeutic approaches targeting EVs, such as inhibition of nSMase2 or Rab27A, extracorporeal EV clearance, and delivery of engineered, bone-targeted vesicles, while addressing translational challenges and regulatory considerations. This review offers a roadmap for leveraging EV biology in predicting, preventing, and treating skeletal metastases by integrating advances across basic biology, bioengineering, and translational science. Full article

Recent pan-cancer transcriptome analysis has revealed differential activity of two alternative PHF19 gene promoters in malignant versus non-malignant gut mucosa. One of these promoters upregulated in colon cancer leads to the expression of the PHF19-207 transcript, suggesting its potential role in tumor promotion. The objective of this study was to investigate the function of PHF19-207 using in silico tools and publicly available data, as well as to assess its expression in colon cancer. Expression analyses were conducted via qPCR and RNA sequencing on RNA extracted from the immortalized colonic epithelial cell line HCEC-1CT, as well as a series of colon cancer cell lines cultured in both 2D and 3D environments. The expression of PHF19-207 was found to be elevated in all malignant cell lines compared to the non-malignant HCEC-1CT cell line in both culture conditions, with the most prominent increase observed in cell lines derived from advanced stages of the disease and in the HCEC-1CT cell line overexpressing KRAS. Furthermore, the PHF19-207 transcript was detected in exosomes derived from malignant cells. These findings suggest that PHF19-207 holds potential as a diagnostic biomarker. In addition, in silico analyses indicate that this transcript may function as a long non-coding RNA involved in the regulation of gene expression. Further functional investigations are required to elucidate its precise role in colon carcinogenesis. Full article

STRAP (serine-threonine kinase receptor-associated protein), a WD domain-containing 38.5 kDa protein, was first identified in TGF-ß signaling and participates in scaffold formation in numerous cellular multiprotein complexes. It is involved in the regulation of several oncogenic biological processes, including cell proliferation, apoptosis, migration/invasion, tumor initiation and progression, and metastasis. STRAP upregulation in epithelial tumors regulates several signaling pathways, such as TGF-ß, MEK/ERK, Wnt/β-Catenin, Notch, PI3K, NF-κB, and ASK-1 in human cancers, including colon, breast, lung, osteosarcoma, and neuroblastoma. The upregulation of STRAP expression is correlated with worse survival in colorectal cancer following post-adjuvant therapy. Strap knockout sensitizes colon tumors to chemotherapy, delays APC-induced tumor progression, and reduces cancer cell stemness. The loss of Strap disrupts lineage differentiation, delays neural tube closure, and alters exon skipping, resulting in early embryonic lethality in mice. Collectively, the purpose of this review is to update and describe the diversity of targets functionally interacting with STRAP and to rationalize the involvement of STRAP in a variety of signaling pathways and biological processes. Therefore, these in vitro and in vivo studies provide a proof of concept that lowering STRAP expression in solid tumors decreases tumorigenicity and metastasis, and targeting STRAP provides strong translational potential to develop pre-therapeutic leads. Full article

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms characterized by perivascular epithelioid cell proliferation. They can occur in various organs, but colonic PEComas are exceptionally rare, showing diagnostic challenges due to their nonspecific clinical presentation and similar features to those of other colorectal tumors. We present a case of a 61-year-old female with defecation accompanied by blood clots, initially diagnosed with a suspected tumor in the sigmoid colon. Despite initial biopsy yielding non-informative material, repeat colonoscopy and imaging studies revealed a malignant tumor with multinucleated giant (osteoclast-like) cells and probable p53 mutation, most likely of mesenchymal origin. Robotic surgical resection was performed, and ultimately pathological examination refined the diagnosis as a malignant PEComa of the colon. This case demonstrates the importance of considering PEComa in the differential diagnosis of colonic tumors. Further research is needed to ascertain the clinical behavior and optimal treatment for colonic PEComas. Full article

Orphan nuclear receptor 4A1 (NR4A1, Nur77) plays a crucial role in regulating immune cell metabolism and function within the tumor microenvironment (TME), thus influencing cancer progression and serving as a potential therapeutic target for cancer immunotherapy. A comprehensive review discussing the multifaceted roles of NR4A1 in immune cells and the exploitation of that knowledge for therapeutic development is lacking in the field. This review explores diverse functions of NR4A1 in tumor-associated immune cells, including T cells, monocytes, natural killer cells, B cells, dendritic cells, macrophages, and neutrophils. NR4A1 contributes to immune regulation by impacting cytokine production, cell differentiation, and immune cell exhaustion. We highlight how NR4A1 in immune cells within the TME may be either a positive (e.g., macrophages in colon cancer) or negative prognostic factor (e.g., T cells in melanoma), depending on the cancer and immune cell context. Additionally, this review also highlights potential therapeutic strategies targeting NR4A1, leading to its inhibition, activation, or degradation to restore immune cell function and enhance anti-tumor immunity. Such therapies could potentially improve patient outcomes by altering immune cell behaviors, blocking intrinsic tumor growth pathways, or via both mechanisms. However, the development of NR4A1-targeted therapies will be dependent on further research to better understand lineage-specific roles of NR4A1 and the underlying mechanisms across different cancer types and immune cells. Full article

Background/Objectives: Mesenchymal tumors of the gastrointestinal tract are rare and can pose significant diagnostic challenges, particularly when located in atypical sites such as the sigmoid colon. Gastrointestinal stromal tumors (GISTs) are often the primary consideration based on imaging findings; however, other spindle cell neoplasms, such as schwannomas, must also be considered. We present a case of a sigmoid colon schwannoma initially suspected to be a GIST and provide a literature review on the diagnostic and therapeutic challenges associated with these tumors. Methods: A literature review based on articles from 2015 to 2024 was conducted to identify cases of mesenchymal tumors of the colon misdiagnosed as GISTs. The review focused on the role of imaging, endoscopic biopsy, and immunohistochemistry in differentiating these neoplasms. Additionally, treatment approaches, including surgical resection versus targeted therapy, were assessed. Results: The literature review revealed that GISTs and schwannomas share overlapping imaging characteristics, including submucosal location, hyperintensity on T2-weighted MRI, and contrast enhancement. However, immunohistochemical markers remain the gold standard for differentiation. Studies also highlighted the increasing role of minimally invasive diagnostic techniques, such as fine-needle aspiration and molecular profiling, in achieving a definitive preoperative diagnosis. Unlike GISTs, which often require adjuvant therapy with tyrosine kinase inhibitors, schwannomas are typically treated with surgical excision alone, with a low risk of recurrence. Conclusions: Current evidence supports a multimodal diagnostic approach combining imaging, biopsy, and immunohistochemistry to accurately classify mesenchymal tumors of the colon. While imaging can suggest a probable diagnosis, histopathological confirmation is essential before initiating targeted therapy. Full article

A recent comprehensive pan-cancer study indicated the high translational potential of the transcript PHF19-207 as a biomarker for colon cancer. This study aimed to analyze the expression of PHF19-207 in colon tissue samples from two different settings to evaluate its clinical utility for diagnosis and screening. Surgical samples of colon tumor and non-tumor tissue were analyzed to determine the diagnostic value of PHF19-207 and its potential correlation with tumor characteristics. Additionally, biopsied samples from individuals undergoing national colorectal cancer screening were examined to assess the potential use of PHF19-207 in early detection. PHF19-207 expression levels were measured in all samples using Real-Time Polymerase Chain Reaction. A statistically significant difference was observed between tumor and non-tumor tissue (p = 0.002) and between tumor tissue and healthy mucosa samples (p < 0.001). Furthermore, polyp samples exhibited significantly higher PHF19-207 expression compared to healthy mucosa (p = 0.035). Receiver operating characteristic (ROC) analysis indicated that PHF19-207 can effectively differentiate malignant from healthy tissue, with an AUC value of 0.9044. Considering the increasing incidence of colorectal cancer in younger populations and the need for improved early detection, PHF19-207 expression could be explored as the basis for a relatively simple and efficient test, enabling a more comprehensive and affordable screening strategy. Full article

Background: Colorectal cancer (CRC) is a term that refers to the combination of colon and rectal cancer as they are being treated as a single tumor. In CRC, 72% of tumors are colon cancer, while the other 28% represent rectal cancer. CRC is a multifactorial disease caused by both genetic and epigenetic changes in the colon mucosal cells, affecting the oncogenes, DNA repair genes, and tumor suppressor genes. Currently, two DNA methylation-based biomarkers for CRC have received FDA approval: SEPT9, used in blood-based screening tests, and a combination of NDRG4 and BMP3 for stool-based tests. Although DNA methylation biomarkers have been explored in colorectal cancer (CRC), the identification of robust and clinically valuable biomarkers remains a challenge, particularly for early-stage detection and precancerous lesions. Patients often receive diagnoses at the locally advanced stage, which limits the potential utility of current biomarkers in clinical settings. Methods: The datasets used in this study were retrieved from the GEO database, specifically GSE75548 and GSE75546 for rectal cancer and GSE50760 and GSE101764 for colon cancer, summing up to a total of 130 paired samples. These datasets represent expression profiling by array, methylation profiling by genome tiling array, and expression profiling by high-throughput sequencing and include rectal and colon cancer samples paired with adjacent normal tissue samples. Differential analysis was used to identify differentially methylated CPG sites (DMCs) and identify differentially expressed genes (DEGs). Results: From the integration of DMCs with DEGs in colorectal cancer, we identified 150 candidates for methylation-regulated genes (MRGs) with two genes common across all cohorts (GNG7 and PDX1) highlighted as candidate biomarkers in CRC. The functional enrichment analysis and protein–protein interactions (PPIs) identified relevant pathways involved in CRC, including the Wnt signaling pathway, extracellular matrix (ECM) organization, among other enriched pathways. Conclusions: Our findings show the strength of our in silco computational approach in jointly identifying methylation-regulated biomarkers for colon cancer and highlight several genes and pathways as biomarker candidates for further investigations. 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

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with limited treatment options for advanced disease stages. Growing evidence implicates the gut microbiota in CRC pathogenesis, prompting interest in probiotics as a potential therapeutic strategy. In this study, we evaluated the effects of two probiotic compositions, CI (a mix of lactobacilli and bifidobacteria) and CII (bifidobacteria alone), in two murine CRC models: the orthotopic MC-38 cecum injection model and the inflammation-driven azoxymethane/dextran sodium sulfate (AOM/DSS) model. CI showed significant anti-tumor effects in the orthotopic model, reducing tumor weight and volume, which was, however, not associated with robust immune activation, suggesting microbiota-driven mechanisms. In contrast, CII was more effective in the AOM/DSS model, reducing colonic inflammation and completely preventing tumor development. Our study demonstrates that probiotics might have great therapeutic potential via modulation of the gut microbiota, and they can exert anti-tumor effects in murine models of CRC with distinct compositions showing differential efficacy depending on the model. CI stabilized the gut microbiome and inhibited pro-tumorigenic taxa in the MC-38 cecum injection model, while CII exhibited anti-inflammatory properties in the AOM/DSS model, highlighting the potential of probiotics as context-specific interventions for CRC. These findings contribute to the growing body of evidence supporting microbiota-targeted strategies in oncology and their relevance for therapeutic applications. Full article