This study introduces TG-ME, an innovative computational framework that integrates transformer with graph variational autoencoder (GraphVAE) models for dissection of tumoral niches using spatial transcriptomics data and morphological images. TG-ME effectively identifies and characterizes niches in bench datasets and a high resolution NSCLC dataset. The pipeline consists in different stages that include normalization, spatial information integration, morphological feature extraction, gene expression quantification, single cell expression characterization, and tumor niche characterization. For this, TG-ME leverages advanced deep learning techniques that achieve robust clustering and profiling of niches across cancer stages. TG-ME can potentially provide insights into the spatial organization of tumor microenvironments (TME), highlighting specific niche compositions and their molecular changes along cancer progression. TG-ME is a promising tool for guiding personalized treatment strategies by uncovering microenvironmental signatures associated with disease prognosis and therapeutic outcomes.

Background: Ovarian cancer (OC) is a heterogeneous malignancy associated with a poor prognosis, necessitating robust biomarkers for risk stratification and therapy optimization. Cellular senescence-related genes (CSGs) are emerging as pivotal regulators of tumorigenesis and immune modulation, yet their prognostic and therapeutic implications in OC remain underexplored. Methods: We integrated RNA-sequencing data from TCGA-OV (n = 376), GTEx (n = 88), and GSE26712 (n = 185) to identify differentially expressed CSGs (DE-CSGs). Consensus clustering, Cox regression, LASSO-penalized modeling, and immune infiltration analyses were employed to define molecular subtypes, construct a prognostic risk score, and characterize tumor microenvironment (TME) dynamics. Drug sensitivity was evaluated using the Genomics of Drug Sensitivity in Cancer (GDSC)-derived chemotherapeutic response profiles. Results: Among 265 DE-CSGs, 31 were prognostic in OC, with frequent copy number variations (CNVs) in genes such as STAT1, FOXO1, and CCND1. Consensus clustering revealed two subtypes (C1/C2): C2 exhibited immune-rich TME, elevated checkpoint expression (PD-L1, CTLA4), and poorer survival. A 19-gene risk model stratified patients into high-/low-risk groups, validated in GSE26712 (AUC: 0.586-0.713). High-risk patients showed lower tumor mutation burden (TMB), immune dysfunction, and resistance to Docetaxel/Olaparib. Six hub genes (HMGB3, MITF, CKAP2, ME1, CTSD, STAT1) were independently predictive of survival. Conclusions: This study establishes CSGs as critical determinants of OC prognosis and immune evasion. The molecular subtypes and risk model provide actionable insights for personalized therapy, while identified therapeutic vulnerabilities highlight opportunities to overcome chemoresistance through senescence-targeted strategies.

Cancer-associated fibroblast (CAF) recruitment and activation within the tumor microenvironment (TME) are increasingly acknowledged as drivers of oral squamous cell carcinoma (OSCC) tumor growth and metastasis. Therefore, the mechanisms underlying tumor cell and fibroblast crosstalk warrant further investigation. We discovered that ectopic interferon-stimulated gene 15 (ISG15) expression, which is a promising and novel oncoprotein biomarker elevated in a variety of cancers, enhanced OSCC growth and elevated collagen and α-smooth muscle actin (α-SMA) expression in ISG15-expressing tumors. Analysis of immunohistochemistry revealed high ISG15 expression in human oral tissues correlated with high expression of α-SMA and fibroblast activation protein (FAP). Fibroblast migration and recruitment by ISG15-expressing OSCC cells were confirmed by in vitro and in vivo experiments. Exogenous ISG15 induced fibroblast migration, morphological changes, and vimentin expression. Enrichment of glycolysis pathway genes, as well as increased glycolysis-related gene expression, glucose uptake, and lactate production were observed in ISG15-treated fibroblasts. Lactate release and fibroblast migration were blocked by a competitive inhibitor of glucose metabolism. Furthermore, the knockdown of integrin αL (ITGAL)/CD11a, a subunit of ISG15 receptor lymphocyte functional-associated antigen-1 (LFA-1), in immortalized fibroblasts diminished extracellular ISG15-mediated glycolysis and migration. Our findings suggest that ISG15 derived from OSCC cells interacts with fibroblasts through the LFA-1 receptor, leading to glycolytic reprogramming and promotion of fibroblast migration into the TME.

Previous studies have suggested that cancer-associated fibroblasts (CAFs) within the tumor microenvironment are a critical factor in tumorigenesis and tumor development. However, the regulatory mechanisms of CAFs on oral squamous cell carcinoma (OSCC) are poorly defined. A CAF-conditioned medium (CAF-CM) was collected and applied to culture OSCC cells. Then, cell viability, proliferation, migration, and invasion were evaluated using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and scratch healing assays. T-Lymphoma Invasion and Metastasis 1 (TIAM1), zinc finger E-box-binding homeobox 2 (ZEB2), E-cadherin, and increased N-cadherin protein levels were determined using western blot. TIAM1 and ZEB2 mRNA levels were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Their interaction was analyzed using Co-immunoprecipitation (Co-IP) assay. SCC25 cells with or without (TIAM1-silencing) CAFs were subcutaneously inoculated in nude mice to assess the effect of TIAM1 in CAFs on OSCC tumor growth in vivo. CAFs expedited OSCC cell proliferation, migration, invasion, and EMT. TIAM1 and ZEB2 expression were upregulated in OSCC patients and OSCC cells, and the TIAM1 level was much higher in CAFs than in OSCC cells. Furthermore, TIAM1 knockdown in CAFs might partly abolish the promotion of CAFs on OSCC cell development, implying that TIAM1 might be secreted by CAFs into the culture medium to exert its effects inside OSCCs. TIAM1 might increase ZEB2 expression, and ZEB2 upregulation might partly reverse the repression of TIAM1 silencing in CAFs on OSCC cell malignant behaviors. In vivo studies confirmed that CAFs accelerated OSCC tumor growth, these effects were partially counteracted by TIAM1 downregulation. Overall, TIAM1 secreted by CAFs could expedite OSCC cell growth and metastasis by regulating ZEB2, providing a promising therapeutic target for OSCC treatment.

Breast cancer remains one of the leading causes of mortality worldwide. While advancements in chemotherapy, immunotherapy, radiotherapy, and targeted therapies have significantly improved breast cancer treatment, many patients are diagnosed at advanced stages, where tumor cells exhibit aggressive behavior and therapy resistance. Understanding the mechanisms driving breast cancer progression is therefore critical. Metastasis is a major factor that drastically reduces patient prognosis and survival, accounting for most breast cancer-related deaths. ZEB proteins have emerged as key regulators of cancer metastasis. Beyond their role in metastasis, ZEB proteins also influence drug resistance. This review focuses on the role of ZEB1 and ZEB2 in regulating breast cancer metastasis. These proteins interact with components of the tumor microenvironment (TME) to drive cancer progression and metastasis. Additionally, ZEB proteins regulate angiogenesis through interactions with VEGF. Targeting ZEB proteins offers potential therapeutic benefits, particularly for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC), which often show poor therapeutic response. ZEB proteins also influence the sensitivity of breast cancer cells to chemotherapy, making them promising targets for enhancing treatment efficacy. Given their upregulation in breast cancer, ZEB proteins can serve as valuable diagnostic and prognostic markers.

One of the effective strategies for the treatment of tumor diseases, including colitis-associated colorectal cancer (CAC), is immunotherapy. During inflammation, NF-κB is activated, which is connected with the hypoxia-inducible factor-HIF, regulating the immune cells functioning and influences the CAC development. Organisms differ according to their hypoxia resistance and HIF expression. Therefore, the aim of the study was to characterize the thymus, spleen and mesenteric lymph nodes morphofunctional features, as well as changes in the subpopulation composition of peripheral blood cells and mesenteric lymph nodes in tolerant and susceptible to hypoxia C57Bl/6 mice in CAC.

Hypoxia tolerance was assessed by gasping time measurement in hypobaric decompression chamber. Based on the outcome, the mice were assigned to three groups characterized as 'tolerant to hypoxia', 'normal', and 'susceptible to hypoxia'. A month after determining hypoxia resistance CAC was modeled by intraperitoneal azoxymethane (AOM) administration and three cycles of dextran sulfate sodium consumption. Mice were sacrificed on the 141st day after the AOM administration, a morphological, morphometric and immunohistochemical study of tumors, morphological and morphometric study of thymus and spleen, and subpopulation composition of peripheral blood cells and mesenteric lymph nodes assessment were carried out.

Tumors in tolerant and susceptible to hypoxia mice were represented by glandular intraepithelial neoplasia and adenocarcinomas, the area of which was larger in susceptible mice. Immunohistochemical study revealed a more pronounced Ki-67+ staining in tumors of susceptible mice. In CAC, only in tolerant mice, expansion of the thymic cortex was observed relative to the control group, while in susceptible ones, no changes were detected. Only in susceptible to hypoxia mice, spleen germinal centers of lymphoid follicles enlargement were observed. Only in susceptible mice during CAC, in comparison to the control group, the relative and absolute number of B-lymphocytes and relative-cytotoxic T-lymphocytes in blood increased. The relative cytotoxic T-lymphocytes and NK cells number in peripheral blood during CAC was higher in susceptible to hypoxia mice compared to tolerant ones. In susceptible to hypoxia mice, more pronounced changes in the mesenteric lymph nodes subpopulation composition of cells were revealed-only in them the absolute and relative number of B-lymphocytes and NK cells, the absolute number of cytotoxic T-lymphocytes increased, and the relative number of macrophages decreased.

Morphofunctional differences in the thymus, spleen, mesenteric lymph nodes and blood immune cells reactions indicated the more pronounced immune response to the CAC development in susceptible to hypoxia mice, which should be taken into account in experimental studies.

Cancer metastasis is a leading cause of cancer-related deaths and represents one of the most challenging processes to study due to its complexity and dynamic nature. Zebrafish (Danio rerio) have become an invaluable model in metastasis research, offering unique advantages such as optical transparency, rapid development, and the ability to visualize tumor interactions with the microenvironment in real time. This review explores how zebrafish models have elucidated the critical steps of metastasis, including tumor invasion, vascular remodeling, and immune evasion, while also serving as platforms for drug testing and personalized medicine. Advances such as patient-derived xenografts and innovative genetic tools have further established zebrafish as a cornerstone in cancer research, particularly in understanding the molecular drivers of metastasis and identifying therapeutic targets. By bridging the experimental findings with clinical relevance, zebrafish continue transforming our understanding of cancer biology and therapy.

In recent years, the near-infrared (NIR) fluorescence theranostic system has garnered increasing attention for its advantages in the simultaneous diagnosis- and imaging-guided delivery of therapeutic drugs. However, challenges such as strong background fluorescence signals and rapid metabolism have hindered the achievement of sufficient contrast between tumors and surrounding tissues, limiting the system's applicability. This study aims to integrate the pegylation strategy with a tumor microenvironment-responsive approach. A novel esterase-activated EPR strategy prodrug, OBHSA-PEG-DCM, was designed. This prodrug links OBHSA, a protein degrader capable of efficient ERα protein degradation, to the PEG-modified fluorescent group (dicyanomethylene-4H-pyran, DCM) via an ester bond. This integration facilitates targeted drug delivery and enhances the retention of the fluorescent group within the tumor, allowing distinct in vivo tumor imaging periods. Experimental results show that, benefiting from overexpressed esterase in cancer cells, OBHSA-PEG-DCM can be efficiently hydrolyzed, releasing OBHSA and pegylated DCM. OBHSA demonstrated potent inhibition against MCF-7 cells (IC50 = 1.09 μM). Simultaneously, pegylated DCM exhibited remarkable in vivo imaging capabilities, lasting up to 12 days in mice, due to the enhanced permeability and retention (EPR) effect. OBHSA-PEG-DCM holds promise as a theranostic agent for ERα-positive breast cancer, offering both therapeutic and diagnostic capabilities. Importantly, this study highlights the utility of pegylated NIR fluorophores for long-circulating drug delivery systems, addressing current challenges in achieving high-contrast tumor imaging and effective targeted drug release.

BackgroundMigrating strategies of the triple-negative breast cancer (TNBC) together with its role in the establishment of tumor microenvironment (TME), supporting metastasis, have been extensively studied. Extracellular matrix (ECM) is a major player for the TME, establishing the 3D spatial networks with interconnected pores necessary for the mechano-physiological function of the cells. Certain collagen aligners and cross-linkers which are necessary for the formation and the stabilization of ECM networks, however, have not been studied either in normal or in abnormal tissues. Complexities in cell-cell and cell-matrix interactions, and different in types and ratios of ECM proteins in a TME challenge to reveal the precise function of a particular protein that is exhibited by special cells and if specifically present in insignificant amount. Cancer-associated fibroblasts (CAFs) predominantly occupy the major stroma of a solid tumor where they deposit extracellular proteins in the excessive amount compared to other tumor-associated cells. For example, the TNBC tumor itself is positive for asporin (ASPN) since CAFs are major ASPN exhibitors. However, the TNBC cells express it insignificantly.ObjectiveThe increase in ECM and its networks suppresses the metastasis.MethodsHere, we studied the expression of collagen type I and ASPN in CAFS and MDA-MB-231 (MM231), and evaluated the role of ASPN in collagen alignment and crosslinking.ResultsTNBC cells have an insignificant expression of ASPN and scanty collagen fibers, some of which aggregate to form the stiff deranged fibers, forming large-size pores in ECM of cancer-cell-dominant outer core of TNBC that support cancer cell invasion and metastasis. Exogenous ASPN and fibroblast-ASPN supported for the collagen alignment and crosslinking that established the small-size pores in the ECM, inhibiting the cancer cell invasion.ConclusionsThe collagen aligner and the cross-linker, ASPN increases the ECM networks and decreases the migration, and this preliminary study provides the hope that ASPN might be used as an anti-metastatic drug after its confirmation through extensive studies in animal, and positive outcomes through preclinical trials.

Tumor therapy has advanced significantly in recent years, but tumor cells can still evade and survive the treatment through various mechanisms. Notably, tumor cells use autophagy to sustain viability by removing impaired mitochondria and clearing excess reactive oxygen species (ROS). In this study, the aim is to amplify intracellular oxidative stress by inhibiting mitochondrial autophagic flux. Multisynergistic environmental-response nanoparticles (ERNs) are engineered by integrating gold nanoparticles and copper peroxide with borosilicate bioactive glass. The controlled release of copper and inhibition of autophagy flux triggered an overabundance and accumulation of oxidative stress within the tumor cells. This stress triggered immunogenic tumor cell death, believed to initiate a systemic immune response. The tumor microenvironment (TME) transitioned back to a normal physiological state as tumor cells are ablated. ERNs responded to the microenvironment changes by depositing hydroxyapatite on the surface and spontaneously enhancing bone regeneration. This innovative formulation facilitates the functional transition of ERNs from "anti-tumor therapy" to "biomineralization" that kills cancers and induces new bone formation. Overall, it is shown that the ERNs effectively eradicate cancers by utilizing chemodynamic therapy, starvation therapy, and immunotherapy.

In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.

For esophageal squamous cell carcinoma (ESCC), universally accepted pathological criteria for classification by differentiation degree are lacking. Tumor budding, single-cell invasion, and nuclear grade, recognized as prognostic factors in other carcinomas, have rarely been investigated for their correlation with differentiation and prognosis in ESCC. This study aims to determine if pathological findings can predict differentiation degree and prognosis in ESCC.

This study reviewed tumor slides from 326 patients who underwent surgery for ESCC between 2007 and 2012. Tumors were evaluated for subtypes, tumor nest size, tumor stroma, and nuclear grade (nuclear diameter and mitosis) across different differentiation groups. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, with group differences assessed using the stratified log-rank test and Cox proportional hazards model.

The mean values of tumor budding invasion margins in well, moderately, and poorly differentiated groups were 25.3%, 30.7%, and 36.3%, respectively. Mean tumor budding/10HPFs were 8.0, 10.3, and 13.0, respectively. Well-differentiated tumors showed more keratinizing subtypes, smaller tumor budding invasion margins, more Grade 1 tumor budding (0-4 cells), absence of single-cell invasion, larger nuclear diameter (≥5 lymphocytes), higher mitotic counts, more submucosal invasion, and less lymphovascular invasion. Conversely, poorly differentiated tumors exhibited opposite characteristics. Multivariate analyses identified the nuclear diameter as independent prognostic factors for OS and DFS.

Pathological features can stratify the differentiation landscape in ESCC patients. The nuclear diameter (4 lymphocytes) can help predict prognosis in ESCC than other pathological features.

We first time report the mean values of tumor budding invasion margins and tumor budding/10HPF in well, moderately, and poorly differentiated groups for esophageal squamous cell carcinoma. The landscape of well differentiation was depicted with more keratinizing subtypes, smaller tumor budding invasion margins, more Grade 1 tumor budding (0-4 cells), absence of single-cell invasion, larger nuclear diameter (≥5 lymphocytes), higher mitotic counts, and less lymphovascular invasion. The nuclear diameter as independent prognostic factors for prognosis. The findings indicate that pathological features can stratify the differentiation landscape in ESCC patients and offer novel insight into definition of well or moderately differentiation.

Liposarcoma is one of the most common soft tissue malignancies. We previously discovered upregulation of minichromosome maintenance 2 (MCM2) expression in liposarcoma tissues. Hereon, we attempt to clarify the biological influence and mechanisms of MCM2 in liposarcoma. The mRNA level of MCM2 expression was detected through the use of quantitative real-time PCR. Immunohistochemistry staining and western blot were employed to detect protein expression of MCM2. The protein expression of fibroblast-activation protein and α-smooth muscle actin was examined by immunofluorescence. Protein concentrations of interleukin (IL)-6, transforming growth factor β, and IL-8 were measured via ELISA. Furthermore, liposarcoma cell viability was assessed through cell counting kit-8 assay, and liposarcoma cell invasiveness and migration were evaluated through transwell assay. For assessing proliferation and apoptosis of liposarcoma cells, colony formation assay and flow cytometry were used. For constructing a mouse tumor model, SW872 cells were introduced into mouse flank via subcutaneous injection. MCM2 expression was boosted in liposarcoma tissues and cells when compared with the controls. MCM2-activated cancer-associated fibroblasts (CAFs)-like phenotype, presenting as increased fibroblast-activation protein expression, α-smooth muscle actin expression, cell migration, IL-6 concentration, IL-8 concentration, and transforming growth factor β concentration. Functional experiments indicated that MCM2-activated-CAFs facilitated proliferation, migration, and invasion of liposarcoma cells. Additionally, 1 μM doxorubicin treatment could not affect proliferation and apoptosis of liposarcoma cells, whereas combined use of MCM2 knockdown and 1 μM doxorubicin evidently repressed cell proliferation and promoted apoptosis. In vivo, silencing of MCM2 impaired tumor growth in mice. MCM2 overexpression promoted CAFs formation and tumor progression, showing potential value in treatment of liposarcoma.

Metastasis, the dissemination of malignant cells from a primary tumor to secondary sites, poses a catastrophic burden to cancer treatment and is the predominant cause of mortality in cancer patients. Metastasis as one of the main aspects of cancer progression could be strongly under the influence of viral infections. In fact, viruses have been central to modern cancer research and are associated with a great number of cancer cases. Viral-encoded elements are involved in modulating essential pathways or specific targets that are implicated in different stages of metastasis. Considering the continuous emergence of new viruses and the establishment of their contribution to cancer progression, the warfare between viruses and cancer appears to be endless. Here we aimed to review the critical mechanism and pathways involved in cancer metastasis and the influence of viral machinery and various routes that viruses adopt to manipulate those pathways for their benefit.

Lung cancer is one of the major cancer types and poses challenges in its treatment, including lack of specificity and harm to healthy cells. Nanoparticle-based drug delivery systems (NDDSs) show promise in overcoming these challenges. While conventional NDDSs have drawbacks, such as immune response and capture by the reticuloendothelial system (RES), extracellular vesicles (EVs) present a potential solution. EVs, which are naturally released from cells, can evade the RES without surface modification and with minimal toxicity to healthy cells. This makes them a promising candidate for developing a lung-cancer-targeting drug delivery system. EVs isolated from vascular endothelial cells, such as human umbilical endothelial-cell-derived EVs (HUVEC-EVs), have shown anti-angiogenic activity in a lung cancer mouse model; therefore, in this study, HUVEC-EVs were chosen as a carrier for drug delivery. To achieve lung-cancer-specific targeting, HUVEC-EVs were engineered to be decorated with GE11 peptides (GE11-HUVEC-EVs) via a postinsertional technique to target the epidermal growth factor receptor (EGFR) that is overexpressed on the surface of lung cancer cells. The GE11-HUVEC-EVs were loaded with vinorelbine (GE11-HUVEC-EVs-Vin), and then characterized and evaluated in in vitro and in vivo lung cancer models. Further, we examined the binding affinity of ABCB1, encoding P-glycoprotein, which plays a crucial role in chemoresistance via the efflux of the drug. Our results indicate that GE11-HUVEC-EVs-Vin effectively showed tumoricidal effects against cell and mouse models of lung cancer.

The tumor microenvironment (TME) plays a critical role in cancer progression and response to immunotherapy. Immunotherapy targeting the immune system has emerged as a promising treatment modality, but challenges in understanding the TME limit its efficacy. Optical imaging strategies offer noninvasive, real-time insights into the interactions between immune cells and the TME.

This review assesses the progress of optical imaging technologies in monitoring immunotherapy within the TME and explores their potential applications in clinical trials and personalized cancer treatment.

This is a comprehensive literature review based on the advances in optical imaging modalities including fluorescence imaging (FLI), bioluminescence imaging (BLI), and photoacoustic imaging (PAI). These modalities were analyzed for their capacity to provide high-resolution, real-time imaging of immune cell dynamics, tumor vasculature, and other critical components of the TME.

Optical imaging techniques have shown significant potential in tracking immune cell infiltration, assessing immune checkpoint inhibitors, and visualizing drug delivery within the TME. Technologies like FLI and BLI are pivotal in tracking immune responses in preclinical models, while PAI provides functional imaging with deeper tissue penetration. The integration of these modalities with immunotherapy holds promise for improving treatment monitoring and outcomes.

Optical imaging is a powerful tool for understanding the complexities of the TME and optimizing immunotherapy. Further advancements in imaging technologies, combined with nanomaterial-based approaches, could pave the way for enhanced diagnostic accuracy and therapeutic efficacy in cancer treatment.

Cancer metabolism is now a key area for therapeutic intervention, targeting unique metabolic reprogramming crucial for tumor growth and survival. This article reviews the therapeutic potential of addressing metabolic vulnerabilities through glycolysis and glutaminase inhibitors, which disrupt cancer cell metabolism. Challenges such as tumor heterogeneity and adaptive resistance are discussed, with strategies including personalized medicine and predictive biomarkers to enhance treatment efficacy. Additionally, integrating diet and lifestyle changes with metabolic targeting underscores a holistic approach to improving therapy outcomes. The article also examines the benefits of incorporating these strategies into standard care, highlighting the potential for more tailored, safer treatments. In conclusion, exploiting metabolic vulnerabilities promises a new era in oncology, positioning metabolic targeting at the forefront of personalized cancer therapy and transforming patient care.

Glioblastoma is a common brain tumor that poses considerable challenges in drug delivery. In this study, we investigated the potential of cell-based nanoparticles for targeted drug delivery to the glioblastoma sites. The anticancer drug of temozolomide (TMZ)-loaded T7-cholesterol nanoparticle micelles efficiently delivered nanoparticles to neutrophils and, subsequently, to the tumors. T7 is a cell-penetrating peptide that enhances the delivery of T7/TMZ to the target cells. T7 also serves as a transferrin target peptide, enabling targeted delivery to tumors. T7-conjugated cholesterol can self-assemble into micelles in aqueous solution and attach to the membrane of neutrophils. We confirmed that T7/TMZ nanoparticle micelles were efficiently located inside the neutrophils. Thereafter, T7/TMZ-conveyed neutrophils were administered to a glioblastoma mouse model, enabling neutrophils to penetrate the blood-brain barrier and deliver drugs directly to the tumor site. We evaluated the drug delivery efficiency and therapeutic effects of intravenous injection of T7/TMZ-conveyed neutrophils to a glioblastoma mouse model. These results demonstrate the promising role of neutrophil-based nanoparticle delivery systems in the targeted therapy of glioblastoma.

Cancer is the second leading cause of death worldwide and disease burden is expected to increase globally throughout the next several decades, with the majority of cancer-related deaths occurring in metastatic disease. Cancers exhibit known hallmarks that endow them with increased survival and proliferative capacities, frequently as a result of de-stabilizing mutations. However, the genomic features that resolve metastatic clones from primary tumors are not yet well-characterized, as no mutational landscape has been identified as predictive of metastasis. Further, many cancers exhibit no known mutation signature. This suggests a larger role for non-mutational genome re-organization in promoting cancer evolution and dissemination. In this review, we highlight current critical needs for understanding cell state transitions and clonal selection advantages for metastatic cancer cells. We examine links between epigenetic states, genome structure, and misregulation of tumor suppressors and oncogenes, and discuss how recent technologies for understanding domain-scale regulation have been leveraged for a more complete picture of oncogenic and metastatic potential.

Effect of the oral cancerous epithelial cells on the extracellular matrix (ECM) and vice versa is also responsible for the growth and progression of cancer. The effect of inflammation on the stroma and its association with progression has also been stated in literature.

The control group consisted of 10 patients with apparently normal mucosa with no history of habits, the study group consisted of 30 patients with oral squamous cell carcinoma (OSCC) confirmed by examination and incisional biopsy. H and E staining, Masson's Trichrome Staining, and Verhoeff's Van Gieson staining were used to study the inflammation, collagen fibers, and elastic fiber, respectively. A few selected specimens were studied under the scanning electron microscope. The grade of inflammation was statistically correlated with collagen and elastic fibers.

Grade of inflammation was closely associated with lymphadenopathy and the density of collagenous and elastic components of the ECM. The scanning electron microscopic evaluation of elastic fibers revealed irregular fragmented elastic fibers.

The stroma is the key to complete removal and treatment of OSCC; however, more studies are needed to define the role of each component, therefore improving the prognosis of a patient.

While collagen density has been associated with poor outcomes in various cancers, its role in prostate cancer (PCa) remains elusive. Our aim was to analyze collagen-related transcriptomic, proteomic, and urinome alterations in the context of detection of clinically significant PCa (csPCa, International Society of Urological Pathology [ISUP] grade group ≥2).

Comprehensive analyses for PCa transcriptome (n = 1393), proteome (n = 104), and urinome (n = 923) data sets focused on 55 collagen-related genes. Investigation of the cellular source of collagen-related transcripts via single-cell RNA sequencing was conducted. Statistical evaluations, clustering, and machine learning models were used for data analysis to identify csPCa signatures.

Differential expression of 30 of 55 collagen-related genes and 34 proteins was confirmed in csPCa in comparison to benign prostate tissue or ISUP 1 cancer. A collagen-high cancer cluster exhibited distinct cellular and molecular characteristics, including fibroblast and endothelial cell infiltration, intense extracellular matrix turnover, and enhanced growth factor and inflammatory signaling. Robust collagen-based machine learning models were established to identify csPCa. The models outcompeted prostate-specific antigen (PSA) and age, showing comparable performance to multiparametric magnetic resonance imaging (mpMRI) in predicting csPCa. Of note, the urinome-based collagen model identified four of five csPCa cases among patients with Prostate Imaging-Reporting and Data System (PI-IRADS) 3 lesions, for which the presence of csPCa is considered equivocal. The retrospective character of the study is a limitation.

Collagen-related transcriptome, proteome, and urinome signatures exhibited superior accuracy in detecting csPCa in comparison to PSA and age. The collagen signatures, especially in cases of ambiguous lesions on mpMRI, successfully identified csPCa and could potentially reduce unnecessary biopsies. The urinome-based collagen signature represents a promising liquid biopsy tool that requires prospective evaluation to improve the potential of this collagen-based approach to enhance diagnostic precision in PCa for risk stratification and guiding personalized interventions.

In our study, collagen-related alterations in tissue, and urine were able to predict the presence of clinically significant prostate cancer at primary diagnosis.

Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.

The cancer-associated fibroblast (CAF)-derived secretome plays critical roles in tumor progression by remodelling tumor microenvironment. Tumorigenesis is accompanied by the transformation of normal fibroblasts (NF) into CAF, leading to significant changes in their secretome. This work aims to identify the differential components of secretome between NFs and CAFs and reveal their functions in gastric cancer (GC). Firstly, our molecular typing studies and immune infiltration analysis showed that CAF infiltration level was increased and showed a significant association with clinical characteristics and poor prognosis of GC patients. Secondly, RNA-seq analysis revealed that a total of 1531 genes showed significant expression changes between NF and CAF. According to the annotation of the Human Protein Atlas (HPA) database, 147 genes encode secreted proteins, including FGF2. Particularly, the cell co-culture and RNA sequencing studies confirmed that exogenous recombinant FGF2 protein treatment promoted GC cell proliferation by enhancing ribosome biogenesis. The rescue assay showed that CAF-secreted FGF2 protein promotes GC cell growth and proliferation in a FGFR1-dependent manner. Our finding provides evidence that targeting blockade of CAF-derived FGF2 protein might be a promising treatment for GC.

The causal relationship between physical activity and anti-cancer effect are not proved by the current studies. However, Ou MC decrescendo phenomenon treatment (OuDPt), a simple exercise treatment, has shown consistent anti-cancer effects, which evinces the consequent anti-cancer effect by physical activity. The anti-cancer effects through OuDPt in the context of physical activity and human body anatomical axes showed to induce apoptosis, restore apical-basal polarity of cancer cells and mitigate epithelial-mesenchymal transition (EMT) with concomitant clinical regression of uterine endometrial cancer, suppression of ovarian and pancreatic cancer growth, regression of early suspicious pancreatic cancer, enhancement of chemotherapy effect of pancreatic cancer and cessation of cancer-related bleeding, which underlines the most important anti-cancer mechanisms. Although such anti-cancer effects by OuDPt show insufficient efficacy for advanced cancer in long-term treatment, OuDPt may be availed as an Ou MC decrescendo phenomenon exercise for cancer prevention. Further study is warranted.

Uncontrolled angiogenesis underlies various pathological conditions such as cancer, age-related macular degeneration (AMD), and proliferative diabetic retinopathy (PDR). Hence, targeting pathological angiogenesis has become a promising strategy for the treatment of cancer and neovascular ocular diseases. However, current pharmacological treatments that target VEGF signaling have met with limited success either due to acquiring resistance against anti-VEGF therapies with serious side effects including nephrotoxicity and cardiovascular-related adverse effects in cancer patients or retinal vasculitis and intraocular inflammation after intravitreal injection in patients with AMD or PDR. Therefore, there is an urgent need to develop novel strategies which can control multiple aspects of the pathological microenvironment and regulate the process of abnormal angiogenesis. To this end, vascular normalization has been proposed as an alternative for antiangiogenesis approach; however, these strategies still focus on targeting VEGF or FGF or PDGF which has shown adverse effects. In addition to these growth factors, calcium has been recently implicated as an important modulator of tumor angiogenesis. This article provides an overview on the role of major calcium channels in endothelium, TRP channels, with a special focus on TRPV4 and its downstream signaling pathways in the regulation of pathological angiogenesis and vascular normalization. We also highlight recent findings on the modulation of TRPV4 activity and endothelial phenotypic transformation by tumor microenvironment through Rho/YAP/VEGFR2 mechanotranscriptional pathways. Finally, we provide perspective on endothelial TRPV4 as a novel VEGF alternative therapeutic target for vascular normalization and improved therapy. © 2024 American Physiological Society. Compr Physiol 14:5389-5406, 2024.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy situated in the posterolateral nasopharynx. NPC poses grave concerns in Southeast Asia due to its late diagnosis. Together with resistance to standard treatment combining chemo- and radiotherapy, NPC presents high metastatic rates and common recurrence. Despite advancements in immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy, the exhaustive T cell profile and other signs of immunosuppression within the NPC tumour microenvironment (TME) remain as concerns to immunotherapy response. Exosomes, extracellular vesicles of 30-150 nm in diameter, are increasingly studied and linked to tumourigenesis in oncology. These bilipid-membrane-bound vesicles are packaged with a variety of signalling molecules, mediating cell-cell communications. Within the TME, exosomes can originate from tumour, immune, or stromal cells. Although there are studies on tumour-derived exosomes (TEX) in NPC and their effects on tumour processes like angiogenesis, metastasis, therapeutic resistance, there is a lack of research on their involvement in immune evasion. In this review, we aim to enhance the comprehension of how NPC TEX contribute to cellular immunosuppression. Furthermore, considering the detectability of TEX in bodily fluids, we will also discuss the potential development of TEX-related biomarkers for liquid biopsy in NPC as this could facilitate early diagnosis and prognostication of the disease.

Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.

Breast cancer is the most common type of cancer and the leading cause of death among women. Recent evidence suggests that mesenchymal stromal/stem cells and cancer-associated fibroblasts (CAFs) have an essential role in cancer progression, invasion and therapy resistance. Therefore, they are considered as highly promising future therapeutic targets against breast cancer. The intrinsic tumour tropism and immunomodulatory capacities of mesenchymal stromal/stem cells are of special relevance for developing mesenchymal stromal/stem cells-based anti-tumour therapies that suppress primary tumour growth and metastasis. In addition, the utilization of therapies that target the stromal components of the tumour microenvironment in combination with standard drugs is an innovative tool that could improve patients' response to therapies and their survival. In this review, we discuss the currently available information regarding the possible use of mesenchymal stromal/stem cells-derived anti-tumour therapies, as well as the utilization of therapies that target CAFs in breast cancer microenvironment. Finally, these data can serve as a guide map for future research in this field, ultimately aiding the effective transition of these results into the clinic. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.

The molecular system of receptor activator of nuclear factor kappa-β (RANK) and its ligand (RANKL) plays a role in a variety of physiological and pathological processes. These encompass the regulation of bone metabolism, mammary gland development, immune function, as well as their involvement and tumorigenesis. Nevertheless, limited knowledge exists regarding their function within the tumor microenvironment.

We explored the significance of RANK expression in cancer-associated fibroblasts (CAFs) as a prognostic biomarker in early breast cancer patients (BCPs) by immunohistochemistry. Results reveal a significant correlation between high RANK expression in CAFs and an increased risk of metastasis (p= 0.006), shorter metastasis-free survival (MFS) [p= 0.007, OR (95%CI) = 2.290 (1.259-4.156)], and lower overall survival (OS) [p= 0.004, OR (95%CI) = 2.469 (1.343-4.541)]. Upon analyzing the phenotype of CD34(-) CAFs isolated from primary tumors in BCPs, we observed co-expression of RANK with CD105 marker by immunofluorescence and flow cytometry, characteristic of mesenchymal stem/stromal cells (MSCs), suggesting the possible cellular origin. Also RANKL-RANK system increase the OCT-4, SOX-2 and DKK-1 (dickkopf 1) gene expression in CD34(-) CAFs by RT-PCR. Moreover, this system plays a crucial role in the migration of these CD34(-) CAFs.

These results support the clinical relevance of RANK in CAFs and propose its potential as a future therapeutic target in the treatment of early BCPs.

Variations in the levels of systemic inflammatory biomarker levels have been linked with outcomes in various malignancies including cervical cancer. In this study, we investigated prognostic implications of pretreatment hematological factors/indices in locally advanced cervical cancers treated with radical radio(chemo)therapy.

Electronic medical records of 1051 patients with cervical cancer of FIGO (International Federation of Gynecology and Obstetrics) stage IB2-IVA treated in various prospective trials at our institute between 2003 and 2017 were reviewed. All clinical parameters such as age (dichotomized at the median), stage (IB2-IIB vs III-IVA), histologic type (squamous vs others), and hematological parameters (hemoglobin, platelets, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count) were recorded. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and prognostic nutritional index (PNI; defined as 10 × albumin concentration [g/dL] + 0.005 × total lymphocyte count [μL]) were calculated. Univariate and multivariate (Cox regression) analyses were performed to evaluate these factors with disease-free survival (DFS) and overall survival (OS).

With a median follow-up of 69 months, the 5-year DFS and OS were 65% and 69%, respectively. On multivariate analysis, FIGO stage (hazard ratio [HR], 1.9; P = .000) and PLR (HR, 1.002; P = .008) significantly affected DFS while FIGO stage (HR, 1.804; P = .000), LMR (HR, 0.92; P = .018), PNI (HR, 0.96; P = .013), and PLR (HR, 1.002; P = .006) significantly affected OS. Apart from FIGO stage, PLR significantly affected both DFS and OS. This correlation of hematological parameters is stronger in stage IIIB cervical cancer.

Hematological indices, including PNI, PLR, and LMR, can serve as reliable prognostic indicators for patients with cervical cancer. By incorporating these indices into routine assessment and monitoring, clinicians can better stratify patients, personalize treatment plans, and more accurately predict outcomes, ultimately improving patient care and management.

Tumor-infiltrating immune cells (TIICs) and metastasis are crucial characteristics for tumorigenesis. However, the potential role of their combination in breast cancer (BRCA) remains elusive. Herein, on the basis of quantifying TIICs and tumor metastasis together, we established a precise prognostic scoring system named metastatic and immunogenomic risk score (MIRS) using a neural network model. MIRS showed better performance when compared with other published signatures. MIRS stratifies patients into a high risk subtype (MIRShigh) and a low risk subtype (MIRSlow). The MIRShigh patients exhibit significantly lower survival rate compared with MIRSlow patients (P < 0.0001 ), higher response to chemotherapy, but lower response to immunotherapy. Conversely, higher infiltration level of TIICs and significantly prolonged survival (P = 0.029 ) are observed in MIRSlow patients, indicating sensitive response in immunotherapy. This work presents a promising indicator to guide treatment options of the BRCA population and provides a predicted webtool that is almost universally applicable to BRCA patients.

The tumor microenvironment (TME) plays a crucial role in regulating the state and function of all cell types residing in the tumor and thus impacts many aspects of tumor biology. The importance of the TME has led to an interest in characterizing the composition of the TME and how TME components regulate cancer and stromal cell biology. Tumor interstitial fluid (TIF) is the local perfusate of the TME that carries metabolites, electrolytes, and soluble macromolecules to tumor-resident cells. Recently, techniques to isolate TIF have been coupled with analytical techniques to interrogate the composition of TIF, providing new insight into TME composition. In this review, we will discuss what TIF studies indicate about TME composition and new avenues TIF analysis provides to delineate how the TME regulates tumor biology.

Breast cancer deaths are primarily caused by metastasis. There are several treatment options that can be used to treat breast cancer. There are, however, a limited number of treatments that can either prevent or inhibit the spread of breast tumor metastases. Thus, novel therapeutic strategies are needed. Studies have increasingly focused on the importance of the tumor microenvironment (TME) in metastasis of breast cancer. As the most abundant cells in the TME, cancer-associated fibroblasts (CAFs) play important roles in cancer pathogenesis. They can remodel the structure of the extracellular matrix (ECM) and engage in crosstalk with cancer cells or other stroma cells by secreting growth factors, cytokines, and chemokines, as well as components of the ECM, which assist the tumor cells to invade through the TME and cause distant metastasis. Clinically, CAFs not only foster the initiation, growth, angiogenesis, invasion, and metastasis of breast cancer but also serve as biomarkers for diagnosis, therapy, and prediction of prognosis. In this review, we summarize the biological characteristics and subtypes of CAFs and their functions in breast cancer metastasis, focusing on their important roles in the diagnosis, prognosis, and treatment of breast cancer. Recent studies suggest that CAFs are vital partners of breast cancer cells that assist metastasis and may represent ideal targets for prevention and treatment of breast cancer metastasis.

Early detection of pre-cancerous adenomas through screening can reduce colorectal cancer (CRC) incidence. Fecal immunochemical tests are commonly used, but have limited sensitivity for pre-cancerous lesions. Blood-based screening may improve test sensitivity. This systematic review and meta-analysis was conducted to evaluate the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions.

We present the accuracy of blood-based biomarkers for the detection of advanced pre-cancerous lesions. EMBASE, Web of Science and PubMed databases were searched, with study populations limited to adults diagnosed with advanced pre-cancerous lesions at colonoscopy, who had a blood-based biomarker test analyzed with reports of sensitivity and specificity.

69 studies were identified, which assessed 133 unique biomarkers sets. The best performing test was a panel of 6 miRNAs, with a sensitivity of 95% and specificity of 90% for advanced pre-cancerous lesions. Only 6 biomarkers demonstrated sensitivity ≥ 50% and specificity ≥ 90% for the detection of advanced pre-cancerous lesions.

Many different blood-based biomarkers have been assessed for detection of advanced pre-cancerous lesions, but few have progressed beyond the discovery stage. While some biomarkers have reported high sensitivity and specificity, larger prospective studies in unbiased intended-use screening populations are required for validation.

Among the different breast cancer subsets, triple-negative breast cancer (TNBC) has the worst prognosis and limited options for targeted therapies. Immunotherapies are emerging as novel treatment opportunities for TNBC. However, the surging immune response elicited by immunotherapies to eradicate cancer cells can select resistant cancer cells, which may result in immune escape and tumor evolution and progression. Alternatively, maintaining the equilibrium phase of the immune response may be advantageous for keeping a long-term immune response in the presence of a small-size residual tumor. Myeloid-derived suppressor cells (MDSCs) are activated, expanded, and recruited to the tumor microenvironment by tumor-derived signals and can shape a pro-tumorigenic micro-environment by suppressing the innate and adaptive anti-tumor immune responses. We recently proposed a model describing immune-mediated breast cancer dormancy instigated by a vaccine consisting of dormant, immunogenic breast cancer cells derived from the murine 4T1 TNBC-like cell line. Strikingly, these 4T1-derived dormant cells recruited fewer MDSCs compared to aggressive 4T1 cells. Recent experimental studies demonstrated that inactivating MDSCs has a profound impact on reconstituting immune surveillance against the tumor. Here, we developed a deterministic mathematical model for simulating MDSCs depletion from mice bearing aggressive 4T1 tumors resulting in immunomodulation. Our computational simulations indicate that a vaccination strategy with a small number of tumor cells in combination with MDSC depletion can elicit an effective immune response suppressing the growth of a subsequent challenge with aggressive tumor cells, resulting in sustained tumor dormancy. The results predict a novel therapeutic opportunity based on the induction of effective anti-tumor immunity and tumor dormancy.

Bioactive materials are a special class of biomaterials that can react in vivo to induce a biological response or regulate biological functions, thus achieving a better curative effect than traditional inert biomaterials. For cancer theranostics, compared with organic or polymer nanomaterials, inorganic nanomaterials possess unique physical and chemical properties, have stronger mechanical stability on the basis of maintaining certain bioactivity, and are easy to be compounded with various carriers (polymer carriers, biological carriers, etc.), so as to achieve specific antitumor efficacy. After entering the nanoscale, due to the nano-size effect, high specific surface area and special nanostructures, inorganic nanomaterials exhibit unique biological effects, which significantly influence the interaction with biological organisms. Therefore, the research and applications of bioactive inorganic nanomaterials in cancer theranostics have attracted wide attention. In this review, we mainly summarize the recent progress of bioactive inorganic nanomaterials in cancer theranostics, and also introduce the definition, synthesis and modification strategies of bioactive inorganic nanomaterials. Thereafter, the applications of bioactive inorganic nanomaterials in tumor imaging and antitumor therapy, including tumor microenvironment (TME) regulation, catalytic therapy, gas therapy, regulatory cell death and immunotherapy, are discussed. Finally, the biosafety and challenges of bioactive inorganic nanomaterials are also mentioned, and their future development opportunities are prospected. This review highlights the bioapplication of bioactive inorganic nanomaterials.

The objectives of this study were to estimate the prognostic value of the tumour-stroma ratio (TSR) and tumour budding (TB) in oral tongue squamous cell carcinoma (OTSCC) and to establish a reliable model to predict the outcome of OTSCC patients.

A total of 103 patients surgically treated at our hospital were enrolled in this study. Chi-square tests, Kaplan-Meier analyses and Cox proportional hazards regression models were performed for statistical analysis.

Fifty-six patients were categorized as stroma-rich, and 47 patients were categorized as stroma-poor. Only pathological grade was associated with the TSR (p = 0.017). Kaplan-Meier analysis showed that stroma-rich, high-intensity budding and high risk groups were associated with worse prognosis. The Cox regression model showed that the TSR was an independent risk factor for OTSCC patients prognosis, and the high risk group was also related to poor prognosis (p < 0.05). TB was significantly associated with poor prognosis but was not an independent risk factor.

We found that patients in the stroma-rich group had a worse long-term prognosis. The TSR is an independent risk factor for OTSCC patients' outcome. In addition, a risk model that combined the TSR and TB proved to be valuable for predicting OTSCC patients' outcome.

In recent years, researchers are developing novel nanoparticles for diagnostic applications using imaging techniques and for therapeutic purposes through drug delivery techniques. The unique physical and chemical properties of mesoporous silica nanoparticles (MSNs) make it possible to integrate a variety of commonly used therapeutic and imaging agents to construct a multimodal synergistic anticancer drug delivery system. Herein, recent advances in MSNs synthesis for drug delivery and smart response applications are reviewed. First, synthetic strategies for the fabrication of ordered MSNs, hollow MSNs, core-shell structured MSNs, dendritic MSNs, and biodegradable MSNs are outlined. Then, the recent research progress in designing functional MSN materials with various controlled release mechanisms in anticancer therapy is discussed, and new properties are introduced to suggest the latest design requirements as drug delivery materials. The review also highlights significant achievements in bioimaging using MSNs and their multifunctional counterparts as delivery vehicles. Finally, personal views on key directions for future work in this area are presented.

Variations in axillary lymph node (ALN) metastatic potential between different breast cancers lead to microscopical alterations in tumor perfusion heterogeneity. This study investigated the usefulness of histogram metrics from iodine maps in the preoperative diagnosis of metastatic ALNs in patients with early-stage breast cancer.

Between October 2020 and November 2021 enhanced spectral computed tomography (CT) was performed in female patients with breast cancer. Quantitative spectral CT parameters and histogram parameters (mean, median, maximum, minimum, 10th percentiles, 90th percentiles, kurtosis, skewness, energy, range, and variance) from iodine maps were compared between patients with metastatic and nonmetastatic ALNs. Continuous variables were compared using Student's t-test or Mann-Whitney U test. Categorical variables were compared using Pearson's chi-square tests or Fisher's exact tests. Associations between ALN status and imaging features were evaluated using Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis.

This study included 113 female patients (62 and 51 in the ALN-negative and ALN-positive groups, respectively). Tumor size, molecular subtypes, and location differed significantly between the ALN-negative and ALN-positive groups (P<0.05). None of the quantitative spectral CT parameters of mass between metastatic and nonmetastatic ALN groups were significantly different (P>0.05). Histogram parameters of iodine maps for breast cancers, including maximum, 10th percentile, range, and energy, were significantly higher in the metastatic ALNs group compared with the nonmetastatic ALNs group (P<0.05). Multivariable logistic regression analyses showed that tumor location and energy were independent predictors of metastatic ALNs in breast cancers. The combination of independent predictors yielded an area under the curve (AUC) of 0.824 (sensitivity 72.5%; specificity 74.2%).

Whole-lesion histogram parameters derived from spectral CT iodine maps may be used as a complementary noninvasive means for the preoperative identification of ALN metastases in patients with early-stage breast cancer.

In vitro cell cultures are most often performed in unphysiological hyperoxia since the oxygen partial pressure of conventional incubators is set at 141 mmHg (18.6%, close to ambient air oxygen 20.1%). This value is higher than human tissue oxygen levels, as the in vivo oxygen partial pressures range from 104 mmHg (lung alveoli) to 8 mmHg (skin epidermis). Importantly, under pathological conditions such as cancer, cells can experience oxygen pressure lower than the healthy tissue. Although hypoxic incubators can regulate gas oxygen, they do not take into account the dissolved oxygen concentration in the cell culture medium. In the context of organ on chip and micro-physiological system development, we present here a new system, called Oxalis (OXygen ALImentation System) that allows fine control of the dissolved oxygen level in the cell culture medium. Oxalis regulates simultaneously the gas composition and the inlet reservoir pressure by modulating the pneumatic valve opening. This dual regulation allows both the pressure driven liquid flowrate and the level of oxygen dissolved in the chip to be controlled independently. Oxalis offers unprecedented features such as an oxygen equilibration time lower than 3 minutes and an accuracy of 3 mmHg. These performances can be reached for chip perfusion flow as low as 1 μL min^-1. This low flow rate allows the shear stress experienced by the cells in the chip to be accurately controlled. In addition, the system enables modulation of the pH in the cell culture medium through the modulation of CO₂. The fine control and monitoring of both O₂ and pH pave the way for new precise investigations on physiological and pathological biological processes. Using Oxalis in the context of tumor-on-chip, we demonstrate the capacity of the system to recapitulate hypoxia-induced gene expression, offering an innovative strategy for future studies on the role of hypoxia in malignant progression and drug resistance.

Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is an aggressive disease predicted to be the 2nd cause of cancer mortality in the US by 2040. While first-line therapy has improved, 5-year overall survival has only increased from 5 to ∼10%, and surgical resection is only available for ∼20% of patients as most present with advanced disease, which is invariably lethal. PDAC has well-established highly recurrent mutations in four driver genes including KRAS, TP53, CDKN2A, and SMAD4. Unfortunately, these genetic drivers are not currently therapeutically actionable. Despite extensive sequencing efforts, few additional significantly recurrent and druggable drivers have been identified. In the absence of targetable mutations, chemotherapy remains the mainstay of treatment for most patients. Further, the role of the above driver mutations on PDAC initiation and early development is well-established. However, these mutations alone cannot account for PDAC heterogeneity nor discern early from advanced disease. Taken together, management of PDAC is an example highlighting the shortcomings of the current precision medicine paradigm. PDAC, like other malignancies, represents an ecoevolutionary process. Better understanding the disease through this lens can facilitate the development of novel therapeutic strategies to better control and cure PDAC. This review aims to integrate the current understanding of PDAC pathobiology into an ecoevolutionary framework.