Medical Oncology最新文献

Breast cancer is the most commonly diagnosed malignancy among women worldwide. Triple-negative breast cancer (TNBC), a particularly aggressive subtype, is unresponsive to endocrine and targeted therapies. It is characterized by high rates of invasion and recurrence, a poor prognosis, and limited treatment options. Resveratrol, a natural polyphenolic compound, possesses well-documented anticancer properties. Given the differential sensitivity of the MDA-MB-231 (TNBC) and MCF-7 (luminal) cell lines to resveratrol, we treated these cells with resveratrol and performed RNA sequencing followed by RT-qPCR validation. Our analysis revealed significantly elevated expression of ECSCR (Endothelial Cell Surface Expressed Chemotaxis and Apoptosis Regulator) in resveratrol-treated MDA-MB-231 cells compared to controls, whereas no significant change was observed in MCF-7 cells. Although the role of ECSCR in breast cancer remains poorly characterized, we investigated its functional significance by establishing lentiviral-mediated ECSCR overexpression in breast cancer cells. In vitro, ECSCR overexpression suppressed cellular proliferation and migration while promoting apoptosis. Consistently, in vivo experiments demonstrated a reduced tumorigenic capacity of ECSCR-overexpressing cells. Collectively, our findings indicate that ECSCR exerts tumor-suppressive effects by inhibiting proliferation and migration, inducing apoptosis, and suppressing tumorigenesis. Notably, the growth-inhibitory effects of resveratrol on TNBC may be mediated through the upregulation of ECSCR. These results identify ECSCR as a promising therapeutic target for breast cancer intervention strategies.

We formulated a micellar nanosystem for selective differentiation therapy of breast cancer stem cells (BCSCs). Hyaluronic acid (HA) coating was used to target CD44⁺ BCSCs, while codelivery of all-trans retinoic acid (ATRA) and histone deacetylase inhibitor (HDACi) was used to revert epigenetic silencing of the RARβ gene, sensitizing resistant tumor cells to treatment. Nanomicelles were formulated using the thin‑film hydration (TFH) method. The anti-cancer effects of nanoparticles (NPs) were evaluated on MDA-MB-231, MDA-MB-468, MCF-7 and MCF10-A cell lines with different stemness properties. The size of the NPs HA-PF127@ATRA, HA-PF127@SB and HA-PF127@ATRA@SB were determined to be 32.02 nm, 47.46 nm and 52.10 nm, respectively. HA-PF127@ATRA@SB NPs mitigated ATRA resistance in MDA-MB-231 cells, significantly inhibited migration, promoted maximum spheroid size reduction, and achieved lower IC₅₀ values compared to the blank drugs. Importantly, it reduced stemness markers ALDH1A1, CD24 and restored retinoic acid receptor beta (RARβ) gene expression in MDA-MB-231 cells, whereas opposite trends were observed in MDA‑MB‑468 and MCF‑7 cells. Finally, nanomicell therapy favored the induction of late apoptosis in MDA-MB-231 cells, while most of the MDA-MB-468 and MCF-7 cells were in the early apoptosis phase. The nanomicelles demonstrate favorable physicochemical characteristics, and elicit maximum and tumor-specific anti-cancer effects based on differentiation therapy upon BCSC-enriched tumors.

Lung cancer is among the most prevalent types of cancer globally and in Türkiye. Basically, lung cancer is divided into 2 different types, of which non-small cell lung cancer (NSCLC) accounts for about 85% of cases. With the elucidation of the mechanism of NSCLC, there is an urgent need to identify effective non-toxic drugs and new target biomarkers. Therefore, an immediate need exists to clarify the mechanism of NSCLC and identify effective, nontoxic drugs and novel target biomarkers. In this study, we aimed to determine intracellular lipid level changes caused by N-Oleoylethanolamine (NOE) and N-Oleoylethanolamine Solid Lipid Nanoparticle (NOESLN) formulations in test cell lines determined by mass spectrometry LC-MS/MS lipidomic analysis. Lipid level changes induced by N-Oleoylethanolamine (NOE) and N-Oleoylethanolamine Solid Lipid Nanoparticle (NOESLN) formulations in test cell lines have been determined by mass spectrometry LC-MS/MS lipidomics analysis. The particle size of the nanoparticle formulation was found to be 100 times smaller compared to the NOE particle size. According to MTT results, IC₅₀ values obtained in Beas-2B and A549 cells treated with NOE were higher than those treated with NOESLN. It was found that an raise in intracellular ceramide concentrations due to ceramidase inhibition can cause apoptotic death of cancer cells in A549 cells induced by N-Oleoylethanolamine (NOE), a unique inhibitor of ceramidase enzymes, and a newly synthesized solid lipid nanoform. This study demonstrates that NOE-loaded solid lipid nanoparticles (NOESLN) significantly enhance cytotoxic effects in NSCLC cells by inducing intracellular ceramide accumulation, suggesting their potential as effective and novel therapeutic agents for lung cancer treatment.

Chordoma resection is challenging due to proximity to the brainstem or spinal cord, and chemotherapy offers limited efficacy. Combining surgery with radiotherapy, particularly using carbon ions (C-ions) for their higher biological effectiveness, improves local control and survival rates. To investigate cellular mechanisms, two human sacral chordoma cell lines were irradiated with varying C-ions doses. Growth, cell cycle, DNA damage response, and protein phosphorylation were analyzed using flow cytometry, protein, and gene expression profiling. The potential of combining treatment with the ALK/MET inhibitor crizotinib to enhance radiosensitivity was also evaluated. C-ions irradiation resulted in a slight dose-dependent decrease in proliferation, a clear G₂/M cell cycle arrest, and a significant activation of key regulators involved in DNA repair and damage response. The ALK/MET inhibitor crizotinib, considered a potential treatment for chordomas, reduced proliferation markers and modulated important genes related to DNA repair and cell cycle regulation, with CDC20 and FOXO4 being particularly significant. The phosphorylation of key regulators involved in DNA repair and damage prevention, as well as MAPKs activated by C-ions irradiation, was partially inhibited by the combination treatment with crizotinib. While crizotinib shows promise as a therapeutic agent for sacral chordomas, its capacity to enhance radiosensitivity appears limited.

Osteosarcoma (OS) is the most prevalent and aggressive primary malignant bone tumor, characterized by early metastasis and a poor prognosis, particularly in patients resistant to conventional multimodal therapies. As survival rates have plateaued, identifying novel therapeutic vulnerabilities is imperative. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, offers a distinct mechanism to overcome drug resistance in OS cells, which frequently exhibit metabolic dependency on iron. This review comprehensively elucidates the regulatory networks of ferroptosis in OS, with a specific focus on the System Xc^-/Glutathione Peroxidase 4 (GPX4) antioxidant axis and lipid metabolism. Beyond direct cytotoxicity, we critically examine the synergistic interplay between ferroptosis and the tumor immune microenvironment (TME). Ferroptosis induction triggers immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs), which promotes dendritic cell maturation and enhances CD8⁺ T cell cytotoxicity. Furthermore, we discuss the mechanistic crosstalk by which ferroptosis remodels the immunosuppressive landscape, specifically affecting the polarization of tumor-associated macrophages (TAMs) and the stability of regulatory T cells (Tregs). Finally, the review addresses critical challenges for clinical translation, including tumor heterogeneity, safety concerns regarding off-target toxicity, and the urgent need for predictive biomarkers and advanced nanodelivery systems. This integrated perspective highlights ferroptosis-based combination immunotherapy as a promising frontier for personalized medicine in osteosarcoma.

KMT2A (MLL1) is an epigenetic enzyme that activates genes via the addition of histone H3 at lysine 4 (H3K4). As a principal component of the COMPASS (complex of proteins associated with Set1), KMT2A coordinates the transcription of key developmental and lineage-specific genes, thereby shaping cellular plasticity, differentiation, and self-renewal. It is critical for regulating the balance between stem cell renewal and differentiation in both physiological and pathological aspects. Abnormal regulation or chromosomal translocations involving KMT2A are frequently implicated in hematologic malignancies and developmental disorders. In leukemias and other cancers, KMT2A fusion proteins disrupt regular transcriptional programs, creating a tumor-permissive epigenetic environment that supports stem-like properties, therapy resistance, and relapse. In addition to its canonical catalytic role, KMT2A influences chromatin remodeling, enhancer-promoter communication, and transcriptional memory, all of which are crucial for maintaining stemness and enabling cancer cell reprogramming. Given its multifaceted role in cancer and stem cell biology, KMT2A is a promising therapeutic target, and inhibitors that disrupt its interactions, enzymatic activity, or fusion pathways are showing encouraging results. Moreover, current clinical trials investigating venetoclax and menin inhibitors offer renewed hope for curative therapies. This review summarizes the current understanding of the transcriptional mechanisms and noncatalytic roles of KMT2A and the translational implications of targeting KMT2A-driven pathways in stemness and cancer, paving the way for advanced therapeutic intervention.

Non-small cell lung cancer (NSCLC) presents significant therapeutic challenges due to resistance and immune evasion. Dihydroartemisinin (DHA), a derivative of artemisinin, exhibits broad anti-tumor activity, but its molecular targets and mechanisms in NSCLC remain unclear. To identify the core therapeutic targets and elucidate the mechanism of action of DHA against NSCLC using an integrated computational and bioinformatics approach. Potential DHA targets were predicted using PharmMapper, SEA, SwissTargetPrediction, SuperPred, and TargetNet. NSCLC-associated targets were retrieved from OMIM, GeneCards, and CTD. Transcriptomic datasets (GSE101929, GSE118370, GSE116959, GSE159857) were integrated and analyzed for differential expression (limma) and co-expression networks (WGCNA). KEGG pathway enrichment identified key pathways. Protein-protein interaction networks, machine learning (Lasso regression, Random Forest), nomogram construction, immune infiltration analysis (ssGSEA), miRNA-mRNA network analysis (miRTarBase), and molecular docking (CB-Dock2) were performed to identify and validate core targets. We identified 1277 potential DHA targets and 44 consensus NSCLC targets. Integration of DEGs (1240 genes) and WGCNA modules (3 key modules, 2860 genes) yielded 1128 overlapping genes. KEGG enrichment revealed 15 key pathways. Machine learning on 196 pathway-enriched DHA targets identified 12 candidate genes. Validation confirmed 6 core targets: AR, CASP3, CDK1, CDK4, PTK2, MMP9. A nomogram based on the 12 targets showed excellent predictive power (AUC = 0.987). Immune profiling revealed significant alterations in 21 immune cell types in NSCLC, and correlation analysis linked core targets (e.g., CDK1/CDK4 with T cell subsets, MMP9 with myeloid cells) to immune dysregulation. Molecular docking confirmed strong binding affinities between DHA and all 6 core targets, with CDK1 exhibiting the highest affinity (- 8.8 kcal/mol). miRNA networks identified key regulators like hsa-miR-15b-5p and hsa-miR-302a-3p. This study delineates AR, CASP3, CDK1, CDK4, PTK2, and MMP9 as core therapeutic targets of DHA in NSCLC. DHA exerts its anti-NSCLC effects through direct inhibition of these targets (particularly high-affinity binding to CDK1) and modulation of the tumor immune microenvironment, including T-cell memory, cytotoxic function, myeloid-mediated remodeling, and immunosuppressive cell subsets. These findings provide a mechanistic foundation for developing DHA as a therapeutic agent or adjuvant for NSCLC, especially in combination with immunotherapy.

Lipids, as core membrane components, energy stores, and signaling molecules, are indispensable for homeostasis; their dysregulation drives obesity, type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Lipid droplets (LDs), originating from the endoplasmic reticulum, are phospholipid-monolayer-enclosed organelles that dynamically interact with mitochondria and peroxisomes, buffering lipotoxicity, sequestering bioactive lipids, and facilitating enzymatic reactions-positioning them as metabolic hubs. PLIN3, a PAT family protein, uniquely regulates LD formation/stabilization andmediates mannose 6-phosphate receptor (MRP) trafficking: its dysfunction links to cancer (amplified growth factor receptor recycling), neurodegeneration (impaired α-synuclein clearance), and metabolic syndrome (hepatic cholesterol retention). This review synthesizes PLIN3's structural features, LD-centric roles, and non-canonical MRP transport, establishing it as a critical node bridging lipid homeostasis and disease, with implications for therapeutic targeting in metabolic, oncologic, and neurodegenerative conditions.

Breast cancer (BC) represents one of the most prevalent malignancies in the female population and constitutes a leading cause of cancer-associated mortality among women globally. The emergence of chemoresistance persists as a critical challenge in current breast cancer therapeutic strategies. Malignant tumors are enveloped by a sophisticated assemblage of cellular and non-cellular components that collectively establish the tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), being one of the most abundant immune infiltrates within the TME, have been demonstrated to play an instrumental role in the development and progression of chemotherapeutic resistance mechanisms. Recent studies have revealed that TAMs and breast cancer cells engage in complex bidirectional interactions. This crosstalk not only facilitates tumor immune evasion but also promotes chemotherapy resistance in breast cancer through the secretion of various cytokines, chemokines, growth factors, and other bioactive molecules. Therefore, elucidating the underlying mechanisms by which TAMs contribute to chemotherapy resistance is of significant importance. This review summarizes the dynamic and bidirectional regulatory network formed between TAMs and BC. Centering on this network, it comprehensively analyzes the molecular mechanisms by which TAMs regulate chemotherapy resistance in BC, summarizes potential targeted drugs that disrupt molecular interactions between TAMs and BC, and discusses the therapeutic prospects of combining these drugs with chemotherapy and immunotherapy. The findings aim to provide novel insights into potential molecular targets for overcoming chemotherapy resistance and to explore new therapeutic strategies for breast cancer patients.