Search Results (15,184)

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights. Full article

The absent decline in cancer mortality rates is primarily due to moderate therapeutic efficacy and intrinsic or acquired tumor cell resistance toward treatments. Combining different oncology treatments increases therapy success and decreases the chance of refractory tumor cells. Therefore, combination cancer treatments are the principal paradigm of 21st-century oncology. Physical modalities such as radiotherapy have a long-standing tradition in such combination treatments. In the last decade, another physical principle emerged as a promising anticancer agent: cold gas plasma. This partially ionized gas, operated at about body temperature, emits multiple bioactive components, including reactive oxygen and nitrogen species (ROS/RNS). This technology’s multi-ROS/RNS nature cannot be phenocopied by other means, and it capitalizes on the vulnerability of tumor cells within metabolic and redox signaling pathways. Many cancer models exposed to mono or combination gas plasma treatments have shown favorable results, and first cancer patients have benefited from cold gas plasma therapy. The main findings and proposed mechanisms of action are summarized. Considering the specific application modes, this review identifies promising gas plasma combination therapies within guideline-directed treatment schemes for several tumor entities. In conclusion, gas plasmas may become a potential (neo)adjuvant therapy to existing treatment modalities to help improve the efficacy of oncological treatments. Full article

Background: Lung cancer is a prevalent malignancy globally, with non-small cell lung cancer (NSCLC) accounting for 80–85% of cases. Solalyraine A1 (SA1) is a steroidal glycoalkaloid derived from Solanum lyratum. However, the effect and mechanism of SA1 on NSCLC remain unclear. Methods: The exosomes from SA1-treated A549 cells were prepared and administered to A549 xenograft mice. Proteomics analysis of SA1-treated A549 cells and their exosomes was conducted to assess the mechanism. Bioinformatics analysis was utilized to identify differentially expressed proteins (DEPs) and key signaling pathways. Western blot analysis confirmed the expression of potential targets. Results: SA1 effectively suppressed tumor growth in A549 xenografts, demonstrating a remarkable inhibition rate of 70.48%. A total of 1154 DEPs were identified in A549 cells, primarily associated with the ribosome pathway. Additionally, 746 DEPs were identified in exosomes, mainly involved in the spliceosome pathway. Five highly regulated DEPs were selected for verification. SA1 was found to suppress MUC5B and elevate APOB expression in A549 cells, while inhibiting MFGM, ANGL4 and increasing GCN1 expression in exosomes. Conclusions: This study demonstrates that SA1 exhibits anti-NSCLC effects by regulating exosome function and related protein expression, providing novel insights for NSCLC treatment. Full article

Human Papillomavirus (HPV), particularly high-risk strains such as HPV16 and HPV18, is a leading cause of cervical cancer and a significant risk factor for several other epithelial malignancies. While the oncogenic mechanisms of viral proteins E6 and E7 are well characterized, the broader effects of HPV infection on host transcriptional regulation remain less clearly defined. This study explores the hypothesis that conserved genomic motifs within the HPV genome may act as molecular decoys, sequestering human transcription factors (TFs) and thereby disrupting normal gene regulation in host cells. Such interactions could contribute to oncogenesis by altering the transcriptional landscape and promoting malignant transformation.We conducted a computational analysis of the genomes of high-risk HPV types using MEME-ChIP for de novo motif discovery, followed by Tomtom for identifying matching human TFs. Protein–protein interactions among the predicted TFs were examined using STRING, and biological pathway enrichment was performed with Enrichr. The analysis identified conserved viral motifs with the potential to interact with host transcription factors (TFs), notably those from the FOX, HOX, and NFAT families, as well as various zinc finger proteins. Among these, SMARCA1, DUX4, and CDX1 were not previously associated with HPV-driven cell transformation. Pathway enrichment analysis revealed involvement in several key biological processes, including modulation of Wnt signaling pathways, transcriptional misregulation associated with cancer, and chromatin remodeling. These findings highlight the multifaceted strategies by which HPV may influence host cellular functions and contribute to pathogenesis. In this context, the study underscores the power of in silico approaches for elucidating viral–host interactions and reveals promising therapeutic targets in computationally predicted regulatory network changes. Full article

Prostate cancer (PCa) progression is shaped by the tumour microenvironment, where hypoxia promotes aggressiveness and contributes to therapy resistance. Extracellular vesicles (EVs), secreted under hypoxia, can deliver modified bioactive cargo that reprograms recipient cells. This study examined whether EVs from hypoxia-conditioned metastatic PCa cells enhance malignant traits in cancerous and non-tumorigenic prostate cell lines via Wnt signalling and epithelial–mesenchymal transition (EMT). EVs from PC3 cells cultured under hypoxia (1% O₂) or normoxia (21% O₂) as control were applied to LNCaP (low metastatic potential) and PNT2 (non-tumorigenic) cells. PC3 hypoxia-derived EVs increased HIF-1α, upregulated mesenchymal markers (Vimentin, N-cadherin) and Wnt-related genes (Wnt3A, Wnt5A, Fzd7), and suppressed the epithelial marker E-cadherin. Functional assessment showed that LNCaP cells treated with PC3 hypoxia EVs showed greater motility and invasiveness, and PNT2 cells displayed transcriptomic reprogramming. These findings show that hypoxia-driven EVs can propagate pro-metastatic signalling in less aggressive and normal prostate cells. The findings highlight EVs as a potential therapeutic target in PCa progression. Full article

Background/Objectives: Multiple myeloma (MM) is the second most common hematological malignancy and remains incurable because of its complex and heterogeneous pathogenesis. UNC13B (unc-13 homolog B) encodes Munc13-2, a presynaptic protein that is involved in vesicle exocytosis. While its role has been explored in neurological diseases, its function in cancer biology remains largely uncharacterized. This study aimed to elucidate the role of UNC13B in regulating MM cell proliferation and apoptosis. Methods:UNC13B mRNA expression was assessed across human MM cell lines. ARD cells, which exhibited the highest UNC13B expression, were transduced with a UNC13B-specific shRNA via a lentiviral vector. Cell proliferation, apoptosis, and expression of associated proteins were evaluated by means of the Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and Western blot analysis. Results: UNC13B was significantly upregulated in MM cell lines. The knockdown of UNC13B in ARD cells markedly inhibited cell proliferation and induced apoptosis. These changes were accompanied by the downregulation of proliferation-related proteins and upregulation of pro-apoptotic markers. Western blot analysis suggests that UNC13B may exert its effects by modulating key regulatory proteins, including PINK1, CDK2, AKR7A3, and Bim. Conclusions: Our findings suggest that UNC13B supports MM cell survival and proliferation, potentially through the regulation of oncogenic and apoptotic signaling pathways. UNC13B may represent a novel therapeutic target in multiple myeloma. Full article

Background: Prostate cancer (PCa) is the primary contributor to male cancer-related mortality and currently lacks effective treatment options. The Modified Guizhi Fuling Decoction (MGFD) is used in clinical practice to treat multiple tumors. This research focused on the mechanisms of action (MOA) in MGFD that inhibit PCa. Methods: The impact of MGFD on PCa cells (PC3 and DU145) was examined via Cell Counting Kit-8, wound healing assays, and transwell assays. To determine the MOA, high-throughput sequencing based high-throughput screening (HTS²) was utilized along with network pharmacology. Results: The findings indicated that MGFD suppressed the proliferation, migration, and invasion of PCa cells. We then utilized the HTS² assay to generate 270 gene expression profiles from PCa cells perturbed by MGFD. Large-scale transcriptional analysis highlighted three pathways closely associated with PCa: the TNF signaling pathway, cellular senescence, and FoxO signaling pathway. Through the combination of network pharmacology and bioinformatics, we discovered four primary targets through which MGFD acts on PCa: AKT serine/threonine kinase 1 (AKT1), Caspase-8 (CASP8), Cyclin-Dependent Kinase 1 (CDK1), and Cyclin D1 (CCND1). Finally, molecular docking demonstrated that the potential bioactive compounds baicalein, quercetin, and 5-[[5-(4-methoxyphenyl)-2-furyl] methylene] barbituric acid strongly bind to CDK1, AKT1, and CASP8, respectively. Conclusions: This research shows that MGFD displays encouraging anticancer effects via various mechanisms. Its multi-target activity profile underscores its promise as a potential therapeutic option for PCa treatment and encourages additional in vivo validation studies. Full article

The gut microbiota plays a critical role in maintaining gastrointestinal homeostasis, immune regulation, and metabolic processes. Recent evidence has highlighted its significant influence on gastric carcinogenesis. Helicobacter pylori, a well-established class I carcinogen, remains the most prominent microbial risk factor for gastric cancer. However, emerging studies indicate that alterations in the broader gastric and intestinal microbial communities, referred to as dysbiosis, may also contribute to tumor initiation, progression, and immune evasion. These microbial shifts can lead to chronic inflammation, genotoxic metabolite production, and modulation of signaling pathways such as NF-κB and Wnt/β-catenin. This review explores the current understanding of the gut microbiome’s contribution to gastric cancer pathogenesis, including microbial signatures associated with precancerous lesions and the tumor microenvironment. Furthermore, the potential of microbiota-based biomarkers and therapeutic interventions, including probiotics, prebiotics, and fecal microbiota transplantation, is discussed as part of emerging precision medicine strategies. Full article

Hepatocellular carcinoma (HCC) is a malignancy that is notorious for its dismal prognosis. Dysregulation of the tumor microenvironment (TME) in HCC has emerged as a key hallmark in determining disease progression and the response to immunotherapy. The aim of this study was to identify novel TME regulators that contribute to therapeutic resistance, thus providing mechanistic insights for targeted interventions. The expression of SMIM25 was evaluated in the the Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC) and Guangxi HCC cohorts, and its clinicopathological significance was assessed. RNA sequencing and bioinformatics analyses were performed to elucidate the potential impact of elevated SMIM25 levels. Immunohistochemistry (IHC) and single-cell mass cytometry (CyTOF) were employed to examine the cellular composition of the tumor microenvironment. The biological effects of SMIM25 on cell proliferation and migration were studied in vitro using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide(MTT) and wound healing assays, while its impact on tumor growth was evaluated in vivo in a nude mouse model. Transcriptomic and single-cell proteomic analyses were integrated to explore the mechanism by which SMIM25 affects the progression of HCC. The expression of SMIM25 was significantly up-regulated in both HCC tissues and cell lines (p < 0.05). RNA sequencing analyses revealed a significant positive correlation between SMIM25 expression and immunosuppression, and between SMIM25 expression and extracellular matrix(ECM)-related molecular features. Single-cell mass cytometry revealed two immunosuppressive cell clusters that were enriched in HCC patients with high SMIM25 expression. Moreover, SMIM25 was associated with immune exclusion and ECM remodeling signals in the TME of HCC. SMIM25 overexpression was associated with the expression of the tumor inflammatory marker cyclooxygenase-2(COX-2), and a COX-2 inhibitor could partially reverse the biological phenotype associated with SMIM25 expression in HCC cells (p < 0.05). Further transcriptome analysis in immunotherapy cohorts suggested the SMIM25-COX-2 axis might have predictive value for the response to immunotherapy. Our results suggest that SMIM25 may serve as a biomarker for the prognosis of HCC patients and may also be a predictive biomarker for the response to immunotherapy, enabling more precise and personalized HCC treatment. Full article

Breast cancer remains a formidable global health challenge, with triple-negative breast cancer (TNBC) posing unique clinical complexities. Characterized by its aggressive nature and limited number of specific therapeutic targets, this breast cancer subtype disproportionately affects African American women, highlighting critical disparities in care. The tumor immune microenvironment (TIME) plays a critical role in breast cancer development and response to immunotherapy, and it is essential in fostering an immunosuppressive and pro-inflammatory niche. Inflammation, primarily mediated by the NF-κB signaling pathway and chemokine signaling, particularly involving CCL2, plays a pivotal role in TNBC progression and therapy resistance. This review describes some of the molecular mechanisms of polyphenols, which are naturally occurring compounds abundant in various dietary sources, and their potential use as therapeutic agents in the management of TNBC. Polyphenolic compounds have been described as modulating the TIME through the inhibition of tumor progression, immune evasion, and therapy resistance, due to their diverse bioactivities, including anti-inflammatory, antioxidant, and anticancer properties, making them attractive candidates for combating the aggressiveness of TNBC and addressing treatment disparities. Polyphenols, such as curcumin, gossypol, butein, epigallocatechin gallate, cardamonin, and resveratrol, have demonstrated efficacy in modulating several signaling pathways within the TIME, which are implicated in the progression of TNBC. This review highlights the potential effects of polyphenols on inflammatory cytokine release, programmed cell death ligand 1 (PD-L1) expression, which is associated with immune evasion by the host cell, and various intracellular signaling cascades, demonstrating their potential use in personalized therapeutic interventions for TNBC. This study also describes differential responses of TNBC cell lines to polyphenol treatment, highlighting the importance of considering genetic variability in therapeutic strategies, as well as the importance of the interaction of polyphenols with the gut microbiome, which may establish the bioavailability and effectiveness of these compounds toward therapeutic outcomes. Further preclinical and clinical studies are warranted to fully elucidate the therapeutic potential of polyphenols and translate these findings into clinical practice, thereby improving outcomes for patients with TNBC worldwide. Full article

Background: The outgrowth of castration-resistant prostate cancer (CRPC) dictates patient morbidity and mortality. Recurrence of prostate cancer (PC) following androgen-deprivation therapy (ADT) often occurs due to constitutively active androgen receptor (AR) splice variants (AR-Vs), primarily AR-V7. Therefore, safe and effective therapies enabling the suppression of both full-length AR (AR-FL) and AR-Vs are urgently needed. The natural compound dimethyl sulfoxide (DMSO) has negligible cytotoxicity at concentrations below 5% and has anticancer potential. DMSO has been broadly used in biomedical research as a solvent for pharmaceuticals, as a cryoprotectant for cells, and as a topical treatment to suppress pain and inflammation. We investigated the effect of low-dose DMSO on AR expression, cell viability, and metastatic ability in PC cell lines expressing both AR-FL and AR-V7 (e.g., 22Rv1) and those expressing only AR-FL (e.g., C4-2B). Methods: MTT cell viability assays were performed to measure DMSO-induced cytotoxicity. Wound-healing assays were conducted to monitor the effect of DMSO on the migratory phenotype of cancer cells. Western blot analyses were performed to study the efficacy of DMSO in suppressing the protein levels of AR-FL and AR-V7, and expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) was measured as a possible mechanism. Results: At concentrations of 0.1–1% (v/v), DMSO treatment showed minimal cytotoxicity, whereas the highest concentration used (2.5%) showed approximately 20% cytotoxicity at 96 h. Interestingly, however, DMSO treatment at concentrations of 1.0 and 2.5% significantly inhibited the migration of PC cells. Treatment with DMSO led to a dose-dependent inhibition of both AR-FL and AR-V7. Notably, in 22Rv1 cells, DMSO potently downregulated the expression of hnRNPH1, a splicing factor often associated with AR expression and signaling. Conclusions: Our findings suggest that low concentrations of DMSO may have potential as an effective anticancer agent, both at the initial and later stages when PC cells become castration resistant. Full article

Lung cancer is responsible for high morbidity and mortality worldwide. In general, lung cancer can be divided into two major types, including small cell lung carcinoma (SCLC) and the more common non-small cell lung carcinoma (NSCLC). Molecular events underlying lung cancer development, growth, and progression remain complex. In addition to a variety of genetic aberrations, alterations in cellular metabolism have been implicated. Epidermal growth factor receptor (EGFR) is a cell surface protein that is frequently mutated in NSCLC. In this review, we discuss the effects of EGFR mutants on cell proliferative and survival signals, as well as metabolic reprogramming, in NSCLC. We also discuss the use and mechanisms of action of tyrosine kinase inhibitors (TKIs) that target EGFR-mutants and mediate their inhibitory effects by inducing cell death. Development of resistance to EGFR-TKIs is a problem in the clinic. We further discuss the approaches that are used to overcome this resistance, including the development of fourth-generation EGFR-TKIs. Immunotherapy is not very effective in EGFR-mutant NSCLC. We also discuss possible underlying mechanisms for the inadequate response of EGFR-mutant tumors to immunotherapeutics. Given that mutant EGFR transduces survival signals, and affects cellular metabolism, a better understanding of the crosstalk between mutant EGFR-mediated signals and metabolic reprogramming is expected to facilitate the development of newer personalized therapeutics to manage lung cancer. Full article

HER2-positive breast cancer represents a biologically aggressive subtype associate with poor prognosis, despite advances in targeted therapies. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), initially approved for hormone-receptor-positive, HER2-negative disease, are now being explored in HER2-positive settings due to their mechanistic synergy with the HER2 signaling pathway. This review synthesizes evolving clinical evidence from trials and highlights further research into biomarker discovery. CDK4/6i may redefine treatment paradigms in HER2-positive breast cancer, offering a potential, non-chemotherapy option with durable benefit in select patient populations. Full article

Background: It is established that depression significantly contributes to tumor development, yet its molecular link to gastric cancer progression remains unclear. Methods: In this study, we examined depression-related gene expression profiles in relation to clinical prognosis and identified estradiol and the NOTCH3 gene as critical factors involved in gastric cancer progression in the context of depression. Using a chronic unpredictable stress-induced tumor-bearing mouse model, we validated the impact of depression on tumor development. Additionally, the underlying molecular mechanisms were explored through a range of biological techniques, including Western blotting, immunofluorescence, flow cytometry and immunohistochemistry. Results: Depression significantly accelerated gastric cancer growth in our mouse model, characterized by decreased estradiol levels and increased NOTCH3 expression. Importantly, exogenous estradiol supplementation effectively counteracted depression-induced tumor growth. Consistently, in vitro studies showed that estradiol treatment suppressed NOTCH3 expression in HGC-27 and YTN3 cell lines. Furthermore, NOTCH3 was shown to modulate intracellular reactive oxygen species levels by regulating SOD2 activity, thereby influencing cell proliferation. Conclusions: This work identified the estrogen/NOTCH3 signaling as a key link between depression and gastric cancer development, offering promising therapeutic strategies to improve outcomes for patients suffering from psychological disorders. Full article