Breast cancer is the most common cancer and the leading cause of cancer-related death in women. Differential gene expression can help identify genes involved in carcinogenesis or serve as biomarkers.

Immunodeficient mouse models are invaluable tools for preclinical research, particularly for cancer therapies and studies of the human immune system. Notably, strains with combined Prkdc (scid) and Il2rg (null) mutations-such as NOG and NSG mice- are widely used due to their profound immunodeficiency, allowing efficient engraftment of various human cells. However, these models were generated by disrupting the Il2rg gene through replacement with a neomycin resistance (Neo) cassette in embryonic stem cells. Incomplete excision of this cassette can inadvertently alter the expression of neighboring genes, thereby introducing potential confounding variables. In addition, they may still express mutant mRNAs that escape nonsense-mediated decay (NMD) and/or produce truncated proteins with residual activity, potentially compromising the interpretation of experimental outcomes. To address this, we developed the N2G mouse strain (NOD-2-Genes KO) where almost all genomic loci of both Prkdc and Il2rg genes are deleted via CRISPR/Cas9 genome editing. N2G mice exhibited tumor growth comparable to NOG mice following the transplantation with several human cancer cell lines. Moreover, human CD34+ cord blood (CB) cells engrafted into N2G mice showed robust reconstitution of human immune cells, especially T cells in peripheral blood, spleen and bone marrow, compared to NSG mice. These results suggest that N2G mice, lacking residual mutant mRNA and the exogenous Neo resistant gene, offer an advanced model for preclinical studies.

Cancer-associated fibroblasts (CAFs) serve as key stromal components within tumor microenvironment (TME), playing a significant role in the development and outcome of esophageal cancer (EC). There is an urgent need to identify genes related to CAFs to improve treatment strategies. The scRNA-sequencing dataset GSE196756 were used to identify fibroblast-related genes. Additionally, a WGCNA analysis was also conducted to identify modules related to CAFs within the TCGA-esophageal carcinoma (ESCA) cohort. By taking the intersection of identified genes of these two sections, CAF-related genes were identified. Expression of RGMA in EC samples compared to normal controls was assessed by RT-qPCR and western blot. In vitro and in vivo experiments were conducted to assess the impact of RGMA on EC cell growth. Compared to adjacent normal tissues, the levels of RGMA were notably reduced in EC tissues. Reduced RGMA levels were linked to a poor prognosis for EC patients. Furthermore, RGMA was found to have a positive correlation with the expression of fibroblast-related gene DCN, and showed a negative correlation with the expression of tumor-promoting chemokines, CXCL1, CXCL3 and CXCL8. Functionally, RGMA overexpression strongly prevented ECA109 cell viability, proliferation and migration, as well as suppresses tumor growth in vivo, suggesting that RGMA may function as a tumor suppressor in EC. Additionally, RGMA levels were also remarkably decreased in human esophageal CAFs relative to esophageal fibroblast cells (NFs). Importantly, the downregulation of RGMA may facilitate the transdifferentiation of NFs into CAFs by activating Akt signaling or upregulating CXCL1, CXCL3, and CXCL8, subsequently contributing to ECA109 cell proliferation. Collectively, RGMA may serve as a prognostic marker and a potential therapeutic target for EC. Clinical trial number Not applicable.

Propolis, a natural resinous substance rich in bioactive compounds, has been traditionally used for its therapeutic properties. This study investigates the cytotoxic and anticancer effects of Anatolian propolis on ovarian cancer cells, focusing on its modulation of the AKT/mTOR pathway and its ability to enhance cisplatin efficacy. Its antimicrobial and antibiofilm properties were also assessed, addressing infection risks in immunocompromised cancer patients. In epithelial ovarian cancer (A2780) cell line, apoptosis, cell cycle progression, and cell viability were evaluated using flow cytometric analysis, propidium iodide/annexin V staining, and MTS assay, respectively. The signaling pathways were analyzed using Western blotting. The IC50 value of propolis was determined as 0.342 ± 0.180 mg/mL in the A2780 cell line and 1.11 ± 0.31 mg/mL in the MCF-10A cell line. Apoptosis in the cells was evaluated using annexin V/PI staining and Caspase-3 expression via flow cytometry after treatment with varying concentrations of propolis and cisplatin. The combination of propolis at IC50 and cisplatin at IC25 demonstrated the highest apoptotic activity. Propolis treatment upregulated pro-apoptotic Bax while downregulating survival proteins (Bcl-2, mTOR/p-mTOR, and AKT/p-AKT) in A2780 cells, demonstrating AKT/mTOR pathway-mediated anticancer activity. Propolis exhibited potent antibacterial and antibiofilm activity against clinically relevant pathogens including MRSA and MDR E. coli, confirming its antimicrobial potential. Anatolian propolis demonstrates anticancer activity by modulating the AKT/mTOR pathway and enhancing cisplatin efficacy. Its antibacterial and antibiofilm properties further highlight its potential as a dual-function therapeutic agent, especially in cancer contexts where secondary infections are a common complication.

MicroRNAs (miRNAs) are key regulators of gene expression that bind to the 3'-untranslated region (3'-UTR) of target mRNAs, modulating protein expression and influencing cancer progression. Among these, microRNA-152 (miR-152) is frequently downregulated in diverse malignancies-including breast, endometrial, gastrointestinal, and hematologic cancers-primarily due to promoter hypermethylation. This epigenetic silencing, mediated by DNMT1, is compounded by competitive sponging from long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), forming intricate regulatory networks. Functionally, miR-152 acts as a tumor suppressor by targeting oncogenic pathways such as PI3K/AKT/mTOR, EMT drivers, and chemoresistance mediators. However, its role is context-dependent, exhibiting dual oncogenic and suppressive effects in prostate cancer and certain leukemias. Therapeutically, restoring miR-152 expression via mimics, demethylating agents, or nanocarrier-based delivery systems shows promise in preclinical studies for reversing chemoresistance and inhibiting metastasis. This review synthesizes miR-152's upstream regulators, downstream targets, and clinical potential, offering a roadmap for its exploitation in precision oncology.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with tumor progression often driven by dysregulated oncogenic pathways. USP6NL, a known regulator of endocytic trafficking, has recently been implicated in tumorigenesis. However, its precise role in CRC remains unclear, and more studies are still needed to deepen our understanding of underlying mechanisms implicated in its oncogenic role. Therefore, silencing USP6NL could provide a novel therapeutic strategy by concurrently disrupting several oncogenic mechanisms, creating a new avenue for CRC management, particularly in patients who develop resistance against conventional therapies. This study investigates the impact of USP6NL knockdown on CRC cell morphology, proliferation, apoptosis, migration, angiogenesis, and metabolic adaptation, providing mechanistic insights into its oncogenic functions.

Optic pathway gliomas (OPGs) bear a high risk of visual acuity (VA) impairment, while balancing disease-related morbidity and potential therapy-related sequelae remains challenging. We assess the predictive value of MRI-based, three-dimensionally assessed tumor burden and growth velocity for VA outcomes in NF1-associated and sporadic OPGs.

Lung cancer is the most common carcinoma reported worldwide. The burden of lung carcinoma on healthcare has been reported in many countries, while a real-life report within Turkey has yet to be published. This study aims to present the available results from a tertiary center specializing in pulmonology.

In acute myeloid leukemia (AML) it is important to elucidate the biological events that lead from remission to relapse, which have a high probability of leading to an adverse disease outcome. The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1A1) is underexpressed in AML cells when compared to healthy cells, both at the RNA level and at the protein level, and at least in the former, both in the bone marrow and in peripheral blood. Nonetheless, ALDH1A1/ALDH1A2 activity increases in AML cells during disease relapse and is higher in adverse prognosis AML in comparison with favorable prognosis AML. Furthermore, especially in relapsed AML and in unfavorable AML, AML cells rich in ALDH1A1 can contain high levels of reactive oxygen species (ROS), in parallel with high ALDH1A1/2 activity. This metabolic feature is clearly incompatible with normal stem cells. The term "stem-like" therefore is useful to coin malignant cells with a variety of genetic makeups, metabolic programming and biomarkers that converge in the function of survival of clones sufficient to sustain, spread and re-establish neoplastic disease. Therefore, AML "stem-like" cells survive cancer treatment that eradicates other malignant cell clones. This fact differentiates AML "stem-like" cells from normal stem and progenitor cells that function in tissue regeneration as part of a distinct hierarchical order of cell phenotypes. The ODYSSEY clinical trial is a Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABD-3001, a novel therapeutic agent, in patients with AML who have relapsed or are refractory to standard treatments. In this context, ABD-3001 is used as an inhibitor of cytosolic ALDH1 enzymes, such as ALDH1A1 and ALDH1A2.

Breast cancer invasion and subsequent metastasis to distant tissues occur when cancer cells lose cell-cell contact, develop a migrating phenotype, and invade the basement membrane (BM) and the extracellular matrix (ECM) to penetrate blood and lymphatic vessels. The identification of the mechanisms which induce the development from a ductal carcinoma in situ (DCIS) to a minimally invasive breast carcinoma (MIBC) is an emerging area of research in understanding tumor invasion and metastatic potential. To investigate the progression from DCIS to MIBC, we analyzed peritumoral collagen architecture using correlative scanning electron microscopy (SEM) on histological sections from human biopsies. In DCIS, the peritumoral collagen organizes into concentric lamellae ('circular fibers') parallel to the ducts. Within each lamella, type I collagen fibrils align in parallel, while neighboring lamellae show orthogonal fiber orientation. The concentric lamellar arrangement of collagen may physically constrain cancer cell migration, explaining the lack of visible tumor cell invasion into the peritumoral ECM in DCIS. A lamellar dissociation or the development of small inter fiber gaps allowed isolated breast cancer cell invasion and exosomes infiltration in the DCIS microenvironment. The radially arranged fibers observed in the peri-tumoral microenvironment of MIBC biopsies develop from a bending of the circular fibers of DCIS and drive a collective cancer cell invasion associated with an intense immune cell infiltrate. Type I collagen fibrils represent the peri-tumoral nano-environment which can play a mechanical role in regulating the development from DCIS to MIBC. Collectively, it is plausible to suggest that the ECM effectors implicated in breast cancer progression released by the interplay between cancer, stromal, and/or immune cells, and degrading inter fiber/fibril hydrophilic ECM components of the peritumoral ECM, may serve as key players in promoting the dissociation of the concentric collagen lamellae.

Gliomas, particularly IDH-wildtype ones, are associated with poor prognosis, yet their immunological landscape remains uncertain. We analyzed RNA sequencing data from 55 glioma patients, estimating immune infiltration with CIBERSORTx and immune cell states via Ecotyper. IDH-wildtype gliomas showed significantly higher immune cell infiltration (p = 0.002), notably of regulatory T cells (Tregs) and macrophages, and a greater proportion of exhausted T cells compared to IDH-mutant gliomas. Clustering based on immune profiles revealed two groups. Cluster A, enriched for IDH-wildtype cases, exhibited heightened immune infiltration but also marked immunosuppression. Cluster B, which included both IDH-wildtype and mutant cases, showed lower levels of immune infiltration. Tumor-infiltrating lymphocyte (TIL) cultured from IDH-wildtype tumors demonstrated limited expansion following anti-PD-1, a CSF1R inhibitor, or a STAT3 inhibitor treatment, without clear cluster-specific differences. Tumor-reactive TILs were mainly observed in cluster A. These findings highlight that IDH-wildtype gliomas have an immunosuppressive and heterogeneous microenvironment, potentially limiting responses to single-agent immunotherapies. A personalized, multi-targeted approach addressing multiple immunosuppressive mechanisms may be essential to improve immunotherapy outcomes in this aggressive glioma subgroup.

Metastatic breast cancer (BC) is a major cause of cancer-related deaths among women. Its progression is influenced by extracellular vesicles (EVs) released by BC cells, which modulate distant tissue environments to promote metastasis. We previously identified the oncogenic protein Kindlin-2 (K2) as a key driver of BC metastasis, including its role in the nucleus in regulating cell senescence. Here, we investigated whether K2-containing EVs facilitate both autologous (cancer-to-cancer) and heterologous (cancer-to-stroma) communication to promote metastasis. We found that 10-15% of EVs from metastatic BC cells contained K2, while this subpopulation was nearly absent in the EVs from K2-knockout (KO) cells, indicating selective packaging. These EVs transferred K2 to recipient K2-KO cells, where they accumulated in the nucleus. Using a 3D tumorsphere assay, we showed that K2+ EVs enhanced cancer cell invasiveness. Moreover, K2+ EVs activated fibroblasts into a cancer-associated phenotype, increasing α-SMA and FAP expression. Conditioned media from these activated fibroblasts further boosted cancer cell invasion. These results show that EV-associated K2 is actively transferred to recipient cells and regulates metastasis through nuclear signaling, suggesting K2+ EVs are critical mediators of BC progression and potential targets for therapy.

Pituitary neuroendocrine tumors (PitNETs) represent a complex pathology based on numerous incompletely elucidated molecular mechanisms. Beyond tumor cells, analyzing the tumor microenvironment may help identify novel prognostic markers and therapies. A key component of this environment is the folliculo-stellate (FS) cell. We examined FS cells in 77 PitNETs obtained by transsphenoidal surgery, using glial fibrillary acidic protein (GFAP) as an immunohistochemical marker. Immunohistochemistry for anterior pituitary hormones and transcription factors was performed to accurately classify the tumors. Our study included 19 somatotroph, 16 mammosomatotroph, 5 plurihormonal PIT-1 positive, 7 corticotroph, 14 gonadotroph, 11 unusual plurihormonal, and 5 null cell PitNETs. FS cells were observed in 55 of the cases, distributed isolated, in small groups or diffuse networks. A considerable number of tumors immunopositive for more than one hormone (including associations between GH/PRL, but also unusual combinations like GH/ACTH) also contained FS cells (p < 0.01), suggesting their involvement in tumor lineages differentiation. In 27 tumors, GFAP-positive cells clustered in highly vascularized areas. Additionally, in 11 of these cases a direct interaction between endothelial cells and FS cells was noted, sustaining their potential role in tumor angiogenesis. Given their complexity, FS cells may be crucial for understanding tumorigenesis mechanisms.

Immunotherapy targeting the immune functions of the tumor microenvironment (TME) is beneficial for colorectal cancer; however, the response rate is poor. Ciprofloxacin is a fluoroquinolone-class antibiotic that is used to treat bacterial infections. The purpose of this study is to assess the mechanism of ciprofloxacin that enhances anti-PD1 in colorectal cancer. We found that ciprofloxacin induced cytosolic DNA, including single-stranded and double-stranded DNA, formation in mouse CT26 colorectal adenocarcinoma cells. Molecules in DNA-sensing signaling such as cGAS, STING, and IFNβ mRNA and protein expression were elicited after ciprofloxacin treatment in CT26 cells. STING siRNA abrogated the cGAS-STING pathway activation by ciprofloxacin. In vivo, ciprofloxacin exhibited a synergistic effect with anti-PD1 to suppress tumor growth in a CT26 syngeneic animal model without biological toxicity. The examination of TME revealed that ciprofloxacin, alone and in combination therapy, induced M1 and red pulp macrophage production in the spleen. In tumors, M1 and M2 macrophage levels were increased by ciprofloxacin, and CD8+ T cell granzyme B expression was increased after combination therapy. STING showed the highest expression in tumor specimens after combination treatment. Ciprofloxacin may enhance the anti-PD1 efficacy and modulate the TME through the cGAS-STING pathway.

Hypoxia is a hallmark of aggressive prostate cancer, but how it disrupts lineage-specific transcriptional programs to drive progression remains unclear. Here, we identify the HIF1α-PHD1-FOXA1 axis as a critical mediator of hypoxic adaptation and androgen signaling suppression. Using genome-wide profiling, we demonstrate that hypoxia reprograms HIF1α chromatin occupancy, shifting its cooperation from AR to FOXA1. Mechanistically, HIF1α physically interacts with FOXA1, destabilizing it via PHD1-mediated hydroxylation-a previously unrecognized post-translational regulatory node. Under hypoxia, loss of FOXA1 attenuates androgen-responsive transcription while activating hypoxia-inducible genes, demonstrating a dual role for this axis in hypoxia adaptation and prostate cancer progression. Genetic or pharmacological disruption of HIF1α-PHD1-FOXA1 impairs prostate cancer proliferation and migration, underscoring its translational relevance. Our findings establish oxygen-dependent FOXA1 degradation as a linchpin connecting microenvironmental stress to transcriptional plasticity in advanced prostate cancer, offering new therapeutic avenues.

High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor in children and adolescents. Poor response to chemotherapy is linked to worse prognosis and increased risk of recurrence and metastasis. However, current assessment methods, such as tumor necrosis evaluation, are time-consuming and delay treatment decisions. Thus, identifying molecular pathways and predictive biomarkers is essential for guiding early therapeutic strategies. In this study, RNA-seq analysis of HGOS tissues revealed enrichment of cholesterol biosynthesis and mitotic pathways in poor responders. Additionally, high HMGCR expression, as analyzed from TCGA data, was associated with poor prognosis in sarcoma. Functional validation using SaOS-2 cells, which exhibited poor drug sensitivity and elevated HMGCR levels, demonstrated that simvastatin enhanced the efficacy of cisplatin and doxorubicin by inducing mitochondrial-mediated apoptosis and downregulating anti-apoptotic proteins. Simvastatin also reduced cell migration and invasion by suppressing epithelial-mesenchymal transition and extracellular matrix degradation. Mechanistically, simvastatin disrupted Ras prenylation and inhibited downstream oncogenic signaling pathways, including Akt/mTOR and Akt/GSK3, which regulate survival and metastasis-associated gene expression. These findings suggest that the cholesterol biosynthesis pathway particularly plays a critical role in chemoresistance and metastasis in HGOS and may serve as a promising predictive molecular target for guiding early therapeutic strategies.

Among the molecules implicated in inflammation-associated tumorigenesis, Chitinase 3-like 1 (CHI3L1/YKL-40/Brp-39) has emerged as a particularly compelling target due to its multifaced roles in immune regulation, tissue remodeling, and cancer progression. Elevated CHI3L1 expression is observed in various human cancers and corresponding animal models. CHI3L1 directly promotes tumor cell proliferation and angiogenesis and also contributes to immune evasion by establishing an immunosuppressive environment in inflamed tissues. Mechanistically, CHI3L1 exerts its effects through the modulation of STAT3, MAPK, and PI3K/Akt signaling pathways and by interacting with cell surface receptors, such as IL-13Rα2 and RAGE. Studies using transgenic and knockout mouse models have revealed a strong association between CHI3L1 expression and cancer progression. In models of colon and lung cancer, CHI3L1 overexpression correlates with increased tumor size and number, whereas CHI3L1 deficiency markedly suppresses tumor formation. However, its involvement appears to be context-dependent and varies among different epithelial tumor types. These findings suggest that CHI3L1 is a potential therapeutic target and diagnostic biomarker for inflammation-associated cancers. Animal studies provide valuable insights into the immunological mechanisms of CHI3L1-mediated tumorigenesis but also highlight the need for cautious interpretation due to inherent technical limitations.

Aberrant activation of the mitogen-activated protein kinase (MAPK) cascade promotes oncogenic transcriptomes. Despite efforts to inhibit oncogenic kinases, such as BRAFV600E, tumor responses in patients can be heterogeneous and limited by drug resistance mechanisms. Here, we describe patient tumors that acquired COP1 or DET1 mutations after treatment with the BRAFV600E inhibitor vemurafenib. COP1 and DET1 constitute the substrate adaptor of the E3 ubiquitin ligase CRL4COP1/DET1, which targets transcription factors, including ETV1, ETV4, and ETV5, for proteasomal degradation. MAPK-MEK-ERK signaling prevents CRL4COP1/DET1 from ubiquitinating ETV1, ETV4, and ETV5, but the mechanistic details are still being elucidated. We found that patient mutations in COP1 or DET1 inactivated CRL4COP1/DET1 in melanoma cells, stabilized ETV1, ETV4, and ETV5, and conferred resistance to inhibitors of the MAPK pathway. ETV5, in particular, enhanced cell survival and was found to promote the expression of the pro-survival gene BCL2A1. Indeed, the deletion of pro-survival BCL2A1 re-sensitized COP1 mutant cells to vemurafenib treatment. These observations indicate that the post-translational regulation of ETV5 by CRL4COP1/DET1 modulates transcriptional outputs in ERK-dependent cancers, and its inactivation contributes to therapeutic resistance.

Canine mammary tumors (CMTs) are the common tumors in female dogs, and approximately 50% of CMTs are malignant tumors, with abnormal regulation of non-coding RNAs being a critical factor in disease progression. Currently, research on long non-coding RNAs (lncRNAs) regulating CMT development remains limited. This study identified a novel lncRNA, aiming to explore the role of lncRNA LOC610012 in CMTs. In this study, immunofluorescence and Western blot analyses were employed to detect protein expression. LncRNA LOC610012 is downregulated in CMT tissues and cells. Stable cells of LOC610012 were constructed by the lentivirus technique. Through a variety of experimental methods, LOC610012 inhibited the proliferation, invasion, and metastasis of CMT cells in in vitro and in vivo experiments conducted using cell culture and mouse models. Mechanistically, LOC610012 regulated the expression of EP3 and GSK-3β by targeting PTGS2, resulting in excessive production of reactive oxygen species (ROS), which inhibited cell viability. Similarly, through transmission electron microscopy, mitochondrial damage caused by LOC610012 was observed in CMT cells, which was manifested as mitochondrial swelling, membrane rupture, and mitochondrial ridge disappearance. PTGS2 could partially restore the inhibition of LOC610012 on cell activity. LOC610012 acts as a tumor suppressor gene in CMTs and as a potential biomarker for the disease.

Although cancer is often considered a genetic disease, genotoxic damage to nuclear DNA caused by carcinogens is not always sufficient to stimulate cancer cell growth, suggesting that other etiological factors are involved. Indeed, many carcinogens are also nephrotoxic and can impair kidney function. In turn, impaired renal function can dysregulate serum inorganic phosphate, leading to hyperphosphatemia and excess phosphate storage in tissues, which causes phosphate toxicity. Moreover, phosphate toxicity can contribute to cancer cell growth by activating cell signaling pathways, overexpressing sodium phosphate cotransporters, and stimulating excessive RNA biogenesis and protein synthesis. The present narrative review proposes a general underlying mechanism by which phosphate toxicity mediates the association of toxin nephropathy with carcinogenesis. This proposed pathway could explain why any factor that impairs renal function, including an overload of nontoxic substances, may indirectly contribute to excess phosphate sequestration in the tumor microenvironment which stimulates cancer cellular growth. Importantly, chemotherapy agents are often nephrotoxic, and carcinogenicity associated with such nephrotoxins could explain the occurrence of second tumors in treated cancer patients. More research is needed to investigate the mediating role of phosphate toxicity in the association of toxin nephropathy with carcinogenesis.