Metastasis Of Solid Tumors Research Articles

A review on intrathecal administration of medications for leptomeningeal metastases in solid tumors

Leptomeningeal disease (LMD) is a particular mode of central metastasis in malignant tumors. It occurs when tumor cells infiltrate the subarachnoid space and cerebrospinal fluid (CSF), spreading throughout the central nervous system (CNS). LMD is a rare but devastating complication of malignant tumors. It can occur in various types of cancers, with lung and breast cancer being the most frequently associated. The treatment approach for LMD includes a combination of supportive care, surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, and intrathecal (IT) therapy, among other modalities. Despite the challenges in determining the optimal treatment for LMD, IT therapy remains one of the primary therapeutic strategies. This therapy can directly circumvent the blood–brain barrier. Moreover, a low-dose medication can achieve a higher drug concentration in the CSF, resulting in better cytotoxic effects. Chemotherapy drugs such as methotrexate, cytarabine, and thiotepa have been widely studied as traditional IT therapies. In recent years, the advent of novel anti-tumor drugs has led to a growing number of agents being employed for IT administration in the treatment of malignant tumors with LMD. This article presents a comprehensive review of the current advancements in IT administration of chemotherapy, targeted, and immunotherapy drugs for the treatment of LMD in solid tumors. In addition, we also discuss the safety issues associated with IT therapy, summarize the advantages of IT administration of different types of anti-tumor drugs, and put forward some suggestions for reducing adverse reactions. It is hoped that future research will focus on exploring more potentially effective anti-tumor drugs for IT treatment, conducting in-depth pharmacokinetic studies, and developing long-acting and low-toxic IT administration regimens for the treatment of meningeal metastases.

Novel N-(3-(1-(4-sulfamoylphenyl)triazol-4-yl)phenyl)benzamide Derivatives as Potent Carbonic Anhydrase Inhibitors with Broad-Spectrum Anticancer Activity: Leveraging Tail and Dual-Tail Approaches.

Carbonic anhydrases (CAs) IX and XII are crucial for the survival and metastasis of solid tumors under hypoxic conditions. We designed compounds 7a-s, integrating triazole and benzenesulfonamide scaffolds known for inhibiting tumor-associated CAs IX/XII. Initial synthesis included compounds 7a-e, followed by diversification with small hydrophobic groups (7f-m) and hydrophilic heterocyclic secondary amines (7n-s). Compounds were evaluated against CA II, IX, and XII to assess activity and selectivity. Chlorinated derivative 7l exhibited the highest efficacy against CA IX (KI = 0.317 μM) and ditrifluoromethylated 7j against CA XII (KI = 0.081 μM). Subsequent testing on 60 cancer cell lines at 10 μM revealed promising anticancer activity, especially for dimethylated derivative 7h (CA IX, KI = 1.324 μM; CA XII, KI = 0.435 μM), with GI50 values ranging from 0.361 to 9.21 μM. Molecular docking analyses elucidated binding mechanisms, highlighting potential inhibitory actions of compound 7h on CAs IX and XII.

Prognostic Correlation of Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor with Radiological Tumor Size in Pediatric Nephroblastoma and Neuroblastoma: A Prospective Study

ABSTRACT Introduction: Angiogenesis plays an important role in the growth, progression, and metastasis of solid tumors. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF); both are potent angiogenic factors implicated with the growth and metastasis of solid tumors mostly in adult studies. Rapidly growing and large-size tumors have a positive correlation with these factors which are measured in serum and urine samples of patients. There is little literature available for pediatric patients that compare the computed tomography findings (size) of pediatric solid tumors with serum VEGF and serum/urinary bFGF. This prospective study aims to determine the correlation of serum VEGF and serum/urinary bFGF with the size of common pediatric solid tumors (nephroblastoma and neuroblastoma [NB]) to determine its diagnostic and prognostic significance. Materials and Methods: A prospective case–control study was done for 3 years (December 2020 to November 2023) at our institute. All children aged 1 day to 18 years admitted with the diagnosis of NB and nephroblastoma (Wilms’ tumor [WT]) were included after parental consent. The control group includes children of varying ages without any malignancy. Blood and urinary samples were collected at admission before or a week after the biopsy and the level of bFGF and VEGF was analyzed with the ELISA method. Triple-phase computed tomographies along with recommended evaluation were performed according to the tumor as per international standard protocols. Appropriate statistical analyses were done. Results: A total of 30 patients were included in the cohort, of which 13 patients were with the diagnosis of WT. Only 7 patients had metastatic disease. All the patients were treated with neoadjuvant chemotherapy, surgery, and radiotherapy according to their presentation and tumor stage. Both the growth factors, i.e., VEGF (median value - 314.38 pg/mL) and bFGF (median value - 18.96 pg/mL), are elevated in all the tumor patients in comparison with the controls (median VEGF - 100.51 pg/mL and bFGF - 15.6 pg/mL). When compared with the tumor size, no significant associations are found (with VEGF P - 0.40 and with bFGF P - 0.44). Conclusion: Although no satistically significant correlations were found between serum/urinary levels of bFGF and VEGF with tumor size, this study showed the raised median serum value of bFGF and VEGF in patients with NB and WT in comparison to controls and provided the rationale to explore this issue on a larger group of patients.

Symptomatic improvement with whole patient care for Leptomeningeal Carcinomatosis diagnosis: A Case Report

Leptomeningeal Carcinomatosis (LC) is the metastasis of solid and hematological tumors to the pia and arachnoid mater, as well as the subarachnoid space. While uncommon, this complication is associated with mortality and remains difficult to treat. This case describes a 53-year-old female who presented with isolated left-sided facial droop and bilateral hearing loss. Her past medical history was significant for left breast carcinoma status post lumpectomy, lymph node dissection, and breast radiation. During the hospital stay, right-sided facial paralysis developed which prompted MRI brain and spine revealing possible leptomeningeal carcinomatosis, further confirmed by lumbar puncture results. The purpose of this case report is to highlight the presenting clinical picture and outpatient treatment following hospitalization in hopes to call attention to this disease and inspire an early consideration of LC as a differential diagnosis among treating physicians.

PERSPECTIVES OF USING THE EXTRACELLULAR NEUTROPHIL TRAP LEVELS IN COLORECTAL CANCER: A LITERATURE REVIEW

Relevance: This literature review evaluates an alternative type of neutrophil immune response – the ability for NETosis or forming neutrophil extracellular traps (NETs). NETs influence the processes of carcinogenesis and cancer metastasis and play a role in the formation of tumor microenvironment and tumor-associated inflammation. The study of netosis has provided a deeper understanding of the mechanisms of intercellular interactions of the tumor microenvironment. NETs can also potentially become prognostic markers and predictors of complications of antitumor treatment of various cancers, including colorectal cancer (CRC). The study aimed to summarize and systematize the current information on NETs and the impact of this phenomenon on the course of CRC and metastasis, as well as identify potential clinical points for using this marker in oncological practice. Methods: The articles were searched and selected in Pubmed, Web of Science, Scopus, and RSCI databases by keywords among articles published in the past 10 years. Results: NETs play an important role in the immune response to tumor niches and the metastasis of various solid tumors. There are data on the possibility of using NETs as a prognostic marker in various oncologic diseases. Experimental and clinical studies showed a potential relationship between NET levels and chemotherapy resistance and the impact of chemotherapy on the incidence of various complications. Chemotherapy with 5-Fluorouracil, according to the results of experimental studies, significantly increases the formation of NETs. The influence on the mechanism of NET release showed limited clinical efficacy of chemotherapy in CRC patients with PIK3CA mutation. The phenomenon of NETs is still poorly understood, and more studies are needed to widely implement this indicator into routine practice; however, research in this direction has the potential to have broad prospects for clinical application. Conclusion: Advances in immunology and the discovery of the netosis process have led to a deeper understanding of the mechanisms of interactions in the tumor microenvironment. Studying this process may make it possible to control or predict cancer progression and complications of antitumor treatment.

Emerging role of EZH2 in solid tumor metastasis.

Cancer cells experience multiple reversible changes during their metastatic spread. Epigenetic reprogramming, being reversible, has emerged as a critical driver of cancer metastasis. Epigenetic modulator Enhancer of Zeste homolog 2 (EZH2) is an important candidate for such reprogramming events. Both EZH2 protein and its catalytic function (H3K27me3) have been shown to promote solid tumor metastasis, although EZH2 functional inhibition has limited impact on primary tumor growth in some cancers. The dichotomous gene regulatory roles of EZH2 and H3K27me3 are currently being investigated to understand how they collectively contribute to promote metastasis. Here, we examine the multifaceted role of EZH2 in modulating solid tumor metastasis and its therapeutic potential.

TFAP2A activates CTHRC1 to influence the migration of lung adenocarcinoma cells by modulating fatty acid metabolism.

Tumor metastasis is the main cause of death in lung adenocarcinoma (LAC) patients. It is known that the collagen triple helix repeats containing 1 (CTHRC1) protein is implicated in tissue remodeling and is tightly linked to the carcinogenesis and metastasis of solid tumors. However, the functional role of CTHRC1 and its potential mechanisms in LAC cell metastasis have not been fully explored. The expression level of CTHRC1 in LAC was measured by using bioinformatics analysis combined with quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB). Small interfering RNA and overexpression methods were employed to investigate the function and molecular mechanisms of CTHRC1 in LAC cells. Through bioinformatics analysis, qRT-PCR, WB, scratch healing assay, Transwell, assay kits, and flow cytometry, the downstream pathways and upstream regulatory genes of CTHRC1 in LAC cells were investigated. The binding sites were verified by using chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene experiments. In this project, CTHRC1 was found to be abnormally upregulated in LAC tissues and cells. CTHRC1 promoted the migration and invasion of LAC cells. The promoting effect of CTHRC1 overexpression on LAC cell migration was weakened after the addition of orlistat (a fatty acid synthase inhibitor). Mechanistically, TF AP-2α (TFAP2A) was directly bound to the upstream sequence of the CTHRC1 promoter and promoted CTHRC1 expression. The TFAP2A-CTHRC1 axis induced the migration of LAC cells by activating fatty acid metabolism. Our results indicated that TFAP2A activates fatty acid metabolism by positively modulating the expression of CTHRC1, thereby facilitating tumor cells' migration and invasion. These findings provided novel insights into LAC treatment and future research.

A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment.

Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and coordinate the process of hypoxia-induced gene expression, leading to cancer progression. Increasing evidence has uncovered that long noncoding RNAs (lncRNAs), which are closely associated with cancer, play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified SZT2-AS1 as a novel lncRNA in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis both in vitro and in vivo. And SZT2-AS1 also mediated the hypoxia-induced HCC progression. Clinical data indicated that SZT2-AS1 level was substantially increased in HCC and closely associated with poor clinical outcomes, acting as an independent prognostic predictor. Mechanistically, SZT2-AS1 recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer, and it was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and as a potential therapeutic target in HCC.

High expression of SLC34A2 contributes to chemoresistance of non-small cell lung cancer against gefitinib: The critical role of miR-124–3p

Gefitinib is a therapeutic agent used to treat lung carcinoma, including non-small cell lung cancer (NSCLC). However, mechanisms underlying NSCLC cell resistance to gefitinib remain largely uncharacterized. In this study, we explored the association between the miR-124–3p/SLC34A2 axis and gefitinib resistance using a series of in vivo and in vitro assays. Data indicated that miR-124–3p is downregulated, while SLC34A2 is upregulated, in gefitinib-resistant NSCLC cells. Overexpression of miR-124–3p reduced NSCLC cell resistance to gefitinib by suppressing cell viability, inducing apoptosis, and decreasing N-cadherin expression. Conversely, inhibiting miR-124–3p in NSCLC cells led to increased cell viability and reduced apoptosis. Overexpression of SLC34A2 in NSCLC cells further heightened gefitinib resistance. In a xenograft mouse model, SLC34A2 overexpression promoted solid tumor growth and metastasis, while miR-124–3p overexpression inhibited these effects. Our results highlight that the interaction between miR-124–3p and SLC34A2 plays an indispensable role in determining gefitinib resistance in NSCLC cells.

Proton pump inhibitor attenuates acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis

The incidence of brain metastasis (BM) is gradually increasing, and the prognosis and therapeutic effect are poor. The emergence of immunotherapy has brought hope for the development of BM treatments. This study revealed that compared with primary cancers (PCs), BMs have a “colder” and more acidic tumor microenvironment (TME), resulting in reduced protein levels of mesothelin (MSLN), a promising target for chimeric antigen receptor-T (CAR-T) cell therapy for triple-negative breast cancer (TNBC) with BMs. These factors could significantly decrease the efficiency of MSLN-CAR-T cells in TNBC BMs. Pantoprazole (PPZ) administration at the most commonly used dose in the clinic notably increased the pondus hydrogenii (pH) of the TME, inhibited lysosomal activity, increased the membrane levels of the MSLN protein and improved the killing ability of MSLN-CAR-T cells both in vitro and in vivo. Similar results were obtained in non-small cell lung cancer (NSCLC) BMs. Hence, when administered in combination with CAR-T cells, PPZ, which increases the protein levels of target antigens, may constitute a new immunotherapeutic strategy for treating solid tumors with BMs.

Albumins constrainting the conformation of mitochondria-targeted photosensitizers for tumor-specific photodynamic therapy

Tumor ablation Preclinical organelle-targeted phototherapies have effectively achieved tumor photoablation for regenerative biomedical applications in cancer therapies. However, engineering effective phototherapy drugs with precise tumor-localization targeting and organelle direction remains challenging. Herein, we report a albumins constrainting mitochondrial-targeted photosensitizer nanoparticles (PSs@BSAs) for tumor-specific photodynamic therapy. X-ray crystallography elucidates the two-stage assembly mechanism of PSs@BSAs. Femtosecond transient absorption spectroscopy and quantum mechanical calculations reveal the implications of conformational dynamics at the excited state. PSs@BSAs can efficiently disable mitochondrial activity, and further disrupt tumor angiogenesis based on the photodynamic effect. This triggers a metabolic and oxidative stress crisis to facilitate photoablation of solid tumor and antitumor metastasis. The study fully elucidates the interdisciplinary issues of chemistry, physics, and biological interfaces, thereby opening new horizons to inspire the engineering of organelle-targeted tumor-specific photosensitizers for biomedical applications.

In Silico Screening of 1,3,4-Thiadiazole Derivatives as Inhibitors of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2).

Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed in many human solid tumors, making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead compounds with azole moiety exhibiting VEGFR-2 inhibitory effects. A ligand-based pharmacophore model was constructed using the X-ray crystallographic structure of VEGFR-2 complexed with tivozanib (PDB ID: 4ASE) to screen the ZINC15 database. Following virtual screening, six compounds demonstrated promising docking scores and drug-likeness comparable to tivozanib. These hits underwent detailed pharmacokinetic analysis to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Furthermore, Density Functional Theory (DFT) analysis was employed to investigate the molecular orbital properties of the top hits from molecular docking. Molecular dynamics (MD) simulations were conducted to evaluate the conformational stability of the complexes over a 100 ns run. Results indicated that the compounds (ZINC8914312, ZINC8739578, ZINC8927502, and ZINC17138581) exhibited the most promising lead requirements for inhibiting VEGFR-2 and suppressing angiogenesis in cancer therapy. This integrated approach, combining pharmacophore modeling, molecular docking, ADMET studies, DFT analysis, and MD simulations, provides valuable insights into the identification of potential anti-cancer agents targeting VEGFR-2.

A multifunctional nutrient transfer nanoCRISPR scaffold induces metabolic remodeling to fuel cancer immunotherapy

Tumor cells are major consumers of glutamine and glucose in the tumor microenvironment (TME), causing nutrient deficiency of immune cells, leading to immune escape and resistance to immunotherapy. However, pharmacological modulation would cause metabolic inhibition in both immune cells and tumor cells. Herein, a multifunctional nutrient transfer nanoCRISPR scaffold (FUEL) is fabricated to realize “nutrient transfer” from tumor cells to immune cells and remodel the metabolism in the TME, thus fueling cancer immunotherapy. FUEL is endowed with characteristics of enhanced blood circulation, specific tumor cell targeting, effective lysosomal escape, cascaded reactive-oxygen-species (ROS)-responsiveness, and ASCT2/GLUT1 dual gene knockout. Consequently, FUEL can restrict nutrient uptake of tumor cells thoroughly, increase glucose and glutamine in the TME remarkably to satisfy metabolic demands of immune cells, and reduce immunosuppressive metabolites concurrently. Metabolomics data shows that energy metabolism and biosynthesis are reduced in tumor cells but enhanced in immune cells. FUEL remarkably impedes the growth, metastasis, and recurrence of solid tumors in mice, further shows stronger anti-tumor immune responses and enhanced tumor inhibition in combination with anti-PD-L1 antibody. Overall, this nutrient transfer strategy enables a “one arrow aiming at three eagles” effect that induces a cascade amplification of antitumor immune responses for the maximized tumor therapy efficacy.

Craniospinal irradiation for leptomeningeal metastasis of solid tumors: survival analysis and prognostic factors.

We conducted a study to examine the treatment outcomes and prognostic factors for patients who underwent craniospinal irradiation (CSI) for leptomeningeal metastasis of solid tumors. This retrospective study included patients who received CSI for leptomeningeal metastasis at a single institute between 2010 and 2021. Data from clinical records and the radiation information system were obtained and analyzed. A total of 25 patients were included in the study. Eighteen patients (72%) completed the scheduled CSI. The median overall survival (OS) period was 4.8months (95% confidence interval (CI): 3.2-10.0months). Symptom relief was achieved in four out of 23 symptomatic patients (17%). Non-hematological adverse events occurred in 12 patients (48%), with 1 patient (4%) developing Grade 3 bacterial meningitis and the other patients having Grade 1-2 events. Twenty patients (80%) had hematological adverse events of Grade 3 or higher. Grade 4 hematologic toxicities occurred in 3 patients (12%) due to neutropenia and in 11 patients (44%) due to lymphopenia. In multivariate Cox regression analysis, the systemic immune-inflammation index (SII) was identified as the only significant parameter for predicting OS. The median OS periods for patients with SII < 607 and SII ≥ 607 were 6.1 and 2.1months, respectively (P = 0.003). In conclusion, this study showed the treatment outcomes of CSI for leptomeningeal metastasis of solid tumors. It was shown that a high baseline SII was associated with shorter OS after CSI. The findings will contribute to the evaluation of prognosis after CSI.

Predicting lymphoma prognosis using machine learning-based genes associated with lactylation

BackgroundLactylation, a newly discovered PTM involving lactic acid, is linked to solid tumor proliferation and metastasis. Lymphoma patients exhibit high lactic acid levels, yet lactylation's role in lymphoma is underexplored. This study aimed to identify lactylation-related genes in lymphoma using tumor databases and assess their predictive value in patient prognosis through cell experiments and clinical specimens. MethodsUsing TCGA and GEO datasets, we analyzed the expression levels of lactylation-related genes in diffuse large B-cell lymphoma patients. We also evaluated the prognostic significance of lactylation gene risk scores, exploring their impact on drug sensitivity and tumor immune function. Key lactylation-affecting genes were identified and functionally validated through cell experiments and mouse in vivo experiments. Additionally, the relationship between lactylation and lymphoma prognosis was examined in clinical specimens. ResultsWe identified 70 genes linked to diffuse large B-cell lymphoma prognosis from the lactylation-related gene set. Using clinical data and a COX regression algorithm, we developed an optimized lactylation Riskscore model. This model significantly correlated with prognosis and showed differences in immune cell infiltration, particularly macrophages. High-risk patients showed resistance to chemotherapy drugs but responded well to immunotherapy. HNRNPH1, a lactylation-related gene, influenced patient prognosis, apoptosis, cell cycle distribution in lymphoma cells, and tumor volume in mice. In lymphoma specimens, lactylation levels correlated with Bcl-2, C-myc, and P53 levels. ConclusionsLactylation impacts diffuse large B-cell lymphoma prognosis, tumor immune function, and drug resistance. Our lactylation-based Riskscore model aids in patient stratification and treatment selection. HNRNPH1 regulates lactylation, thereby affecting patient prognosis.

The Activity of the Proapoptotic Protein Caspase-3 Changes in Glial Cells of the Peritumoral Zone of Secondary Brain Tumors, and its Relationship with Intraoperative Photodynamic Therapy

The metastasis of solid tumors to the central nervous system is a pressing issue due to its association with poor prognosis and low survival rates. Recent studies have shown that glial cells can promote metastasis even before the appearance of tumor cells, highlighting the need for new treatment methods. One potential method is intraoperative photodynamic therapy (PDT), which has been shown to improve the success of neuro-oncological surgeries and local control. However, the role of glial cell apoptosis in the development of brain metastases and the impact of PDT on apoptosis are still unclear. In this study, biopsy samples were collected from 25 patients undergoing surgery at the Polenov Neurosurgical Institute, including 16 women and 9 men with an average age of 63.04 years (ranging from 39 to 78 years). PDT was administered using the drug "Photoditazine" at a dosage of 1 mg per 1 kg of body weight. Histological sections stained with hematoxylin and eosin, as well as immunohistochemical (IHC) reactions with a rabbit polyclonal antibody to active caspase-3, were analyzed in the pathology department. The results showed that in the peritumoral zone of metastases, oligodendrocytes were the main cells undergoing apoptotic death, and PDT also induced apoptosis in astrocytes. The use of PDT significantly increased apoptosis in brain tissue (p&lt;0.05). These findings suggest that targeting gliocyte apoptosis and caspase-dependent apoptosis mechanisms may be a potential therapeutic approach in the comprehensive treatment of metastatic carcinomas.

Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies.

The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it a promising target for antitumor drug development through synthetic lethality. In this study, we present the discovery and detailed characterization of AD1058, a highly potent and selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy in inhibiting cell proliferation, disrupting the cell cycle, and inducing apoptosis compared to AZD6738. AD1058 displays potent antitumor effects as a single agent or in combination with clinically approved tumor therapies such as PARP inhibitors, ionizing radiotherapy, or chemotherapy in vivo. Considering its enhanced ability to permeate the blood-brain barrier, AD1058 is a promising clinical candidate for the treatment of brain metastases and leptomeningeal metastases in solid tumors. Additionally, among reported ATR inhibitors, AD1058 features the shortest synthesis route and the highest efficiency to date.

NDRG1 enhances the sensitivity to Cetuximab by promoting Stat1 ubiquitylation in colorectal cancer

IntroductionCetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated. ObjectiveOur study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity. MethodsThrough mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo. ResultsStat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo. ConclusionOur study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.

The Role of Platelet Activation in the Development and Metastasis of Solid Tumors

The blood coagulation system is actively involved in the development of cancer. It is known that many solid tumors express tissue factor, a “trigger” of the cascade of plasma coagulation reactions, which leads to an increased risk of cancer-associated thrombosis and venous thrombosis in cancer patients. It has also long been known that platelets - small cellular fragments that are the basis of blood clots - play a critical role in metastasis by binding to the tumor cell after it enters the blood vessel, “shielding” it from the immune system and promoting the adhesion and extravasation of the tumor cell into tissues and the formation metastasis. In addition, platelets, being mobile “storehouses” of growth factors, are actively attracted and, in some cases, consumed by the tumor, which contributes to its development and vascularization. Platelet attraction occurs both through activation of the blood coagulation system in the tumor area and through exposure of the adhesive surface by the tumor. Activated in the tumor vicinity, platelets attract and induce neutrophil activation and the formation of neutrophil extracellular traps (NETs), thereby modulating the tumor microenvironment. When activated, platelets are known to secrete a variety of growth factors that promote both tumor development and vascularization. In addition to direct interaction, platelets and tumor cells exchange mRNA, micro-RNA and other regulatory molecules through microvesicles, while platelets are containers for the spread of tumor genetic material (circulating nucleic acids) throughout the body. In this review, we consider the molecular mechanisms of platelet participation in the development and metastasis of solid tumors, and also discuss possible options for pharmacological interruption of this interaction.

Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer.

Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) invitro. Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels invitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. The substantial expression of Trop-2 in cerebral metastases, along with our preclinical invitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.