Subcutaneous Tumor Research Articles

CARMIL1 regulates liver cancer cell proliferation by activating the ERK/mTOR pathway through the TRIM27/p53 axis

Capping protein regulatory factor and myosin 1 linker 1 is termed CARMIL1. CARMIL1 is involved in several physiological processes; it forms an actin filament network and plasma membrane-bound cellular projection tissues and positively regulates the cellular components and tissues. CARMIL1 exhibits important biological functions in cancer; nonetheless, these functions have not been completely explored. We aimed to investigate the novel functions of CARMIL1 in liver cancer, particularly in cell proliferation. The cell counting kit-8, 5-ethynyl-2′-deoxyuridine, Component A experiments, and subcutaneous tumor formation model suggest that CARMIL1 is central to the proliferation of liver cancer cells both in vivo and in vitro. We extracted CARMIL1 samples from The Cancer Genome Atlas Program and analyzed its enrichment. CARMIL1 regulated the pathway activity by affecting the expression of star molecular proteins of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Moreover, it influenced the proliferation ability of liver cancer cells. Western blotting suggested that CARMIL1 downregulation could affect ERK and mTOR phosphorylation. Results of the co-immunoprecipitation demonstrated that CARMIL1 binds to tripartite motif (TRIM)27, which in turn binds to p53. Subsequently, CARMIL1 can regulate p53 stability and promote its degradation through TRIM27. Additionally, CARMIL1 inhibition enhanced the sensitivity of liver cancer cells to sorafenib. Tumor growth was significantly inhibited in the group treated with sorafenib and CARMIL1, compared with the group treated with CARMIL1 alone. Sorafenib is a first-line targeted chemotherapeutic drug for hepatocellular carcinoma treatment. It increases the long-term survival of hepatocellular carcinoma by 44%. In this study, downregulated CARMIL1 combined with sorafenib significantly reduced the tumor volume and weight of the mouse subcutaneous tumor model, indicating the potential possibility of combining CARMIL1 with sorafenib in hepatocellular carcinoma treatment. In summary, CARMIL1 promotes liver cancer cell proliferation by regulating the TRIM27/p53 axis and activating the ERK/mTOR pathway.

Nanogalvanic Cells Release Highly Reactive Electrons in Tumors to Effectively Eliminate Tumors.

External stimuli triggering chemical reactions in cancer cells to generate highly reactive chemical species are very appealing for cancer therapy, in which external irradiation activating sensitizers to transfer energy or electrons to surrounding oxygen or other molecules is critical for generating cytotoxic reactive species. However, poor light penetration into tissue, low activity of sensitizers, and reliance on oxygen supply restrict the generation of cytotoxic chemical species in hypoxic tumors, which lowers the therapeutic efficacy. Here, we present galvanic cell nanomaterials that can directly release highly reactive electrons in tumors without external irradiation or photosensitizers. The released reactive electrons directly react with surrounding biomolecules such as proteins and DNA within tumors to destroy them or react with other surrounding (bio)molecules to yield cytotoxic chemical species to eliminate tumors independent of oxygen. Administering these nanogalvanic cells to mice results in almost complete remission of subcutaneous solid tumors and deep metastatic tumors. The results demonstrate that this strategy can further arouse an immune response even in a hypoxic environment. This method offers a promising approach to effectively eliminate tumors, similar to photodynamic therapy, but does not require oxygen or irradiation to activate photosensitizers. This article is protected by copyright. All rights reserved.

SOLITARY CUTANEOUS NEOPLASMS: ANALYSING THE UNCERTAIN BEHAVIOUR WITH THE AID OF HISTOPATHOLOGY

INTRODUCTION: Skin tumours can be benign or malignant, resulting from proliferation of one or more skin constituents. The incidence of skin cancer has increased over last few decades, necessitating histopathological evidence to distinguish between them. OBJECTIVES: To describe epidemiology, clinical presentation, uncertain behaviour and histopathological spectrum of various skin tumours. METHODOLOGY: Present study is a prospective study conducted over a period of four years from July 2019 to July 2023 in the Out-patient Department of DVL, Government General Hospital, Anantapur. Cystic and infectious swellings and patients having multiple lesions and patients who didn’t consent for this study are excluded. All excisional biopsies of solitary cutaneous swellings are sent for Histopathological confirmation and tumours are categorised based on WHO classification. RESULTS: The study has 123 solitary cutaneous tumours, out of which, 98 cases (79.67%) were benign and 25(20.32%) are malignant. Adults aged 26-44 years are most affected (31.7%) followed by middle aged (30.08%).Males are 57(46.34%) and females are 66(53.65%).Extremities constituted the most common site with 53 cases (43.08%) followed by head and neck (29.26%). According to WHO classification of skin tumours, subcutaneous tissue tumours accounted for 42 cases (34.14%) followed by 31 cases(25.20%) of soft tissue tumours. Keratinocyte tumours are 26(21.13%), appendageal tumours are 16(13%) and least common are melanocytic and neural tumours with 4(3.25%) and 4(3.25%) respectively. Majority of benign tumours originated from subcutaneous tissues, while malignant developed from keratinocytic differentiation. CONCLUSION: In our study, most tumours had ambiguous clinical behaviour, which resulted in misdiagnosis; hence, histopathological confirmation is essential for accurate diagnosis and prompt management.

Notch-targeted Therapeutic in Colorectal Cancer by Notch1 Attenuation via Tumor Microenvironment-Responsive Cascade DNA Delivery.

The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, we design a tumor microenvironment-responsive and injectable hydrogel to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch-targeted gene therapy of colorectal cancer (CRC). The hydrogels were prepared through cross-linking between phenylboric acid groups-containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), which were used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM-F) (PAMAM-F/shNotch1). In response to low pH and H2O2 in tumor microenvironment, the hydrogel can be dissociated and release the complexes for precise delivery of shNotch1 into tumor cells and inhibit Notch1 activity to suppress malignant biological behaviors of CRC. In the subcutaneous tumor model of CRC, PAMAM-F/shNotch1-loaded hydrogels can accurately attenuate Notch1 activity and significantly inhibit tumor growth without affecting Notch signal in adjacent normal tissues. Therefore, this therapeutic system can precisely inhibit Notch1 signal in CRC with high responsiveness and low toxicity, providing a promising Notch-targeted gene therapeutic for human malignancy. This article is protected by copyright. All rights reserved.

Pepsinogen C Interacts with IQGAP1 to Inhibit the Metastasis of Gastric Cancer Cells by Suppressing Rho-GTPase Pathway

Aim: This study systematically explored the biological effects and mechanisms of PGC on gastric cancer (GC) cells in vitro and in vivo. Method: The critical biological roles of PGC in GC were assessed via EdU staining, Hoechst staining, flow cytometry, mouse models, CCK-8, wound healing, transwell, and sphere-forming assays. The interaction study with IQ-domain GTPase-activating protein 1 (IQGAP1) was used by Liquid chromatography-mass spectrometry co-immunoprecipitation, immunofluorescence staining, CHX-chase assay, MG132 assay, and qRT-PCR. Results: PGC inhibited the proliferation, viability, epithelial–mesenchymal transition, migration, invasion, and stemness of GC cells and promoted GC cell differentiation. PGC suppressed subcutaneous tumor growth and peritoneal dissemination in vivo. The interaction study found PGC inhibits GC cell migration and invasion by downregulating IQGAP1 protein and IQGAP1-mediated Rho-GTPase signaling suppression. In addition, PGC disrupts the stability of the IQGAP1 protein, promoting its degradation and significantly shortening its half-life. Moreover, the expression levels of PGC and IQGAP1 in GC tissues were significantly negatively correlated. Conclusion: PGC may act as a tumor suppressor in the development and metastasis of GC. PGC can downregulate its interacting protein IQGAP1 and inhibit the Rho-GTPase pathway, thereby participating in the inhibition of GC cell migration and invasion.

Estrogen induces LCAT to maintain cholesterol homeostasis and suppress hepatocellular carcinoma development.

Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified LCAT as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol (HDL-C) production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC.

Tumor-derived nanovesicles enhance cancer synergistic chemo-immunotherapy by promoting cGAS/STING pathway activation and immunogenetic cell death

AimsCheckpoint blockade immunotherapy is a promising therapeutic modality that has revolutionized cancer treatment; however, the therapy is only effective on a fraction of patients due to the tumor environment. In tumor immunotherapy, the cGAS-STING pathway is a crucial intracellular immune response pathway. Therefore, this study aimed to develop an immunotherapy strategy based on the cGAS-STING pathway. Materials and methodsThe physicochemical properties of the nanoparticles EM@REV@DOX were characterized by TEM, DLS, and WB. Subcutaneous LLC xenograft tumors were used to determine the biodistribution, antitumor efficacy, and immune response. Blood samples and tissues of interest were harvested for hematological analysis and H&E staining. SignificanceOverall, our designed nanovesicles provide a new perspective on tumor immunotherapy by ICD and cGAS-STING pathway, promoting DCs maturation, macrophage polarization, and activating T cells, offering a meaningful strategy for accelerating the clinical development of immunotherapy. Key findingsEM@REV@DOX accumulated in the tumor site through EPR and homing targeting effect to release REV and DOX, resulting in DNA damage and finally activating the cGAS-STING pathway, thereby promoting DCs maturation, macrophage polarization, and activating T cells. Additionally, EM@REV@DOX increased the production of pro-inflammatory cytokines (e.g., TNF-α and IFN-β). As a result, EM@REV@DOX was effective in treating tumor-bearing mice and prolonged their lifespans. When combined with αPD-L1, EM@REV@DOX significantly inhibited distant tumor growth, extended the survival of mice, and prevented long-term postoperative tumor metastasis, exhibiting great potential in antitumor immunotherapy.

MRI radiomics captures early treatment response in patient-derived organoid endometrial cancer mouse models

BackgroundRadiomics can capture microscale information in medical images beyond what is visible to the naked human eye. Using a clinically relevant mouse model for endometrial cancer, the objective of this study was to develop and validate a radiomic signature (RS) predicting response to standard chemotherapy.MethodsMice orthotopically implanted with a patient-derived grade 3 endometrioid endometrial cancer organoid model (O-PDX) were allocated to chemotherapy (combined paclitaxel/carboplatin, n=11) or saline/control (n=13). During tumor progression, the mice underwent weekly T2-weighted (T2w) magnetic resonance imaging (MRI). Segmentation of primary tumor volume (vMRI) allowed extraction of radiomic features from whole-volume tumor masks. A radiomic model for predicting treatment response was derived employing least absolute shrinkage and selection operator (LASSO) statistics at endpoint images in the orthotopic O-PDX (RS_O), and subsequently applied on the earlier study timepoints (RS_O at baseline, and week 1-3). For external validation, the radiomic model was tested in a separate T2w-MRI dataset on segmented whole-volume subcutaneous tumors (RS_S) from the same O-PDX model, imaged at three timepoints (baseline, day 3 and day 10/endpoint) after start of chemotherapy (n=8 tumors) or saline/control (n=8 tumors).ResultsThe RS_O yielded rapidly increasing area under the receiver operating characteristic (ROC) curves (AUCs) for predicting treatment response from baseline until endpoint; AUC=0.38 (baseline); 0.80 (week 1), 0.85 (week 2), 0.96 (week 3) and 1.0 (endpoint). In comparison, vMRI yielded AUCs of 0.37 (baseline); 0.69 (w1); 0.83 (week 2); 0.92 (week 3) and 0.97 (endpoint). When tested in the external validation dataset, RS_S yielded high accuracy for predicting treatment response at day10/endpoint (AUC=0.85) and tended to yield higher AUC than vMRI (AUC=0.78, p=0.18). Neither RS_S nor vMRI predicted response at day 3 in the external validation set (AUC=0.56 for both).ConclusionsWe have developed and validated a radiomic signature that was able to capture chemotherapeutic treatment response both in an O-PDX and in a subcutaneous endometrial cancer mouse model. This study supports the promising role of preclinical imaging including radiomic tumor profiling to assess early treatment response in endometrial cancer models.

DCAF1 interacts with PARD3 to promote hepatocellular carcinoma progression and metastasis by activating the Akt signaling pathway

BackgroundHepatocellular carcinoma (HCC) is a fatal malignancy with poor prognosis due to lack of effective clinical interference. DCAF1 plays a vital role in regulating cell growth and proliferation, and is involved in the progression of various malignancies. However, the function of DCAF1 in HCC development and the underlying mechanism are still unknown. This study aimed to explore the effect of DCAF1 in HCC and the corresponding molecular mechanism.MethodsQuantitative real-time PCR, Western blot and immunostaining were used to determine DCAF1 expression in tumor tissues and cell lines. Subsequently, in vitro and in vivo experiments were conducted to explore the function of DCAF1 in tumor growth and metastasis in HCC. Coimmunoprecipitation, mass spectrometry and RNA sequencing were performed to identify the underlying molecular mechanisms.ResultsIn this study, we found that DCAF1 was observably upregulated and associated with poor prognosis in HCC. Knockdown of DCAF1 inhibited tumor proliferation and metastasis and promoted tumor apoptosis, whereas overexpressing DCAF1 yielded opposite effects. Mechanistically, DCAF1 could activate the Akt signaling pathway by binding to PARD3 and enhancing its expression. We also found that the combined application of DCAF1 knockdown and Akt inhibitor could significantly suppress subcutaneous xenograft tumor growth.ConclusionsOur study illustrates that DCAF1 plays a crucial role in HCC development and the DCAF1/PARD3/Akt axis presents a potentially effective therapeutic strategy for HCC.Graphical

Scutellarin-loaded pH/H2O2 dual-responsive polymer cyclodextrin mesoporous silicon framework nanocarriers for enhanced cancer therapy

Stimulus-responsive nanomaterials, particularly with targeting capabilities, have garnered significant attention in the cancer therapy. However, the biological safety of these innovative materials in vivo remains unknown, posing a hurdle to their clinical application. Here, a pH/H2O2 dual-responsive and targeting nano carrier system (NCS) was developed using core shell structure of Fe3O4 mesoporous silicon (MSN@Fe3O4) as main body, scutellarin (SCU) as antitumor drug and polymer cyclodextrin (PCD) as molecular switch (denoted as PCD@SCU@MSN@Fe3O4, abbreviated as NCS). The NCS, with an average particle size of 100 nm, displayed exceptional SCU loading capacity, a result of its uniform radial channel structure. The in vitro investigation under condition of pH and H2O2 indicated that NCS performed excellent pH/H2O2-triggered SCU release behavior. The NCS displayed a higher cytotoxicity against tumor cells (Huh7 and HCT116) due to its pH/H2O2 dual-triggered responsiveness, while the PCD@MSN@Fe3O4 demonstrated lower cytotoxicity for both Huh7 and HCT116 cells. In vivo therapeutic evaluation of NCS indicates significant inhibition of tumor growth in mouse subcutaneous tumor models, with no apparent side-effects detected. The NCS not only enhances the bioavailability of SCU, but also utilizes magnetic targeting technology to deliver SCU accurately to tumor sites. These findings underscore the substantial clinical application potential of NCS.

Prostate-Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer.

The uptake of large (>10nm) non-targeted nanocarriers by bulk tumors is thought to be dominated by passive extravasation through porous tumor vessels and limited lymphatic drainage, the enhanced permeability and retention (EPR) effect. Prior studies demonstrated radiolabeled tumor-targeted and non-targeted 4-arm 40kDa star polyethylene glycol (StarPEG) polymers for cancer imaging. By adding small molecule ligands targeting prostate-specific membrane antigen (PSMA) to the StarPEG polymer, marked increase in tumor uptake, penetration and retention in the tumor core was observed. These prior studies support the application of imaging surrogates for the evaluation of targeted delivery of chemotherapeutic nanomedicines and the potential for therapy using analogous β-emitting radiopharmaceuticals. To evaluate the delivery and therapeutic efficacy of PSMA-targeted StarPEG nanocarriers, StarPEG nanodrugs with or without three copies of PSMA-targeting, ACUPA, ligands were designed and synthesized. One copy of the radiometal chelator, DOTA, was conjugated to each nanocarrier for labelling with b-emitting 177Lu, providing non-targeted [177Lu]PEG-(DOTA)1 and PSMA targeting [177Lu]PEG-(DOTA)1(ACUPA)3, for SPECT imaging and therapy. The radiolabeled nanodrugs were evaluated in vitro and in vivo using PSMA+ PC3-Pip and/or PSMA- PC3-Flu cell lines, subcutaneous xenografts and disseminated metastatic models. The nanocarriers PEG-(DOTA)1 and PEG-(DOTA)1(ACUPA)3 were efficiently radiolabeled with 177Lu with molar activities of 10.8-15.8 MBq/nmol. Along with excellent in vitro PSMA binding affinity (kD = 51.7nM in PC3-Pip cells), the targeted nanocarrier [177Lu]PEG-(DOTA)1(ACUPA)3 demonstrated excellent in vivo single-photon emission computed tomography (SPECT) imaging contrast with 21.3% ID/g uptake in PC3-Pip tumors at 192h post injection. Single doses of 18.5 MBq [177Lu]PEG-(DOTA)1(ACUPA)3 showed complete resolution of the PC3-Pip xenografts, without any regrowth up to 138 days. The StarPEG nanocarriers demonstrated high PSMA-targeted delivery of the therapeutic isotope 177Lu with excellent imaging contrast. The targeted nanocarrier eliminated subcutaneous and metastatic PC3-Pip tumors. Overall, these preclinical results demonstrated high treatment efficacy of the PSMA-targeted nanocarrier [177Lu]PEG-(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation. This article is protected by copyright. All rights reserved.

Alginate/Carboxymethyl Chitosan Core-Shell Microspheres Coloaded with Doxorubicin/DocetaxelReverse Chemotherapy Resistance in Anaplastic Thyroid Carcinoma.

Drug resistance is a major obstacle in the treatment of anaplastic thyroid carcinoma (ATC) with the combination of docetaxel (DTX) and doxorubicin (DOX). Excessive intracellular drug efflux is considered a key factor contributing to drug resistance. Therefore, developing drug-loaded microspheres to enhance cellular uptake and inhibit efflux of docetaxel and doxorubicin may be an effective strategy to overcome chemoresistance. Alginate-Doxorubicin@carboxymethyl chitosan-Docetaxel (A-DOX@C-DTX) microspheres were prepared using an electrostatic spraying-assisted microfluidic device. The microspheres were characterized, and the in vitro drug release profiles and extracellular efflux rates were determined. The effects of A-DOX@C-DTX microspheres on drug-resistant ATC cells were evaluated in vitro. In vivo, a subcutaneous tumor model was established in mice to investigate the effects of A-DOX@C-DTX microspheres on tumor growth, as well as the accumulation and release of the materials at the tumor site. We successfully prepared ALG/CMC microspheres with a core-shell structure. These microspheres exhibited controllable size, good monodispersity, excellent biocompatibility, high encapsulation efficiency for doxorubicin and docetaxel, and high drug loading capacity. Moreover, the microspheres promoted cellular uptake of doxorubicin and docetaxel while inhibiting their efflux. A-DOX@C-DTX microspheres showed significant inhibition of viability, proliferation, migration, and invasion of drug-resistant ATC cells in vitro. In vivo, A-DOX@C-DTX microspheres suppressed tumor growth, induced tumor tissue necrosis, and promoted tumor cell apoptosis. Additionally, the microspheres facilitated the enrichment of active substances in the tumor and their sustained release. A-DOX@C-DTX microspheres exhibited superior anti-tumor effects compared to free drug treatment both in vitro and in vivo, particularly against drug-resistant ATC cells. This improved therapeutic efficacy may be attributed to the enhanced drug uptake and reduced drug efflux in drug-resistant ATC cells facilitated by ALG/CMC microspheres.

VBP1 promotes tumor proliferation as a part of the hypoxia-related signature in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor in East Asia. Hypoxia, a hallmark of solid tumors, significantly alters redox homeostasis inside tumor microenvironment. This alteration drives tumor proliferation, invasion, and metastasis, leading to poor prognostic outcomes. However, the role of hypoxia-related genes in ESCC remains poorly understood. We employed RNA sequencing to identify differentially expressed genes in ESCC. Clinical data, transcriptome profiles, and a hypoxia-related gene set were extracted from open-source databases. A prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression, which was then validated through Cox regression analysis. Within this prognostic model, we pinpointed and investigated a key hypoxia-related gene affecting prognosis. The gene's expression was validated using real-time PCR and immunohistochemistry in both esophageal carcinoma and normal tissues. Tumor proliferation was examined through in vitro and in vivo assays, including the Cell Counting Kit-8, EdU, colony formation, and subcutaneous tumor models. A robust four-gene prognostic model (VBP1, BGN, CDKN1A, and PPFIA1) was successfully constructed and validated. Among these, VBP1 emerged as a key gene, exhibiting high expression levels that correlated with poor prognosis in ESCC. Functional experiments confirmed that VBP1 significantly accelerated tumor proliferation both in vitro and in vivo. VBP1 is identified as a pivotal gene within the hypoxia-related prognostic signature, and it significantly promotes tumor proliferation in ESCC.

Controlled In Situ Self-Assembly of Biotinylated Trans-Cyclooctene Nanoparticles for Orthogonal Dual-Pretargeted Near-Infrared Fluorescence and Magnetic Resonance Imaging.

A pretargeted strategy that decouples targeting vectors from radionuclides has shown promise for nuclear imaging and/or therapy in vivo. However, the current pretargeted approach relies on the use of antibodies or nanoparticles as the targeting vectors, which may be compromised by poor tissue penetration and limited accumulation of targeting vectors in the tumor tissues. Herein, we present an orthogonal dual-pretargeted approach by combining stimuli-triggered in situ self-assembly strategy with fast inverse electron demand Diels-Alder (IEDDA) reaction and strong biotin-streptavidin (SA) interaction for near-infrared fluorescence (NIR FL) and magnetic resonance (MR) imaging of tumors. This approach uses a small-molecule probe (P-Cy-TCO&Bio) containing both biotin and trans-cyclooctene (TCO) as a tumor-targeting vector. P-Cy-TCO&Bio can efficiently penetrate subcutaneous HeLa tumors through biotin-assisted targeted delivery and undergo in situ self-assembly to form biotinylated TCO-bearing nanoparticles (Cy-TCO&Bio NPs) on tumor cell membranes. Cy-TCO&Bio NPs exhibited an "off-on" NIR FL and retained in the tumors, offering a high density of TCO and biotin groups for the concurrent capture of Gd-chelate-labeled tetrazine (Tz-Gd) and IR780-labeled SA (SA-780) via the orthogonal IEDDA reaction and SA-biotin interaction. Moreover, Cy-TCO&Bio NPs offered multiple-valent binding modes toward SA, which additionally regulated the cross-linking of Cy-Gd&Bio NPs into microparticles (Cy-Gd&Bio/SA MPs). This process could significantly (1) increase r1 relaxivity and (2) enhance the accumulation of Tz-Gd and SA-780 in the tumors, resulting in strong NIR FL, bright MR contrast, and an extended time window for the clear and precise imaging of HeLa tumors.

LEPR/FOS/JUNB signaling pathway contributes to chronic restraint stress-induced tumor proliferation

Background & AimsPsychosocial stress has become an unavoidable part of life, which was reported to promote tumor development. Chronic stress significantly promotes the norepinephrine (NE) secretion and the expression of leptin receptor (LEPR), leading to tumor invasion, metastasis, and proliferation. However, the mechanism of chronic stress-induced tumor proliferation remains unclear. MethodsTo reveal the effect of chronic stress on tumor proliferation, subcutaneous tumor models combined with chronic restraint stress (CRS) were established. Combined with the transcript omics database of liver cancer patients, the target pathways were screened and further verified by in vitro experiments. ResultsThe results showed that the CRS with subcutaneous tumor transplantation (CRS+tumor) group exhibited significantly larger tumor sizes than the subcutaneous tumor transplantation (tumor) group. Compared with the tumor group, CRS obviously increased the mRNA levels of LEPR, FOS, and JUNB of tumor tissues in the CRS+ tumor group. Furthermore, the treatment with norepinephrine (NE) significantly elevated the survival rate of H22 cells and enhanced the expression of LEPR, FOS, and JUNB in vitro. Silencing LEPR significantly reduced the expression of FOS and JUNB, accompanied by a decrease in H22 cell viability. ConclusionsOur study demonstrated that CRS activates the LEPR-FOS-JUNB signaling pathway by NE, aggravating tumor development. These findings might provide a scientific foundation for investigating the underlying pathological mechanisms of tumors in response to chronic stress.

Apoptosis-induced treatment for ovarian cancer from self-assembled nanocomposites of Fe3O4 nanoparticles and porous organic cages

HypothesisOvarian cancer is one of the most common tumors in gynecology and imposes a heavy burden on patients and their families. Fe3O4 nanoparticles are one of the few nanomaterials approved by the FDA for clinical use, which has been widely used in the diagnosis and treatment of tumor. ExperimentsThe aqueous colloids made from hydrophobic building blocks were fabricated through an oil-in-water emulsion confined assembly strategy. In vitro, the proliferation, migration, invasion of SKOV3 cell after the treatment of iron oxide based assemblies were detected using Test-EdU assay and wound-healing assay. The ovarian cancer of the Nude Mice model was used to investigate the anti-cancer effect of Fe3O4 assemblies and Fe3O4-CC3 co-assemblies in vivo. FindingsThe applied nanocomposites inhibited ovarian cancer cells by CytC/caspase-3 pathway. The results in vivo revealed that treatment of nanocomposites significantly restrained the growth of subcutaneous transplantation tumor in Ovarian Cancer of the Nude Mice model. Our study demonstrated that colloidal nanocomposites assembled from Fe3O4 nanoparticles and porous organic cages inhibits cancer progression and induces apoptosis via caspase pathway. The effect of Fe3O4-CC3 co-assemblies is more profound due to their better contact with the biological matter.

SMC2 knockdown inhibits malignant progression of lung adenocarcinoma by upregulating BTG2 expression

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer worldwide. Structural maintenance of chromosomes 2 (SMC2) serves as a predictor of poor prognosis across various cancer types. This study aims to explore the role and underlying mechanisms of SMC2 in LUAD progression. The expression of SMC2 in LUAD tissues and its correlation with prognosis were analyzed by public databases. Knockdown of SMC2 was performed to assess the proliferation, migration and invasion ability of LUAD cells. Bulk RNA sequencing analysis identified enriched cellular pathways and remarkable upregulation of BTG anti-proliferation factor 2 (BTG2) expression after SMC2 knockdown in LUAD cells. Then, BTG2 was silenced to assess the malignant behavior of LUAD cells. Subcutaneous transplantation and intracranial models of LUAD cells in BALB/c nude mice were established to assess the antineoplastic effect of SMC2 knockdown in vivo. Additionally, a lung metastasis model was created to evaluate the pro-metastatic effect of SMC2. Our findings indicated that SMC2 was upregulated in LUAD tissues and cell lines, with higher expression correlating with poor prognosis. SMC2 silencing suppressed the proliferation, migration and invasion ability of LUAD cells by upregulating BTG2 expression via p53 and inactivating ERK and AKT pathways. BTG2 silencing reversed the effects of SMC2 downregulation on malignant behaviors of LUAD cells and restored the phosphorylated ERK and AKT levels. Furthermore, SMC2 knockdown effectively prevented the formation of subcutaneous, intracranial and metastatic tumor in vivo, and upregulation of BTG2 expression after SMC2 knockdown was confirmed in tumor models. This study revealed that SMC2 knockdown restrained the malignant progression of LUAD through upregulation of BTG2 expression and inactivation of ERK and AKT pathway, and SMC2 could be a potential therapeutic target for LUAD treatment.

Knockdown of CENPM activates cGAS-STING pathway to inhibit ovarian cancer by promoting pyroptosis.

We aimed to screen novel gene signatures for ovarian cancer (OC) and explore the role of biomarkers in OC via regulating pyroptosis using bioinformatics analysis. Differentially expressed genes (DEGs) of OC were screened from GSE12470 and GSE16709 datasets. Hub genes were determined from protein-protein interaction networks after bioinformatics analysis. The role of Centromeric protein M (CENPM) in OC was assessed by subcutaneous tumor experiment using hematoxylin-eosin and immunohistochemical staining. Tumor metastasis was evaluated by detecting epithelial-mesenchymal transition-related proteins. The proliferation, migration, and invasion were determined using cell counting kit and transwell assay. Enzyme-linked immunosorbent assay was applied to measure inflammatory factors. The mRNA and protein expression were detected using real-time quantitative PCR and western blot. We determined 9 hub genes (KIFC1, PCLAF, CDCA5, KNTC1, MCM3, OIP5, CENPM, KIF15, and ASF1B) with high prediction value for OC. In SKOV3 and A2780 cells, the expression levels of hub genes were significantly up-regulated, compared with normal ovarian cells. CENPM was selected as a key gene. Knockdown of CENPM suppressed proliferation, migration, and invasion of OC cells. Subcutaneous tumor experiment revealed that CENPM knockdown significantly suppressed tumor growth and metastasis. Additionally, pyroptosis was promoted in OC cells and xenograft tumors after CENPM knockdown. Furthermore, CENPM knockdown activated cGAS-STING pathway and the pathway inhibitor reversed the inhibitory effect of CENPM knockdown on viability, migration, and invasion of OC cells. CENPM was a novel biomarker of OC, and knockdown of CENPM inhibited OC progression by promoting pyroptosis and activating cGAS-STING pathway.

Strategically Staged Tumor Ablation and Inflammation Suppression Using Shell‐Core Nanoparticles to Eradicate Bladder Tumors and Prevent Recurrence

AbstractNanomedicine shows promise in the therapy of eradicating bladder tumors and preventing tumor recurrence caused by cancer‐related inflammation. Shell‐core structured BNN6/Z8@ALA/Z67 nanoparticles with sequential release kinetics is designed, aiming to eliminate tumors and curb inflammation, thereby ablating bladder tumors and preventing their recurrence. The shell of this nanoparticle comprises zeolitic imidazolate framework‐67 (Z67) and 5­aminolevulinic acid (ALA), while the core comprises zeolitic imidazolate framework‐8 (Z8) and N,N’‐di‐sec‐butyl‐N,N’‐dinitroso‐1,4‐phenylenediamine (BNN6). Modified with polydopamine‐methoxypolyethylene glycol amine, these nanoparticles efficiently target bladder tumors. In the acidic tumor environment, the outer‐layered Z67 breaks down rapidly, releasing ALA, which transforms into protoporphyrin IX (PpIX) in mitochondria. Additionally, the degraded Z67 triggers the conversion of hydrogen peroxide into oxygen, aiding PpIX to generate reactive oxygen species under ultrasound, facilitating tumor ablation. As Z67 decomposes, the inner‐layered Z8 releases BNN6 in the acidic environment. Ultrasound exposure prompts the release of nitric oxide, effectively reducing inflammation. Under ultrasound, BNN6/Z8@ALA/Z67 showcased outstanding staged anti‐tumor and anti‐inflammatory effects in both in vitro and murine subcutaneous tumor model tests, and effectively prevents tumor recurrence in rat bladder tumor models. These findings underscore the promising potential of the designed shell‐core nanoparticle with staged tumor ablation and inflammation suppression in preventing bladder tumor recurrence.

NIO-1, A Novel Inhibitor of OCT1, Enhances the Antitumor Action of Radiofrequency Ablation against Hepatocellular Carcinoma.

Radiofrequency ablation (RFA) is an important treatment strategy for patients with advanced hepatocellular carcinoma (HCC). However, its therapeutic effect is unsatisfactory and recurrence often occurs after RFA treatment. The octamer-binding transcription factor OCT1 is a novel tumour-promoting factor and an ideal target for HCC therapy. This study aimed to expand the understanding of HCC regulation by OCT1. The expression levels of the target genes were examined using qPCR. The inhibitory effects of a novel inhibitor of OCT1 (NIO-1) on HCC cells and OCT1 activation were examined using Chromatin immunoprecipitation or cell survival assays. RFA was performed in a subcutaneous tumour model of nude mice. Patients with high OCT1 expression in the tumour tissue had a poor prognosis after RFA treatment (n = 81). The NIO-1 showed antitumor activity against HCC cells and downregulated the expression of the downstream genes of OCT1 in HCC cells, including those associated with cell proliferation (matrix metalloproteinase-3) and epithelial-mesenchymal transition-related factors (Snail, Twist, N-cadherin, and vimentin). In a subcutaneous murine model of HCC, NIO-1 enhanced the effect of RFA treatment on HCC tissues (n = 8 for NIO-1 and n = 10 for NIO-1 + RFA). This study demonstrated the clinical importance of OCT1 expression in HCC for the first time. Our findings also revealed that NIO-1 aids RFA therapy by targeting OCT1.