Tumor Invasion Research Articles

Clinical implications of epithelial-to-mesenchymal transition in cancers which potentially spread to peritoneum.

Epithelial-to-mesenchymal transition (EMT) is a biological process by which epithelial cells increase their motility and acquire invasive capacity. It represents a crucial driver of cancer metastasis and peritoneal dissemination. EMT plasticity, with cells exhibiting hybrid epithelial/mesenchymal states, and its reverse process, mesenchymal-to-epithelial transition (MET), allows them to adapt to different microenvironments and evade therapeutic intervention. Resistance to conventional treatments, including chemotherapy, is a major problem. Therapies targeting EMT may inhibit tumour cell migration and invasion, while affecting normal cells and repair mechanisms, resulting in potential side effects. This paper addresses the question of the impact of EMT status on cancers with potential spread to the peritoneum, which has remained unclear in literature. Relevant studies were selected from 2000 to 2024. Three macrosections were analysed: (i) pathological characteristics, (ii) surgical implications and (iii) oncological therapies. The focus was on survival and peritoneal recurrence time in patients who underwent surgical treatment.

The Patterns of P53, E-Cadherin, β-Catenin, CXCR4 and Podoplanin Expression in Oral Squamous Cell Carcinoma Suggests a Hybrid Invasion Model: an Immunohistochemical Study on Tissue Microarrays.

Oral squamous cell carcinoma (OSCC) is a significant public health challenge associated with high mortality rates primarily due to its invasive and metastatic behavior. This study aimed to evaluate the expression patterns of five critical biomarkers: β-catenin, E-cadherin, podoplanin (PDPN), CXCR4, and p53 in OSCC tissues and to investigate their correlations with clinicopathologic features and patient outcomes. We conducted an immunohistochemical analysis utilizing tissue microarrays (TMAs) from 95 patients diagnosed with primary OSCC. The expression levels of the five biomarkers were quantified using H-scores. Statistical analyses, including Kruskal-Wallis tests, Dunn's post-hoc tests, and correlation analyses, were performed to explore the associations between biomarker expression, clinicopathologic parameters, and overall patient survival. The study found that loss of E-cadherin and β-catenin expression was significantly associated with increased tumor depth and lymphatic invasion, corroborating their role in the process of epithelial-mesenchymal transition (EMT). High levels of PDPN were noted in both early and late-stage OSCC, indicating its potential involvement in initiating invasive behaviors. Notably, CXCR4 expression exhibited positive correlations with E-cadherin and β-catenin, suggesting a hybrid invasion phenotype incorporating both EMT and collective invasion strategies. Although Cox regression analysis did not reveal significant associations between biomarker expression and overall survival (OS) or disease-specific survival (DSS), factors such as alcohol consumption, tumor size, lymph node involvement, and advanced clinical stage emerged as significant negative predictors of both OS and DSS. The expression profiles of β-catenin, E-cadherin, PDPN, CXCR4, and p53 in OSCC tissues provide valuable insights into a hybrid model of invasion that integrates mechanisms of EMT with an important rule in the tumor invasion. This nuanced understanding of OSCC progression highlights the potential of PDPN and CXCR4 as novel therapeutic targets, emphasizing the need for further investigation into their roles in OSCC biology and the development of targeted treatments that could improve patient outcomes and survival rates.

A Comprehensive Analysis of Neoadjuvant Chemotherapy in Breast Cancer: Adverse Events, Clinical Response Rates, and Surgical and Pathological Outcomes-Bozyaka Experience.

Objectives: To evaluate the neoadjuvant chemotherapy (NACTx) process in breast cancer (BC), its significant treatment-related adverse events (trAEs), tumor clinical response rates, and surgical and pathological outcomes, and to analyze factors influencing cavity shaving and axillary lymph node dissection (ALND) following sentinel lymph node biopsy (SLNB). Methods: A comprehensive retrospective study was conducted at a single center on patients who received NACTx for BC between 2015 and 2021. Results: Medical records of 242 patients were reviewed. Approximately one-fifth encountered grade ≥ 3 trAEs (21.5%), leading 3.3% to discontinue chemotherapy. Anthracycline cardiotoxicity (2.2%) caused one death (mortality rate = 0.4%). For clinical response and surgical and pathological outcomes, 229 patients were eligible. Clinical progression occurred in 3.9% of the patients (14% in triple-negative BC, p = 0.004). Breast-conserving surgery (BCS) was performed in 55% of the patients. There was no significant difference between the type of breast surgery (BCS vs. mastectomy) and molecular subtype, histology, tumor size, or tumor's pathological response degree. Cavity shaving was required in one-fifth of the patients who underwent BCS (n = 134) due to an invasive tumor at the surgical margin (SM). Tumor histology (invasive ductal vs. invasive lobular carcinoma; OR: 4.962, 95% CI 1.007-24.441, p = 0.049) and tumor SUVMax value (OR: 0.866, 95% CI 0.755-0.993, p = 0.039) had significant independent efficacy on SM positivity. Initially, 75% underwent SLNB, but nearly half of them needed ALND. ALND rates were significantly higher in the luminal A and LB-HER2(-) groups (87% vs. 69%) than in the HER2(+) and TN groups (43% to 50%) (p = 0.001). All luminal A patients and those with lobular histology required ALND after SLNB, but no patients in the HER2-enriched group required ALND. ER positivity and higher PR expression levels were associated with an increased need for ALND after SLNB, whereas HER2 positivity and higher SUVMax values of LN(s) were associated with a significantly reduced need for ALND. About 27% of the patients achieved overall pCR. No pCR was achieved in the LA group. Conclusions: The BC NACTx process requires close monitoring due to severe AEs and disease progression. NACTx decisions must be made on experienced multidisciplinary tumor boards, considering tumor characteristics and expected targets.

The Proapoptotic Effect of MB-653 Is Associated with the Modulation of Metastasis and Invasiveness-Related Signalling Pathways in Human Colorectal Cancer Cells.

Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate. In this study, we investigated the cytotoxic, proapoptotic, and anti-invasive effects of the synthetic indole phytoalexin MB-653. The antiproliferative effect was determined using an MTT assay, showing IC50 values of 5.8 ± 0.3 μmol/L for HCT116 cells and 6.1 ± 2.1 μmol/L for Caco2 cells. Flow cytometry and Western blot analysis were employed to investigate the molecular mechanisms underlying cytotoxicity, proapoptotic action, and anti-invasion effects. The proapoptotic activity was evidenced by the activation of caspases 3 and 7, mitochondrial dysfunction, and an increased number of apoptotic cells, confirmed by annexin V/PI and AO/PI staining. Additionally, MB-653 induces dose-dependent G2/M phase cell cycle arrest, the cause of which could be cyclin B1/CDC2 complex dysfunction and/or a decrease in α-tubulin protein expression. Another important observation was that MB-653 modulated several signalling pathways associated with various cellular activities, including survival, proliferation, tumour invasiveness, metastasis, and epithelial-mesenchymal transition (EMT). We further demonstrated its safety for topical and parenteral application. To sum up, our results indicate the real potential of MB-653 in treating colorectal cancer.

Nanostructured lipid carriers for enhanced batimastat delivery across the blood-brain barrier: an in vitro study for glioblastoma treatment.

Glioblastoma presents a significant treatment challenge due to the blood-brainbarrier (BBB) hindering drug delivery, and the overexpression of matrix metalloproteinases (MMPs), which promotes tumor invasiveness. This study introduces a novel nanostructured lipid carrier (NLC) system designed for the delivery of batimastat, an MMP inhibitor, across the BBB and into the glioblastoma microenvironment. The NLCs were functionalized with epidermal growth factor (EGF) and a transferrin receptor-targeting construct to enhance BBB penetration and entrapment within the tumor microenvironment. NLCs were prepared by ultrasonicator-assisted hot homogenization, followed by surface functionalization with EGF and the construct though carbodiimide chemistry. The construct was successfully conjugated with an efficiency of 81%. Two functionalized NLC formulations, fMbat and fNbat, differing in the surfactant amount, were characterized. fMbat had a size of 302nm, a polydispersity index (PDI) of 0.298, a ζ-potential (ZP) of -27.1mV and an 85% functionalization efficiency (%FE), whereas fNbat measured 285nm, with a PDI of 0.249, a ZP of -28.6mV and a %FE of 92%. Both formulations achieved a drug loading of 0.42μg/mg. In vitro assays showed that fNbat was cytotoxic and failed to cross the BBB, while fMbat showed cytocompatibility at concentrations 10 times higher than the drug's IC50. Additionally, fMbat inhibited MMP-2 activity between 11 and 62% across different cell lines and achieved a three-fold increase in BBB penetration upon functionalization. Our results suggest that the fMbat formulation has potential for enhancing GB treatment by overcoming current drug delivery limitations and may be combined with other therapeutic strategies for improved outcomes.

The Dual Role of ADAMTS9-AS1 in Various Human Cancers: Molecular Pathogenesis and Clinical Implications.

Long non-coding RNA (lncRNA) is a type of non-coding RNA distinguished by a length exceeding 200 nucleotides. Recent studies indicated that lncRNAs participate in various biological processes, such as chromatin remodeling, transcriptional and post-transcriptional regulation, and the modulation of cell proliferation, death, and differentiation, hence influencing gene expression and cellular function. ADAMTS9-AS1, an antisense long non-coding RNA situated on human chromosome 3p14.1, has garnered significant interest due to its pivotal involvement in the advancement and spread of diverse malignant tumors. ADAMTS9-AS1 functions as a competitive endogenous RNA (ceRNA) that interacts with multiple microRNAs (miRNAs) and plays a crucial role in regulating gene expression and cellular functions by modulating essential signaling pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, and Ras/MAPK pathways. Dysregulation of this factor has been linked to tumor development, migration, invasion, and resistance to apoptotic mechanisms, including as iron-induced apoptosis, underscoring its intricate function in cancer pathology. While current research has clarified certain pathways involved in cancer formation, additional clinical and in vivo investigations are necessary to enhance comprehension of its specific involvement across various cancer types. This review encapsulates the recent discoveries on the correlation of ADAMTS9-AS1 with numerous malignancies, clarifying its molecular mechanisms and its prospective role as a therapeutic target in oncology. Furthermore, it identifies ADAMTS9-AS1 as a potential early diagnostic biomarker and therapeutic target, offering novel opportunities for targeted intervention in oncology.

A Pilot Study of Exosome Proteomic Profiling Reveals Dysregulated Metabolic Pathways in Endometrial Cancer.

Background/Objectives: Endometrial cancer (EC) is the second most frequent gynecological malignant tumor in postmenopausal women. Pathogenic mechanisms related to the onset and development of the disease are still unknown. To identify dysregulated proteins associated with EC we exploited a combined in vitro/in silico approach analyzing the proteome of exosomes with advanced MS techniques and annotating their results by using Chymeris1 AI tools. Methods: To this aim in this pilot study, we performed a deep proteomics analysis with high resolution MS (HRMS), advanced computational tools and western blotting for proteomics data validation. Results: That allowed us to identify 3628 proteins in serum albumin-depleted exosomes from 10 patients with EC compared to 10 healthy controls. This is the largest number of proteins identified in EC serum EVs. After quantification and statistical analysis, we identified 373 significantly (p < 0.05) dysregulated proteins involved in neutrophil and platelet degranulation pathways. A more detailed bioinformatics analysis revealed 61 dysregulated enzymes related to metabolic and catabolic pathways linked to tumor invasion. Through this analysis, we identified 49 metabolic and catabolic pathways related to tumor growth. Conclusions: Altogether, data shed light on the metabolic pathways involved in tumors. This is very important for understanding the metabolism of EC and for the development of new therapies.

Transferrin receptor uptakes iron from tumor-associated neutrophils to regulate invasion patterns of OSCC

BackgroundTransferrin receptor (TFRC) uptakes iron-loaded transferrin (TF) to acquire iron and regulates tumor development. Nonetheless, the clinical values and the precise functions of TF-TFRC axis in the development of oral squamous cell carcinoma (OSCC) were still undiscovered, especially the impacts of their regional heterogeneous expression.MethodsImmunohistochemistry (IHC) was used to analyze the expression of TFRC in 106 OSCC patients. Then the prognostic value of TFRC was compared between high and low worst pattern of invasion (WPOI) patients. OSCC cells with low or high expression of TFRC were constructed, and functional experiments were performed to elucidate the effects of TFRC on the migration and proliferation of OSCC cells. Multi-immunofluorescence was applied to stain TF and tumor-associated neutrophils (TANs). The stimulating effects of TF were compared between normal and high TFRC cells in vitro and across different OSCC patients’ subgroups in our sample bank and TCGA database.ResultsHigher TFRC was expressed at invasive tumor front (ITF) in OSCC and correlated with WPOI. Only at ITF in patients with WPOI 4–5, TFRC was a prognostic factor. High TFRC promoted migration and proliferation of cancer cells. Additionally, TANs secreted TF outside. Exogenous TF promoted migration and proliferation of cells with high expression of TFRC. Compared to the TANslowTFRClow OSCC patients, TANshighTFRChigh OSCC patients had poorer clinical outcomes.ConclusionsHigher expression of TFRC at ITF and TANs-TF-TFRC axis promoted OSCC invasion at ITF by facilitating cell migration and proliferation, which may result from increased cellular iron uptake through regulating iron metabolism.

Selenium-Chondroitin Sulfate Nanoparticles Inhibit Angiogenesis by Regulating the VEGFR2-Mediated PI3K/Akt Pathway.

Chondroitin sulfate (CS), a class of glycosaminoglycans covalently attached to proteins to form proteoglycans, is widely distributed in the extracellular matrix and cell surface of animal tissues. In our previous study, CS was used as a template for the synthesis of seleno-chondroitin sulfate (SeCS) through the redox reaction of ascorbic acid (Vc) and sodium selenite (Na2SeO3) and we found that SeCS could inhibit tumor cell proliferation and invasion. However, its effect on angiogenesis and its underlying mechanism are unknown. In this study, we analyzed the effect of SeCS on tube formation in vitro, based on the inhibition of tube formation and migration of human umbilical vein endothelial cells (HUVECs), and evaluated the in vivo angiogenic effect of SeCS using the chick embryo chorioallantoic membrane (CAM) assay. The results showed that SeCS significantly inhibited the angiogenesis of chicken embryo urothelium. Further mechanism analysis showed that SeCS had a strong inhibitory effect on VEGFR2 expression and its downstream PI3K/Akt signaling pathway, which contributed to its anti-angiogenic effects. In summary, SeCS showed good anti-angiogenic effects in an HUVEC cell model and a CAM model, suggesting that it may be a potential angiogenesis inhibitor.

Germ Cell Neoplasia In situ in Undescended Testis: A Myth or Reality?

ABSTRACT Background: Untreated cryptorchid testes are in risk of intratubular germ cell neoplasia and subsequently may give rise to invasive germ cell tumors. Materials and Methods: Tissue samples were obtained from patients undergoing orchidectomy or orchiopexy and were subjected to routine histopathological and immunohistochemical examinations. Results: Forty-three patients were enrolled in this study out of which 30 samples were collected. The mean age of patients was 9.16 years. One case (6.7%) showed positivity of the germ cell neoplasia with anto placental alkaline phosphatase and Anto CD-117 positive. Other histopathological findings such as fibrocollagenous tissue and Leydig cell hyperplasia were reported. Conclusion: Early surgical management is of importance for a better outcome in cases of undescended testes.

Tissue stresses caused by invasive tumour: a biomechanical model.

Malignant tumorigenesis is a complex process involving growth, invasion and mechanical deformation of a cancerous tissue. In this paper, a biomechanical model is proposed to couple the mechanical and biological mechanisms governing invasive tumour development. As an example, this model is applied to investigate the spatio-temporal evolution of tissue stresses in an invasive tumour spheroid and its host tissue. I show that cancer invasiveness lowers the compressive tissue stresses and blurs the stress distribution across the cancerous-normal tissue boundary, both consistent with experimental observations. Importantly, with the steady propagation of the cancerous region driven by persistent cancer invasion, tumour stresses are predicted to saturate rather than keep increasing as in benign tumour growth. The model is further used to analyse the deformation and stress state of a cancerous tissue being cut into two pieces, and reproduces the bulge of the cut surface observed in experiments. I hope this study can pave the way for the quantitative evaluation of mechanical states in cancer.

Lymph Node Metastasis for pN+ Superficial Esophageal Squamous Cell Carcinoma.

This study aimed to analyze lymph node metastasis (LNM) distribution in superficial esophageal squamous cell carcinoma (ESCC) and its impact factors on survival. We reviewed 241 pT1N+ ESCC cases between February 2012 and April 2022 from 10 Chinese hospitals with a high volume of esophageal cancer (EC). We analyzed clinicopathological data to identify overall survival (OS) risk factors and LNM distribution in relation to tumor invasion depth. Of the 241 patients, 26 (10.8%) had pT1a cancer and 215 (89.2%) had pT1b cancer. We showed that N3 stage, ≤ 28 lymphadenectomies, and nerve infiltration (NI) were negative factors for OS in superficial pN+ ESCC, whereas the OS was not definitively affected by the tumor depth and the choice of adjuvant therapy. In general, the LNM rates of the 193 pT1N+ ESCC cases can be ranked in the following order: station 106recR > station 106recL > station 1 > station 7 > station 2. With deeper tumor invasion, the higher LNM rate was observed near the bilateral recurrent laryngeal nerves (RLN), but there was no statistically significant difference. In superficial ESCC, LNM was frequently observed along the 106recR (35.8%) and 106recL (25.6%) stations. Advanced N-staging (N3) was a major negative impact factor in prognosis, and adequate lymph nodes dissected (LND) (N > 28) improved OS of pT1N+ ESCC. However, in superficial ESCC, tumor infiltration depth did not affect patients' OS or the distribution of positive LNs. The optimal adjuvant treatment that favors survival for these patients required further investigation.

Gradients in cell density and shape transitions drive collective cell migration into confining environments.

Epithelial cell collectives migrate through tissue interfaces and crevices to orchestrate development processes, tumor invasion, and wound healing. Naturally, the traversal of cell collective through confining environments involves crowding due to narrowing spaces, which seems tenuous given the conventional inverse relationship between cell density and migration. However, the physical transitions required to overcome such epithelial densification for migration across confinements remain unclear. Here, in a system of contiguous microchannels of varying confinements, we show that epithelial (MCF10A) monolayers accumulate higher cell density and undergo fluid-like shape transitions before entering narrower channels. However, overexpression of breast cancer oncogene ErbB2 did not require such accumulation of cell density to migrate across matrix confinement. While wild-type MCF10A cells migrated faster in narrow channels, this confinement sensitivity was reduced after +ErbB2 mutation or with constitutively active RhoA. This physical interpretation of collective cell migration as density and shape transitions in granular matter could advance our understanding of complex living systems.

Enhanced antitumor immunity in breast cancer: Synergistic effects of ADAM10/ADAM17 inhibition, metabolic modulation, and camptothecin-loaded selenium nanoparticles.

In this study, we investigate the impact of a multi-targeted therapeutic approach that includes camptothecin (CPT), a potent chemotherapeutic topoisomerase inhibitor; metformin (Met), a metabolic modulator with emerging anti-tumor effects; and GW280264X, an inhibitor of ADAM 10/ADAM 17 enzymes, which are associated with tumor invasion and immune response. The study aims to assess the combined effects of these agents in enhancing CD8+ T cell-mediated anti-tumor immunity and suppressing cancer cell growth in triple-negative breast cancer (TNBC) models, both in vitro and in vivo. Cell viability was performed on the 4T1 human TNBC cell line. Furthermore, we examined c-MYC protein expression by western blot, TOX and NR4A expression by Real-time PCR, and the number of CD8+ CD28+ T cells by immunofluorescence assay to demonstrate the anticancer effects of combined of CPT, Met and GW280264X in BC growth, exhaustion and senescence of T cells. Regarding cell viability, HA-Se@CPT+Met and HA-Se@CPT+Met+GW280264X treatments decreased 4T1 cell growth (p<0.001). Combination therapy of Met, HA-Se@CPT, and GW280264X significantly reduced tumor volume and weight in vivo. This treatment also increased the number of CD8+ CD28+ T cells in the tumor microenvironment (TME) of BC (p<0.0001) and decreased the expression of TOX and NR4A (p<0.0001, p<0.01). Furthermore, decreased expression of c-MYC as an oncogene protein was seen in the single and combined treatment by HA-Se@CPT and GW280264X (p<0.05). These findings suggest that of HA-Se@CPT, Met, and GW280264X may inhibit tumor progression in BC by improving the function and infiltration of CD8+ T cells. Their effect is more pronounced when used in combination.

Prognostic factors in patients with localized and metastatic alveolar rhabdomyosarcoma. A report from two studies and two registries of the Cooperative Weichteilsarkom Studiengruppe CWS.

The histologic classification of rhabdomyosarcoma (RMS) as alveolar (aRMS) or embryonal (eRMS) is of prognostic importance, with the aRMS being associated with a worse outcome. Specific gene fusions (PAX3/7::FOXO1) found in the majority of aRMS have been recognized as markers associated with poor prognosis and are included in current risk stratification instead of histologic subtypes in localized disease. In metastatic disease, the independent prognostic significance of fusion status has not been definitively established. The objective of this analysis was to evaluate survival outcomes of patients with localized and metastatic aRMS and its association with fusion status and subtype (PAX3/7::FOXO1, FOXO1 break), and clinical prognostic factors. A total of 470 patients with aRMS ≤21 years of age enrolled in two CWS-trials and two registries was eligible for the analysis. The 5-year event-free survival (EFS) and overall survival (OS) rates for all patients with localized vs. metastatic tumors were: 56% and 65% vs. 18% and 22%, respectively. Of the 368 (78%) tumors tested, specific fusion was found in 330 (90%), considered "fusion positive" FP (PAX3::FOXO1 in 280, PAX7::FOXO1 in 49, FOXO1 break in 59 tumors). In patients with localized tumors, univariate analysis revealed that clinical group, tumor invasiveness (T1 vs.T2), regional lymph node involvement (N0 vs. N1) and FOXO1 fusion were significantly associated with EFS and OS, tumor size and PAX variant with OS only. In patients with metastatic aRMS, age, bone/marrow (B/BM) metastases, FOXO1 fusion and PAX variant were associated with EFS and OS, T status with OS only. Multivariate analysis identified PAX3::FOXO1 fusion as an independent adverse prognostic factor for EFS in patients with localized disease and for EFS and OS in patients with metastatic disease, B/BM metastases for EFS. PAX3::FOXO1 fusion should replace FOXO1 fusion as an adverse prognostic factor in risk stratification. The prognostic relevance of PAX7::FOXO1-positive and FOXO1 fusion negative aRMS, along with the clinical factors described in this report, allows further refinement of risk assessment of patients with localized and metastatic aRMS.

A novel piperine derivative HJJ_3_5 inhibits colorectal cancer progression by modulating EMT signaling pathways.

Colorectal cancer (CRC) is a fatal cancer prevalent worldwide, and epithelial-mesenchymal transition (EMT) is a key factor in tumor invasion and metastasis. Piperine, a natural alkaloid known for its antitumor properties, faces limitations in clinical use due to its moderate potency. To address this, our team synthesized and validated a new derivative, HJJ_3_5, which has shown potent antitumor activity against CRC cells. We assessed HJJ_3_5's inhibitory effects on the colon cancer cell line HCT116 through MTT, colony formation, and assays for cell migration and invasion. To uncover HJJ_3_5's molecular mechanisms, we utilized transcriptomics, weighted gene co-expression network analysis (WGCNA), and machine learning to identify key EMT-related genes. Western blot and immunofluorescence experiments confirmed the expression changes of these key proteins. Our findings indicate that HJJ_3_5 significantly suppressed the proliferation, migration, and invasion of HCT116cells in vitro, outperforming piperine. We discovered that HJJ_3_5 downregulated the expression of COL12A1, PJA2, VCAN, MEF2C, DPYD, and DDR2 genes in HCT116cells, which resulted in a decrease in the EMT regulator SNAI1, thus inhibiting EMT in these cells. In summary, this study presents novel evidence that the piperine derivative HJJ_3_5 inhibits the migration and invasion of colorectal cancer cells through SNAI1-mediated EMT.

Iron regulates MT1-MMP-mediated proMMP-2 activation and cancer cell invasion

Cellular iron plays a crucial role in many crucial physiological processes. Excessive iron retention due to iron influx and efflux imbalance contributes to cancer development and proliferation, as well as malignant conversion. Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a crucial role in tumor invasion and metastasis, because this enzyme can degrade various extracellular matrix components and cleave membrane tethered proteins on the cell surface. Herein, we demonstrate that cellular iron regulates MT1-MMP-mediated proMMP-2 activation and thereby cancer cell invasion. Iron depletion downregulated MT1-MMP expression in cancer cells, accompanied by inhibition of proMMP-2 activation. Conversely, iron loading stimulated MT1-MMP expression and MT1-MMP-containing extracellular vesicle secretion, thereby promoting proMMP-2 activation, which was inhibited through antioxidant treatment. Iron chelator deferasirox suppressed cancer cell invasion but not fibroblasts. Thus, this study indicated that iron accumulation in cancer may contribute to not only cell proliferation but also invasion by activating the MT1-MMP-MMP-2 axis.

TFAP2A Activates ADAM8 to Promote Lung Adenocarcinoma Angiogenesis Through the JAK/STAT Signaling Pathway.

As the most prevalent subtype of lung cancer, lung adenocarcinoma (LUAD) is closely associated with angiogenesis, which is fundamental to its progression. ADAM8 (A disintegrin and metalloproteinase 8) is an enzyme associated with tumor invasion, while its implications in LUAD angiogenesis are a field that awaits exploration. A thorough investigation into the impacts of ADAM8 on LUAD angiogenesis could contribute to the development of therapeutic drugs for LUAD. Bioinformatics delineated the expression profiles of TFAP2A and ADAM8 in LUAD tissues, focusing on ADAM8-enriched pathways. qRT-PCR confirmed their expression in LUAD cells. The CCK-8 assay was applied to gauge cell viability, and Western blot detected the presence of JAK2/STAT3 pathway proteins and VEGFR-2 and VEGF. Angiogenesis assays quantified the length of angiogenesis, and dual-luciferase and Chromatin immunoprecipitation assays verified the TFAP2A-ADAM8 binding. ADAM8 exhibited high expression in LUAD tissues and cells, with notable enrichment in the VEGF and JAK/STAT pathways. Cellular assays revealed that elevated ADAM8 expression enhanced cell viability, promoted the phosphorylation of JAK2 and STAT3, and boosted angiogenic capacity. The JAK inhibitor Peficitinib reversed the proangiogenic effects induced by ADAM8 overexpression. We also discovered overexpression of TFAP2A, an upstream transcription factor of ADAM8, in LUAD. Rescue experiments indicated that ADAM8 overexpression could counteract the inhibitory effects of TFAP2A knockdown on LUAD angiogenesis. This study reveals for the first time the critical role of ADAM8 in LUAD angiogenesis, demonstrating that TFAP2A promotes JAK/STAT pathway conduction by activating ADAM8. This finding not only provides a new perspective for understanding the pathogenesis of LUAD but also lays the foundation for the development of new therapies targeting ADAM8.

Optimizing Xenograft Models for Breast Cancer: A Comparative Analysis of Cell-Derived and Patient-Derived Implantation Techniques in Pre-Clinical Research.

The high mortality rate of breast cancer motivates researchers to search for effective treatments. Due to their ability to simulate human conditions, xenograft models such as CDX (Cell line-Derived Xenografts) and PDX (Patient-Derived Xenografts) have gained popularity in pre-clinical research. The choice of xenograft technique is influenced by the type of tumor employed, particularly in more aggressive tumor models like TNBC with metastases. Subcutaneous or orthotopic implantation may influence tumor engraftment rates and the applicability of the models for drug testing. To optimize xenograft models and support the development of breast cancer drugs, selecting a suitable transplantation technique is essential to attaining the best results. This scoping review used PRISMA-Scr methodology to summarize findings from eleven articles published between 2012 and 2024 on pre-clinical trials related to xenograft models for breast cancer considering PDX began traction after 2010. Using specific criteria, the review included studies from electronic platforms. The inclusion criteria ensured relevant English sources were available in full text, while the exclusion criteria eliminated certain types of articles and inadequately comprehensive studies. Subcutaneous and orthotopic implantation are critical methods for xenograft models in cancer research. Subcutaneous implantation is less invasive and more manageable but does not fully mimic the tumor's natural environment. Orthotopic implantation accurately mimic the migration, invasion, and molecular characteristics of the original tumor, although the procedure is more complex and requires specialized techniques. The specific research objectives determine their choice, the need for accurate tumor replication, and the testing convenience. Orthotopic implantation is the preferable method for developing PDX and CDX models of breast cancer because it closely mimics the tumor microenvironment and metastatic behavior, yielding clinically relevant results for drug testing. Subcutaneous implantation may result in higher engraftment rates, but it cannot accurately represent the complexity of tumors.

Hypoxia-responsive nanoparticles for fluorescence diagnosis and therapy of cancer.

Hypoxia, caused by rapid tumor growth and insufficient oxygen supply, is a defining characteristic of numerous solid tumors and exerts a significant influence on tumor growth, metastasis, and invasion. Early diagnosis and effective killing of tumor cells are crucial for cancer treatment. In recent years, the emergence of nanomaterials has overcome the difficulties in the delivery of chemotherapeutic drugs and contrast agents to tumor area. In this review, we summarize the development of hypoxia-responsive nanoparticles for fluorescence imaging and tumor therapy in the last five years, and further discuss their design strategies and applications in bioimaging. In addition, we discuss the therapeutic strategies of hypoxia-responsive prodrugs on different nanoplatforms and the future prospects of hypoxia-responsive nanomedicine in tumor therapy.