Aptamers, short oligonucleotide sequences that bind specifically to cellular proteins and receptors, are emerging as versatile tools in molecular nanomedicine. Unlike passive tumor targeting via the enhanced permeability and retention (EPR) effect, aptamers enable precise drug delivery, enhancing therapeutic efficacy while minimizing side effects. Developed through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process, aptamers offer compact size, robust structure, chemical versatility, and cost-effective synthesis. They serve as effective delivery vehicles for therapeutic molecules, including miRNA, siRNA, and small-molecule drugs, and function as antibody-like ligands for applications in cancer, diabetes, and autoimmune disorders. Since the approval of Macugen, the first aptamer targeting VEGF, aptamers have also shown promise as diagnostic sensors and theranostic agents. This review explores SELEX-derived aptamers in nanomedicine, focusing on their therapeutic and diagnostic roles, particularly in precision cancer therapies. It also addresses challenges such as degradation and clinical translation alongside prospects in vaccines, tissue engineering, and regenerative medicine.

In situ and metastatic malignant tumors are primary diseases that threaten human life. Among all the metastases, liver metastasis is the most difficult to detect. As most imaging probes have high liver accumulation, it is difficult to distinguish tiny metastases from normal liver tissue with strong background signal. In this study, the design of a novel second near-infrared window (NIR-II) fluorescence probe for precise detection of carcinoma in situ and liver metastases is presented. The probe called Tg-RGD utilizes a commercially available cyanine dye IR-806 as the signaling moiety, a disulfide bond linker as the responsive moiety, an RGD-capped poly(ethylene glycol) (PEG) as the water soluble enhancer, and the tumor targeting moiety. Tg-RGD shows good glutathione (GSH) responsiveness and selectivity, where its NIR-II fluorescence intensity can enhance 50-fold after activation. In vivo study indicates that Tg-RGD shows much better imaging and targeting effects than Tg-PEG with a similar structure but without RGD moiety for both orthotopic breast cancer and osteosarcoma. Most importantly, Tg-RGD can detect tiny liver metastases with high signal-to-background ratio (3.2). Thus, this study reports a high-performance tumor-specific NIR-II fluorescence probe for in situ and tiny metastatic tumor detection, and may further broaden the applications into related tumor lesions.

This paper aims to investigate the dielectric properties of blood for tumor detection and staging. The application of complex thermodynamic models and the study of the trend over time of some thermodynamic functions have allowed us to highlight the generation of displacement currents caused by changes in charge, i.e., by the activation and consequent accumulation of platelets on migrating tumor cells. Although few studies exist to date in this regard, the technique used has provided promising results, especially in terms of building a database. In this context, the evaluation of the dielectric parameters of healthy and cancerous blood can be exploited for the staging of cancer. The main advantages of this method include easy application, non-invasiveness, low cost, and online monitoring.

Anoikis and immune cell infiltration are pivotal factors in the pathophysiological mechanism of diabetic nephropathy (DN), yet a comprehensive understanding of the mechanism is lacking. This work aimed to pinpoint distinctive anoikis-related genes (ARGs) in DN and delve into their impact on the immune landscape. Three datasets (GSE30528, GSE47184, and GSE96804) were downloaded from the gene expression omnibus (GEO) dataset. Differentially expressed genes (DEGs) were identified using the "limma" package, while ARGs were obtained from GSEA, GeneCard, and Harmonizome datasets. The intersection of DEGs and ARGs was analyzed for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The CIBERSORT algorithm was employed to estimate the infiltration percentage of 22 immune cell types in DN renal tissue. Subsequently, the least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) algorithms were adopted to screen key ARGs related to DN. After that, receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of each gene and the real-time quantitative polymerase chain reaction (RT-qPCR) was adopted to quantitatively detect the expression of biomarkers in DN cell models. Finally, correlations between key genes and immune cell infiltration were analyzed, and a competitive endogenous ribonucleic acid (RNA) (ceRNA) network based on key genes was constructed. A total of 59 DEARGs were identified. GO functional annotation enrichment analysis revealed their involvement in kidney development, extracellular matrix (ECM), cytoplasmic vesicle cavity, immunoinflammatory response, and cytokine effect. KEGG pathway analysis indicated that MAPK, PI3K -Akt, IL -17, TNF, and HIF- 1 signaling pathways are critical for DN. In addition, seven key genes, including PDK4, S100A8, HTRA1, CHI3L1, WT1, CDKN1B, and EGF, were screened by machine learning algorithm. Most of these genes exhibited low expression in renal tissue of DN patients and positive correlation with neutrophils, and their expressions were verified in an external dataset cell model. The ceRNA analysis suggested potential regulatory pathways (H19/miR-15b-5p/PDK4 and KCNQ1T1/miR-1207-3p/WT1) influencing early DN progression. This work provided a comprehensive analysis of the role of DEARGs in DN for the first time, offering valuable insights for further understanding the disease mechanism and guiding clinical diagnosis, treatment, and research of DN.

The coagulation system plays a complex role in cancer therapy. Endothelial damage and tissue factor increased by chemotherapy initiate the coagulation cascade, producing active FXa and releasing thrombin. Thrombin triggers tumor growth and metastasis, leading to severe thromboembolic events in cancer patients. Direct thrombin inhibitors do not have the expected anti-metastatic effect as PAR-2 remains active and increases the risk of bleeding. Therefore, dual inhibition of thrombin by FXa inhibition and plasmin inhibition, which converts fibrin to fibrinogen, is targeted. Clinical studies show that the use of tranexamic acid in patients on NOAC therapy may be beneficial without increasing the risk of bleeding. This approach offers a promising strategy to provide an anti-metastatic effect in cancer treatment.

This study aimed to identify differentially expressed genes (DEGs) that are associated with hepatocarcinogenesis and metastasis in hepatocellular carcinoma (HCC) and to explore their value in predicting overall survival (OS). The methods used included bioinformatics analysis of gene expression datasets and in vitro experiments using HCC cell lines.

Gene expression profiles from metastatic and non-metastatic liver cancer specimens were analyzed using the limma R package. Functional enrichment was performed using Metascape. A prognostic 5-gene signature was constructed using the LASSO algorithm based on TCGA-LIHC data. Kaplan-Meier survival analysis assessed the association of these genes with clinical outcomes (DFI, DSS, OS, and PFS). In vitro, Huh7 and Hep3B cells were transfected with shRNA for SPP1 knockdown. Cell viability was measured with CCK-8 assays, and migration was assessed with Transwell and wound-healing assays. Protein expression was evaluated via western blotting.

The analysis of gene expression profiles led to the identification of 11 DEGs associated with immune response, phagocytosis, and cell migration. From these DEGs, the LASSO algorithm identified a 5-DEG signature (MASP1, MASP2, MUC1, TREM1, and SPP1) that was predictive of OS in liver cancer patients. Among the five genes, SPP1 was the most upregulated in cancer samples and was significantly associated with poorer outcomes, including DFI, DSS, OS, and PFS. In vitro experiments confirmed that SPP1 knockdown in Huh7 and Hep3B cells significantly inhibited cancer cell viability and migration. Western blot analysis showed alterations in key proteins, with a reduction in vimentin and Ki-67 and an increase in E-cadherin following SPP1 knockdown.

This study highlights the pivotal effect of SPP1 on HCC development and underscores its potential as a biomarker for the OS of liver cancer patients. The identified DEGs may serve as predictive markers for OS and potential therapeutic targets for HCC treatment.

Breast cancer is one of the leading causes of death worldwide. The aggressive behaviour of breast tumor results from their metastasis. Notably, the brain tissue is one of the common regions of metastasis, thereby reducing the overall survival of patients. Moreover, the metastatic tumors demonstrate poor response or resistance to therapies. In addition, breast cancer brain metastasis provides the poor prognosis of patients. Therefore, it is of importance to understand the mechanisms in breast cancer brain metastasis. Both cell lines and animal models have been developed for the evaluation of breast cancer brain metastasis. Moreover, different tumor microenvironment components and other factors such as lymphocytes and astrocytes can affect brain metastasis. The breast cancer cells can disrupt the blood-brain barrier (BBB) during their metastasis into brain, developing blood-tumor barrier to enhance carcinogenesis. The breast cancer brain metastasis can be increased by the dysregulation of chemokines, STAT3, Wnt, Notch and PI3K/Akt. On the other hand, the effective therapeutics have been developed for the brain metastasis such as introduction of nanoparticles. Moreover, the disruption of BBB by ultrasound can increase the entrance of bioactive compounds to the brain tissue. In order to improve specificity and selectivity, the nanoparticles for the delivery of therapeutics and crossing over BBB have been developed to suppress breast cancer brain metastasis.

To assess whether high Ki-67 protein expression level could independently predict the distant recurrence in early-stage breast cancer with low Oncotype Dx scores (≤ 25).

This single-center retrospective cohort study included 278 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-), T1-2N0M0, low Oncotype Dx recurrence score (RS) (≤ 25) breast cancer. We identified 2 groups: "high Ki-67″ ≥ 15% (n = 130, 47%) and "low Ki-67″ < 15% (n = 148, 53%). Clinical characteristics, treatment and survival were abstracted from chart review. Fisher's exact test was used to assess differences between Ki-67 groups. Cox-regression models were used to assess differences in survival.

After a median follow up of 7 years, 13 (4.7%) patients experienced distant metastasis. Recurrence rate was significantly higher in the "high Ki-67″ group 9.2% (12/130) versus the "low Ki-67″ group 0.7% (1/148) (P = .001). Distant metastasis-free survival (dMFS) was significantly shorter in the "high Ki-67″ group (HR 12.90, 95% CI, 12.53-13.27, P = .008). Tumor size ≥ 2 cm was associated with shorter dMFS (HR, 12.90; 95% CI, 12.53-13.27; P < .001). In a multivariable analysis, tumor size ≥ 2 cm and "High Ki-67″ were independent prognosis factors for dMFS.

Ki-67 expression level may help to identify a subset of low risk Oncotype Dx patients who could benefit from adjuvant chemotherapy.

Advanced breast cancer, as well as ineffective treatments leading to surviving cancer cells, can result in the dissemination of these malignant cells from the primary tumor to distant organs. Recent research has shown that microRNA 200c (miR-200c) can hamper certain steps of the invasion-metastasis cascade. However, it is still unclear whether miR-200c expression alone is sufficient to prevent breast cancer cells from metastasis formation. Hence, we performed a xenograft mouse experiment with inducible miR-200c expression in MDA-MB 231 cells. The ex vivo analysis of metastatic sites in a multitude of organs, including lung, liver, brain, and spleen, revealed a dramatically reduced metastatic burden in mice with miR-200c-expressing tumors. A fundamental prerequisite for metastasis formation is the motility of cancer cells and, therefore, their migration. Consequently, we analyzed the effect of miR-200c on collective- and single-cell migration in vitro, utilizing MDA-MB 231 and MCF7 cell systems with genetically modified miR-200c expression. Analysis of collective-cell migration revealed confluence-dependent motility of cells with altered miR-200c expression. Additionally, scratch assays showed an enhanced predisposition of miR-200c-negative cells to leave cell clusters. The in-between stage of collective- and single-cell migration was validated using transwell assays, which showed reduced migration of miR-200c-positive cells. Finally, to measure migration at the single-cell level, a novel assay on dumbbell-shaped micropatterns was performed, which revealed that miR-200c critically determines confined cell motility. All of these results demonstrate that sole expression of miR-200c impedes metastasis formation in vivo and migration in vitro and highlights miR-200c as a metastasis suppressor in breast cancer.

Studies for new treatment strategies on cancer continue, and new searches continue in the diagnosis and evaluation of cancer. This study examined the possible anticarcinogenic effect of Rutin on the brain tissues of male mice with Ehrlich ascites carcinoma (EAC).

We used micro-computed tomography (micro-CT) and histologically Hematoxylin&Eosin (H&E) staining methods for evaluation.

In the evaluation results, we saw a significant decrease in the brain volume of the tumor group to the control group. The difference in volume between the Rutin treatment group and the control group was not significant. In the brain tissues of the tumor group, numerous degenerated neurons characterized by pericellular/perivascular space expansion, cell swelling, or expansion were detected in the cortex and hippocampus regions. We showed a reduction in the damage rate in the Rutin treated group.

As a result, Rutin was found to have an anticarcinogenic effect. In addition to the classical histological evaluation, we used a newer method, micro-CT, in our study. We believe that this study has important results both in terms of its originality and adding new information to the literature.

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents.

Effective drug delivery relies on the selection of suitable carriers, which is crucial for protein-based therapeutics such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). One of the key advantages of TRAIL is its ability to selectively induce apoptosis in cancer cells excluding healthy tissues by binding to death receptors DR4 and DR5, which are highly expressed in various cancer cells. Despite this promise, the clinical application of TRAIL has been limited by its short half-life, limited stability, and inefficient delivery to tumor sites. To overcome currently available clinical and engineering approaches, a series of sophisticated strategies is required: (a) the design of biomaterial-mediated carriers for enhanced targeting efficacy, particularly via optimizing selected materials, composition, formulation, and surface modulation. Moreover, (b) development of genetically modified cellular products for augmented TRAIL secretion toward tumor microenvironments and (c) cell surface engineering techniques for TRAIL immobilization onto infusible cell populations are also discussed in the present review. Among these approaches, living cell-based carriers offer the distinct advantage of systemically administered TRAIL-functionalized cells capturing circulating tumor cells in the bloodstream, thereby preventing secondary tumor formation. This review provides insight into the development of novel TRAIL delivery platforms, discusses considerations for clinical translation, and suggests future directions and complementary strategies to advance the field of TRAIL-based cancer therapeutics.

Caveolin-1 (CAV1) is a membrane protein that promotes migration, invasion and metastasis of cancer cells when phosphorylated on tyrosine-14 (Y14) by a cell intrinsic mechanism involving the activation of a novel Rab5-Rac1 signaling axis. Moreover, CAV1 expressed in aggressive cancer cells is included into extracellular vesicles (EVs) and such EVs increase the metastatic potential of recipient lower grade cancer cells. However, the relevance of CAV1 Y14 phosphorylation in these extrinsic EV-stimulated events remained to be determined. Here we used B16F10 mouse melanoma cells over-expressing wild-type CAV1, phospho-mimetic CAV1(Y14E) or phospho-null CAV1(Y14F) as models to determine how the EV protein content was affected by Y14 phosphorylation and how these EVs modulated the metastatic potential of recipient B16F10 cells lacking CAV1. EVs from B16F10 cells over-expressing wild-type and CAV1(Y14/E) contain CAV1, and other proteins linked to signaling pathways associated with cell adhesion and migration. CAV1 inclusion in EVs was reduced by the Y14F mutation and global protein composition was also significantly different. Moreover, CAV1 wild-type and CAV1(Y14E) EVs promoted migration, as well as invasion of cells lacking CAV1 [B16F10(Mock) cells]. In addition, β3 integrin was transferred via CAV1(Y14E) EVs to B16F10 (Mock) cells, and treatment with such EVs promoted metastasis of recipient B16F10(Mock) cells. Finally, CAV1(Y14E) EV-enhanced migration, invasion and metastasis of recipient cells was blocked by anti-αVβ3 antibodies. In conclusion, CAV1 phosphorylated on Y14 not only intrinsically promotes migration, invasion and metastasis of cells expressing the protein (in cis), but also favors the inclusion of CAV1 into EVs, as well as the extrinsic acquisition of malignant traits in recipient cells, through integrin transfer (in trans).

Brain metastasis is thought to be related to the high mortality and poor prognosis of lung cancer. Despite significant advances in the treatment of primary lung cancer, the unique microenvironment of the brain renders current therapeutic strategies largely ineffective against brain metastasis. The lack of effective drugs for brain metastasis treatment is primarily due to the incomplete understanding of the mechanisms underlying its initiation and progression. Currently, our understanding of brain metastasis remains limited, primarily due to the absence of appropriate models that can realistically simulate the entire process of tumor cell detachment from the primary site, circulation through the bloodstream, and eventual colonization of the brain. Therefore, there is a pressing need to develop more suitable lung cancer brain metastasis models that can effectively replicate these critical stages of metastasis. Here, based on the traditional carotid artery injection model, we established a novel orthotopic mouse model by using a light-controlled hydrogel to repair the puncture site on the carotid artery, with sustained cerebral blood circulation and the capability of multiple delivery cancer cell to mimic lung cancer brain metastasis. The optimized orthotopic mouse model significantly reduced cerebral ischemia and improved cerebral oxygenation by 60% compared to the traditional orthotopic mouse model, enhancing post-operative survival rates. It also showed a reduction in pro-inflammatory cytokines and featured less inflammatory and more resting states of microglial and astrocyte cells. Furthermore, the optimized orthotopic mouse model markedly increased the success rate and absolute number of the metastatic clones in the brain. Additionally, the multiple delivery model based on the optimized orthotopic mouse model substantially augmented the tumor clone number and formation rates compared to single injection in the optimized orthotopic mouse model. This model overcomes previous limitations by maintaining cerebral circulation, providing a more accurate simulation of the continuous entry of tumor cells into cerebral circulation. It offers a robust platform for studying the interactions of cancer cells with the brain microenvironment and testing new therapeutic approaches.

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.

Thyroid cancer is the most prevalent endocrine cancer. The prognosis depends on the type and stage at diagnosis. Thyroid cancer treatments involve surgery, possibly followed by additional therapeutic options such as hormone therapy, radiation therapy, targeted therapy and chemotherapy. Besides the well-known thyroid tumor biomarkers, new circulating biomarkers are now emerging. Advances in genomic, transcriptomic and proteomic technologies have allowed the development of novel tumor biomarkers. This review explores the current literature data to critically analyze the benefits and limitations of routinely measured circulating biomarkers for the diagnosis and monitoring of thyroid cancer. The review also sheds light on new circulating biomarkers, focusing on the challenges of their use in the clinical management of thyroid cancer, underlining the need for the identification of a new generation of circulating biomarkers.

Metastatic dissemination is driven by genetic, biochemical, and biophysical cues that favor the distant colonization of organs and the formation of life-threatening secondary tumors. We have previously demonstrated that endothelial cells (ECs) actively remodel during extravasation by enwrapping arrested tumor cells (TCs) and extruding them from the vascular lumen while maintaining perfusion. In this work, we dissect the cellular and molecular mechanisms driving endothelial remodeling. Using high-resolution intravital imaging in zebrafish embryos, we demonstrate that the actomyosin network of ECs controls tissue remodeling and subsequent TC extravasation. Furthermore, we uncovered that this cytoskeletal remodeling is driven by altered endothelial-calcium (Ca2+) signaling caused by arrested TCs. Accordingly, we demonstrated that the inhibition of voltage-dependent calcium L-type channels impairs extravasation. Lastly, we identified P2X4, TRP, and Piezo1 mechano-gated Ca2+ channels as key mediators of the process. These results further highlight the central role of endothelial remodeling during the extravasation of TCs and open avenues for successful therapeutic targeting.

A crucial cellular mechanism that has a complex impact on the biology of cancer, particularly in solid tumors, is autophagy. This review explores how metabolic processes trigger autophagy, which helps metastatic tumor cells go dormant and recur. During metastasis, tumor cells frequently encounter severe stressors, such as low oxygen levels and nutritional deprivation, which causes them to activate autophagy as a survival tactic. This process allows cancer stem cells (CSCs) to withstand severe conditions while also preserving their features. After years of dormancy, dormant disseminated tumor cells (DTCs) may reappear as aggressive metastatic cancers. The capacity of autophagy to promote resistance to treatments and avoid immune detection is intimately related to this phenomenon. According to recent research, autophagy promotes processes, such as the epithelial-to-mesenchymal transition (EMT) and helps build a pre-metastatic niche, which makes treatment strategies more challenging. Autophagy may be a promising therapeutic target because of its dual function as a tumor suppressor in early-stage cancer and a survival promoter in advanced stages. To effectively treat metastatic diseases, it is crucial to comprehend how metabolic processes interact with autophagy and affect tumor behavior. In order to find novel therapeutic approaches that can interfere with these processes and improve patient outcomes, this study highlights the critical need for additional investigation into the mechanisms by which autophagy controls tumor dormancy and recurrence.

Neoadjuvant immunotherapy seeks to harness the primary tumor as a source of relevant tumor antigens to enhance systemic anti-tumor immunity through improved immunological surveillance. Despite having revolutionized the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC), a significant portion of patients remain unresponsive and succumb to metastatic recurrence post-treatment. Here, we found that optimally scheduled neoadjuvant administration of anti-4-1BB monotherapy was able to counteract metastases and prolong survival following surgical resection. Phenotypic and transcriptional profiling revealed enhanced 4-1BB expression on tumor-infiltrating intermediate (T int ), relative to progenitor (T prog ) and terminally exhausted (T term ) T cells. Furthermore, T int was enriched in low-affinity T cells. Treatment with anti-4-1BB drove clonal expansion of T int , with reduced expression of tissue-retention marker CD103 in T prog . This was accompanied by increased TCR clonotype sharing between paired tumors and pre-metastatic lungs. Further interrogation of sorted intratumor T cells confirmed enhanced T cell egress into circulation following anti-4-1BB treatment. In addition, gene signature extracted from anti-4-1BB treated T int was consistently associated with improved clinical outcomes in BRCA patients. Combinatorial neoadjuvant anti-4-1BB and ablation of tumor-derived CXCL16 resulted in enhanced therapeutic effect. These findings illustrate the intratumor changes underpinning the efficacy of neoadjuvant anti-4-1BB, highlighting the reciprocity between local tissue-retention and distant immunologic fortification, suggesting treatment can reverse the siphoning of intratumor T cells to primary tumor, enabling redistribution to distant tissues and subsequent protection against metastases.

H1.4 is one of the 11 variants of linker histone H1, and is associated with tumorigenesis and development of various cancers. However, it is unclear for the role of histone H1.4 in non-small cell lung cancer (NSCLC). In this study, we found that overexpression of H1.4 significantly inhibited the cell viability, migration, invasion and epithelial-mesenchymal transition (EMT) processes, whereas silencing H1.4 by shRNA knockdown promoted these processes in NSCLC cell lines A549 and H1299. We further showed that H1.4 overexpression reduced ERK1/2 expression or its phosphorylation levels, while H1.4 knockdown increased ERK1/2 expression or phosphorylation levels in NSCLC. Furthermore, we demonstrated that H1.4 bound to the promoter of ERK1/2, and acted as a transcriptional suppressor to inhibit ERK1/2 expression in A549 or H1299 cells. Importantly, we found that ERK ecto-expression can largely recovered the inhibitory effects of H1.4 on cell viability, migration, invasion and EMT processes. In summary, our study reveals that the H1.4-ERK pathway is crucial for cell viability, migration, invasion and EMT of NSCLC and could be a therapeutic target for NSCLC.

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

Breast cancer remains a leading cause of mortality among women worldwide, with existing therapeutic options often accompanied by significant side effects and a persistent risk of disease recurrence. This highlights the need for novel drug candidates with new mechanisms of action by targeting alternative signaling pathways. While hERG channel is notoriously regarded as an off-target due to drug-induced cardiotoxicity, its therapeutic potential as a drug target remains largely unexplored.

This study investigated the role of hERG in breast cancer progression and its impact on patient survival. The anti-proliferative, anti-migratory, anti-invasive and pro-apoptotic effects of hERG activators were evaluated using the Cell Counting Kit-8, wound healing assay, transwell assay and cell apoptosis assay, respectively. Western blotting, Ca2+ imaging and immunofluorescence assays were employed to study their antitumor mechanisms of actions.

We identified two novel hERG activators, SDUY429 and SDUY436, which effectively inhibited the proliferation and migration of MDA-MB-231 and MCF-7 cells. In addition, SDUY436 demonstrated significant anti-invasive and pro-apoptotic effects in MDA-MB-231 cells. Mechanistically, the anti-proliferative activity of hERG activators were mediated through calcineurin activation via enhanced calcium ion influx, which facilitated the nuclear translocation of nuclear factor of activated T cells (NFAT) and upregulated p21Waf/Cip expression. Furthermore, both SDUY429 and SDUY436 remarkably suppressed the migration and invasion of MDA-MB-231 cells by downregulating the protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK3β)/β-catenin signaling pathway. The observed reduction in phospho-AKT-Ser473 (pAKTS473) expression resulted in the decreased levels of phospho-GSK3β-Ser9 (pGSK3βS9), thereby limiting the nuclear localization of β-catenin, which led to the inhibition of cell migration and invasion. Notably, combining SDUY429 or SDUY436 with the AKT inhibitor MK-2206 produced synergistic anti-proliferative effects.

These findings suggest that hERG activators hold promise as new potential therapeutic agents for the treatment of breast cancer, paving the way for future investigations into their clinical applications.

Cancer stem cells play an important role in tumor progression and chemotherapy resistance. Leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) has been identified as a cancer stem cell marker in several cancer types. LGR5 is involved in cancer development and progression via several pathways including WNT/β-catenin signaling pathway. LGR5 plays a role in tumor progression by promoting cancer cell migration, invasion, metastasis, and angiogenesis in many cancers including colorectal, brain, gastric, and ovarian cancer. This review summarises the current knowledge on the expression and functional role of LGR5 in cancers, the molecular mechanisms regulated by LGR5, and the relationship between LGR5 and chemotherapy resistance. The review also includes highlights potential strategies to inhibit LGR5 expression and function. The majority of functional studies have shown that LGR5 plays an important role in promoting cancer progression, metastasis and chemotherapy resistance however, in some contexts LGR5 can also activate tumor-suppressive pathways and LGR5 negative cells can also promote cancer progression. The review highlights that targeting LGR5 is a promising anti-cancer treatment but the functional effect of LGR5 on tumor cells is complex may be dependent on cancer type, tumor microenvironment and cross-talk with other molecules in the LGR5 signaling pathway.

Colorectal cancer (CRC) poses a substantial global health concern, exhibits inconspicuous early symptoms, and is typically diagnosed at advanced stages leading to unfavorable outcomes. The intricate tumor microenvironment plays a crucial role in CRC development and progression, where chemokines contribute significantly. These chemokines exhibit widespread expression within tumor cells, facilitating immune cell infiltration, angiogenesis, and the establishment of distant metastases. The dysregulation of various chemokines in the context of CRC has emerged as a pivotal factor in the disease's pathogenesis.

To explore the relationship between chemokine gene expression and CRC patient survival, as well as to clarify their biological roles,We conducted RNA-sequencing (RNA-seq) analysis on a cohort of 88 CRC patients with tumor samples, thereby enabling a detailed exploration of chemokine involvement in CRC. This study was rigorously augmented using comprehensive datasets from The Cancer Genome Atlas (TCGA), ensuring a robust analysis of gene expression patterns associated with clinical outcomes.

Through data analysis, we identified key genes from the chemokine family thought pertinent to CRC outcomes. Consequently, we constructed a novel prognostic model based on the risk score derived from these chemokine expressions. Validation against clinical metadata, executed through immunohistochemistry analysis, affirmed the relevance and accuracy of our model in predicting patient survival.

Our findings illuminate the critical role of chemokines in shaping the immune microenvironment of CRC, thereby highlighting potential therapeutic targets for future treatment strategies. Our new prognostic model could provide important information for the development of targeted therapies for CRC, enhancing personalized treatment approaches andultimately improving survival for CRC patients.

Our objective was to elucidate the pivotal roles of BCAR1 in unfolded protein response (UPR), autophagy and vasculogenic mimicry (VM) formation, processes that essential for the metastasis of lung adenocarcinoma (LUAD) cells.

The morphological assessment of endoplasmic reticulum (ER) status and autolysosomes in H1975 and H1299 LUAD cells following BCAR1 knockout (KO) was conducted using transmission electron microscope. The expression of markers and cellular functions related to the UPR, autophagy, and VM formation were examined in LUAD cells tissues. Additionally, proteomic analysis of LUAD cells was performed via mass spectrometry, and the pertinent signaling pathways were analyzed using bioinformatics tools.

BCAR1-KO inhibited autophagy and UPR induced triggered starvation in LUAD cells. Cleaved-ATF6a-mediated UPR and subsequent autophagy, enhanced by BCAR1, were confirmed using the UPR stimulator and blocker. High BCAR1 expression, along with elevated UPR and autophagy, predicts poor prognosis in LUAD patients. BCAR1-KO reduced tube formation and VM markers expressions in LUAD cells. Additionally, BCAR1 expression positively correlated with VM formation in BALB/c-nu mice xenografts and LUAD patient tissues.

BCAR1 promotes LUAD metastasis by enhancing cancer cell survival in nutrient-poor environments through ATF6-mediated UPR activation and autophagy. As BCAR1 induces VM formation, metastatic lesions eventually colonize. Thus, BCAR1 is a promising anti-metastasis target.

Breast cancer remission after treatment is sometimes long-lasting, but in about 30% of cases, there is a relapse after a so-called dormant state. Cellular cancer dormancy, the propensity of disseminated tumor cells (DTCs) to remain in a nonproliferative state for an extended period, presents an opportunity for therapeutic intervention that may prevent reawakening and the lethal consequences of metastatic outgrowth. Therefore, identification of dormant DTCs and detailed characterization of cancer cell-intrinsic and niche-specific [i.e., tumor microenvironment (TME) mediated] mechanisms influencing dormancy in different metastatic organs are of great importance in breast cancer. Several microenvironmental drivers of DTC dormancy in metastatic organs, such as the lung, bone, liver, and brain, have been identified using in vivo models and/or in vitro three-dimensional culture systems. TME induction and persistence of dormancy in these organs are mainly mediated by signals from immune cells, stromal cells, and extracellular matrix components of the TME. Alterations of the TME have been shown to reawaken dormant DTCs. Efforts to capitalize on these findings often face translational challenges due to limited availability of representative patient samples and difficulty in designing dormancy-targeting clinical trials. In this chapter, we discuss current approaches to identify dormant DTCs and provide insights into cell-extrinsic (i.e., TME) mechanisms driving breast cancer cell dormancy in distant organs.

Triple-negative breast cancer (TNBC) is characterized by high mortality rates, primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937, and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of dual-specificity phosphatase 1 (DUSP1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified activating transcription factor 3 (ATF3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the metastatic mechanisms of TNBC. SIGNIFICANCE STATEMENT: This study constructs a high-throughput phenotypic screening system utilizing epithelial-mesenchymal transition marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.

Stem cell-based therapies hold significant potential for cancer treatment due to their unique properties, including migration toward tumor niche, secretion of bioactive molecules, and immunosuppression. Mesenchymal stem cells (MSCs) from adult tissues can inhibit tumor progression, angiogenesis, and apoptosis of cancer cells. We have previously reported the isolation and characterization of placenta-derived decidua basalis mesenchymal stem cells (DBMSCs), which demonstrated higher levels of pro-migratory and anti-apoptotic genes, indicating potential anti-cancer effects. In this study, we analyzed the anti-cancer effects of DBMSCs on human breast cancer cell lines MDA231 and MCF7, with MCF 10A used as control. We also investigated how these cancer cells lines affect the functional competence of DBMSCs. By co-culturing DBMSCs with cancer cells, we analyzed changes in functions of both cell types, as well as alterations in their genomic and proteomic profile. Our results showed that treatment with DBMSCs significantly reduced the functionality of MDA231 and MCF7 cells, while MCF 10A cells remained unaffected. DBMSC treatment decreased epithelial-to-mesenchymal transition (EMT)-related protein levels in MDA231 cells and modulated expression of other cancer-related genes in MDA231 and MCF7 cells. Although cancer cells reduced DBMSC proliferation, they increased their expression of anti-apoptotic genes. These findings suggest that DBMSCs can inhibit EMT-related proteins and reduce the invasive characteristics of MDA231 and MCF7 breast cancer cells, highlighting their potential as candidates for cell-based cancer therapies.

Lymph node metastasis is a critical indicator of cancer progression, profoundly affecting diagnosis, staging, and treatment decisions. This review article delves into the recent advancements in molecular imaging techniques for lymph nodes, which are pivotal for the early detection and staging of cancer. It provides detailed insights into how these techniques are used to visualize and quantify metastatic cancer cells, resident immune cells, and other molecular markers within lymph nodes. Furthermore, the review highlights the development of innovative, lymph node-targeted therapeutic strategies, which represent a significant shift towards more precise and effective cancer treatments. By examining cutting-edge research and emerging technologies, this review offers a comprehensive overview of the current and potential impact of lymph node-centric approaches on cancer diagnosis, staging, and therapy. Through its exploration of these topics, the review aims to illuminate the increasingly sophisticated landscape of cancer management strategies focused on lymph node assessment and intervention.

Renal cell carcinoma is the most common type of primary renal cancer, and clear cell carcinoma is the most common subtype, accounting for approximately 70% of all adult renal cell carcinoma cases. At the time of diagnosis, many patients already have metastatic manifestations. Cutaneous metastasis of renal clear cell carcinoma is very rare and usually represents a poor prognosis, mostly affecting the head and neck. In this paper, we report a case of renal clear cell carcinoma with multiple cutaneous metastases, including a chest wall mass for more than 10 years and an abdominal wall mass for 1 year. A 69-year-old man with a history of diabetes mellitus was admitted to the hospital for examination of a right chest and abdominal wall mass and peripheral pain, and ultrasonography suggested a solid space-occupying lesion in the left kidney, which was considered malignant, and a solid mass in the right chest and abdominal wall, which was considered metastatic. A subsequent abdominal CT scan showed malignant tumors in the left kidney and adrenal region, and multiple metastatic tumors in the liver, pancreas, right thoracoabdominal wall, and the abdomen. To clarify the nature of the pathology, an ultrasound-guided puncture of the right abdominal wall mass was performed, and the pathological diagnosis was clear cell carcinoma, with immunohistochemistry suggesting a renal clear cell carcinoma origin. The patient died within 6 months.

Metastasis is the leading cause of death in patients with cancer, driving considerable scientific and clinical interest in immunosurveillance of micrometastases. We investigated this process by creating a multiscale mathematical model to study the interactions between the immune system and the progression of micrometastases in general epithelial tissue. We analyzed the parameter space of the model using high-throughput computing resources to generate over 100,000 virtual patient trajectories. We demonstrated that the model could recapitulate a wide variety of virtual patient trajectories, including uncontrolled growth, partial response, and complete immune response to tumor growth. We classified the virtual patients and identified key patient parameters with the greatest effect on the simulated immunosurveillance. We highlight the lessons derived from this analysis and their impact on the nascent field of cancer patient digital twins (CPDTs). While CPDTs could enable clinicians to systematically dissect the complexity of cancer in each individual patient and inform treatment choices, our work shows that key challenges remain before we can reach this vision. In particular, we show that there remain considerable uncertainties in immune responses, unreliable patient stratification, and unpredictable personalized treatment. Nonetheless, we also show that in spite of these challenges, patient-specific models suggest strategies to increase control of clinically undetectable micrometastases even without complete parameter certainty.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia-inducible factor-1α (HIF1α) nuclear retention and function. NPTX1 is overexpressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1α hypoxic response in PDAC. Significance: We identified the NPTX1-AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis. Therapeutic NPTX1 targeting outperformed a common chemotherapy regimen in inhibiting liver metastasis and suppressed primary tumor growth in preclinical models, revealing a novel therapeutic strategy targeting hypoxic response in PDAC.

The occurrence of most cancers is due to the clonal proliferation of tumor cells, immune evasion, and the ability to spread to other body parts. Rho GTPases, a family of small GTPases, are key regulators of cytoskeleton reorganization and cell polarity. Additionally, Rho GTPases are key proteins that induce the proliferation and metastasis of tumor cells. This review focuses on the complex regulatory mechanisms of Rho GTPases, exploring their critical role in promoting tumor cell proliferation and dissemination. Regarding tumor cell proliferation, attention is given to the role of Rho GTPases in regulating the cell cycle and mitosis. In terms of tumor cell dissemination, the focus is on the role of Rho GTPases in regulating cell migration and invasion. Overall, this review elucidates the mechanisms of Rho GTPases members in the development of tumor cells, aiming to provide theoretical references for the treatment of mammalian tumor diseases and related applications.

Metastatic disease is a major issue of treatment failure in nasopharyngeal carcinoma (NPC) patients and often linked to high mortality. L48H37, a synthetic analog of curcumin with augmented bioavailability over its parent compound, has demonstrated several oncostatic characteristics. This study was aimed to explore the anti-metastatic effect of L48H37 on NPC cancer cells and its underlying mechanism.

Cell viability was evaluated using MTT assay. Regulation of signaling pathways was elucidated by immunoblotting, and specific kinase inhibitors.

In this study, we showed that L48H37 suppressed TPA-stimulated invasive and migratory capacities of NPC cell lines and gave rise to very little cytotoxic responses. Such anti-cancer effect of L48H37 was accompanied with attenuated expression levels and enzymatic activities of matrix metalloproteinase-9 (MMP-9), a pivotal mediator of metastatic processes. In addition, L48H37 interfered with TPA-induced JNK activation, and the treatment of L48H37 combined with a JNK antagonist demonstrated a synergistic effect on restraining TPA-stimulated MMP-9 activity and migration events in NPC cells.

Our results revealed that L48H37 impeded the invasive potential of NPC cells via impairment of MMP-9 function and abundance, highlighting possible complementary therapies using curcumin or its effective analogs to manage NPC dissemination.

Prostate cancer (PCa) metastasis is one of the leading causes of cancer-related mortality in men worldwide, primarily due to its tendency to metastasize, with bones of axial skeleton being the favored target-site. PCa bone-metastasis (PCa-BM) presents significant clinical challenges, especially by the weakening of bone architecture, majorly due to the formation of osteoblastic lesions, leading to severe bone fractures. Another complication is that the disease predominantly affects elderly men. Further exploration is required to understand how the circulating tumor cells (CTCs) adapt to varying microenvironments and other biomechanical stresses encountered during the sequential steps in metastasis, finally resulting in colonization specifically in the bone niche, in PCa-BM. Deciphering how CTCs encounter and adapt to different biochemical, biomechanical and microenvironmental factors may improve the prospects of PCa diagnosis, development of novel therapeutics and prognosis. Moreover, the knowledge developed is expected to have broader implications for cancer research, paving the way for better therapeutic strategies and targeted therapies in the realm of metastatic cancer progression across different types of cancers. Our review begins with analyzing the challenges in PCa diagnosis, treatment and management, and delves into the formation and dynamics of CTCs, highlighting their role in PCa metastasis and bone-tropism. We further explore the pivotal role of individual factors in dictating the predisposition of tumors to metastasize to specific secondary sites, such as the noteworthy tendency of PCa bone-metastasis. Finally, we highlight the unresolved questions and potential avenues for further exploration.

Chemotherapy drug efflux, toxic side effects, and low efficacy against drug-resistant cells have plagued safe and efficient cancer theranostics. However, the materials or methods that resolve these defects all-in-one are scarce. Here, a new cancer theranostics strategy is proposed by utilizing changes in lysosomal acidity in cancer cells to activate the membranolytic model to overcome these obstacles together. Therefore, a simple fluorescent anthracene derivative Lyso-Mito is developed, which has a perfect pKa (4.62) value that falls between the pH of lysosomes in cancer and normal cells. Lyso-Mito itself can precisely target and convert the pH perturbation of lysosomes in cancer cells to fluorescent response and membranolytic module activity to accomplish the low drug efflux, weak toxic side effects, and low drug-resistant cancer diagnosis and treatment without linking other functional units or any additional assistance. Hereby, a new cancer theranostics strategy of integrating organelle microenvironment and the membranolytic model is realized.

The high mortality associated with certain cancers can be attributed to the invasive nature of the tumor cells. Yet, the complexity of studying invasion hinders our understanding of how the tumor spreads. This work presents a microengineered three-dimensional (3D) in vitro model for studying cancer cell invasion and interaction with endothelial cells. The model was generated by printing a biomimetic hydrogel scaffold directly on a chip using 2-photon polymerization that simulates the brain's extracellular matrix. The scaffold's geometry was specifically designed to facilitate the growth of a continuous layer of endothelial cells on one side, while also allowing for the introduction of tumor cells on the other side. This arrangement confines the cells spatially and enables in situ microscopy of the cancer cells as they invade the hydrogel scaffold and interact with the endothelial layer. We examined the impact of 3D printing parameters on the hydrogel's physical properties and used patient derived glioblastoma cells to study their effect on cell invasion. Notably, the tumor cells tended to infiltrate faster when an endothelial cell barrier was present. The potential for adjusting the hydrogel scaffold's properties, coupled with the capability for real-time observation of tumor-endothelial cell interactions, offers a platform for studying tumor invasion and tumor-endothelial cell interactions.

Small cell lung cancer (SCLC) represents an aggressive neuroendocrine (NE) tumor within the pulmonary region, characterized by very poor prognoses. Druggable targets for SCLC remain limited, thereby constraining treatment options available to patients. Immuno-chemotherapy has emerged as a pivotal therapeutic strategy for extensive-stage SCLC (ES-SCLC), yet it fails to confer significant efficacy in cases involving liver metastases (LMs) originating from SCLC. Therefore, our attention is directed towards the challenging subset of SCLC patients with LMs. Disease progression of LM-SCLC patients is affected by various factors in the tumor microenvironment (TME), including immune cells, blood vessels, inflammatory mediators, metabolites, and NE substances. Beyond standard immuno-chemotherapy, ongoing efforts to manage LMs in SCLC encompass anti-angiogenic therapy, radiotherapy, microwave ablation (MWA) / radiofrequency ablation (RFA), trans-arterial chemoembolization (TACE), and systemic therapies in conjunction with local interventions. Prospective experimental and clinical investigations into SCLC should prioritize precise and individualized approaches to enhance the prognosis across distinct patient cohorts.