Lactoferrin is an iron-binding glycoprotein that provides natural protective effects to the human body. Its biological properties, including antibacterial, antiviral, anti-inflammatory, immune-regulatory, and iron metabolism-regulating functions, have been extensively studied. With further research, lactoferrin's impact on tumorigenesis and tumor microenvironment has become increasingly evident, as it inhibits tumor proliferation, invasion, and metastasis through multiple pathways. This article summarizes the molecular mechanisms underlying lactoferrin's anticancer effects, explores its association with the malignant progression of various cancers, and highlights its clinical translational potential as a potential cancer biomarker and drug delivery carrier to enhance anticancer therapy efficiency. Due to the high safety profile of lactoferrin, its widespread application in the field of cancer treatment is highly anticipated.

This study investigated the relationship between the preoperative cachexia index (CXI) and long-term outcomes in patients who underwent radical resection for biliary tract cancer (BTC).

We analyzed 128 patients who underwent BTC resection at a single institute between 2014 and 2022. The diagnoses of the patients included intrahepatic cholangiocarcinoma (n = 27), perihilar cholangiocarcinoma (n = 17), distal cholangiocarcinoma (n = 36), gallbladder carcinoma (n = 20), and ampullary cholangiocarcinoma (n = 28). The relationship between CXI and long-term outcomes after BTC resection was investigated. CXI was calculated on the basis of the preoperative skeletal muscle index, serum albumin level, and neutrophil-to-lymphocyte ratio.

The low-CXI group (36/69, 52.1%) had a significantly higher rate of lymph node metastasis than the high-CXI group (14/59, 23.7%). The multivariate analysis confirmed that lymph node metastasis, poor differentiation (poor), and inclusion in the low-CXI group were independently associated with disease-free survival (DFS) and overall survival (OS) in patients who underwent radical resection for BTC. After propensity score matching, the low-CXI group had a significantly worse prognosis than the high-CXI group in terms of both DFS and OS.

CXI may be a useful prognostic factor for DFS and OS after resection of BTC.

Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.

Neoadjuvant systemic therapy (NAT) represents an attractive option for improved outcomes of early-stage breast cancer (BC) patients, as it can significantly reduce tumor burden thus permitting breast-conserving resections. Equally important, the eradication of viable cancer cells post-NAT, also known as pathological complete response (pCR), has emerged as a strong prognostic biomarker, reflecting tumor's biology and subsequent treatment responses. Yet to date, no validated markers predictive of pCR have been identified.

The present retrospective study aimed to explore the value of neutrophil-tolymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as potential predictors of pCR.

Despite no statistically significant associations have been reported, NLR and PLR dynamics during NAT, as longitudinal inflammatory phenotypes, merit further investigation in larger cohorts.

In the future, the integration of a comprehensive inflammatory biomarker panel into clinical practice could assist in a priori treatment selection process.

Tumors are complex ecosystems composed of malignant and non-malignant cells embedded in a dynamic extracellular matrix (ECM). In the tumor microenvironment, molecular phenotypes are controlled by cell-cell and ECM interactions in 3D cellular neighborhoods (CNs). While their inhibition can impede tumor progression, routine molecular tumor profiling fails to capture cellular interactions. Single-cell spatial transcriptomics (ST) maps receptor-ligand interactions but usually remains limited to 2D tissue sections and lacks ECM readouts. Here, we integrate 3D ST with ECM imaging in serial sections from one clinical lung carcinoma to systematically quantify molecular states, cell-cell interactions, and ECM remodeling in CN. Our integrative analysis pinpointed known immune escape and tumor invasion mechanisms, revealing several druggable drivers of tumor progression in the patient under study. This proof-of-principle study highlights the potential of in-depth CN profiling in routine clinical samples to inform microenvironment-directed therapies. A record of this paper's transparent peer review process is included in the supplemental information.

Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs' differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies.

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic malignancies. Despite the remarkable improvement concerning treatment, late detection and resistance to clinically used chemotherapeutic agents remain major challenges. Trichostatin A (TSA), a histone deacetylase inhibitor, has been recognized as an effective therapeutic agent against PDAC by inhibiting proliferation, inducing apoptosis, and sensitizing PDAC cells to chemotherapeutic agents such as gemcitabine. Microgravity has become a useful tool in cancer research due to its effects on various cellular processes. This paper presents a deep molecular and proteomic analysis investigating cell growth, the modulation of cytokeratins, and proteins related to apoptosis, cellular metabolism, and protein synthesis after TSA treatment in simulated microgravity (SMG)-exposed PaCa44 3D cells. Our analysis concerns the effects of TSA treatment on cell proliferation: the impairment of the cell cycle with the downregulation of proteins involved in Cdc42 signaling and G1/G2- and G2/M-phase transitions. Thus, we observed modification of survival pathways and proteins related to autophagy and apoptosis. We also observed changes in proteins involved in the regulation of transcription and the repair of damaged DNA. TSA treatment promotes the downregulation of some markers involved in the maintenance of the potency of stem cells, while it upregulates proteins involved in the induction and modulation of the differentiation process. Our data suggest that TSA treatment restores the cell phenotype prior to simulated microgravity exposure, and exerts an intriguing activity on PDAC cells by reducing proliferation and inducing cell death via multiple pathways.

Over the last two decades, the diagnosis and treatment of breast cancer patients have improved considerably. However, brain metastases remain a major clinical challenge and a leading cause of mortality. Thus, a better understanding of the pathways involved in the metastatic cascade is essential. To this end, we have investigated the reciprocal effects of astrocytes and breast cancer cells, employing traditional 2D cell culture and our unique 3D multicellular tumouroid models. Our findings revealed that astrocytes enhance the proliferation, migration and invasion of breast cancer cells, suggesting a supportive role for astrocytes in breast cancer outgrowth to the brain. Elucidating the key players in astrocyte-breast cancer cells crosstalk, we found that CCL2 is highly expressed in breast cancer brain metastases tissue sections from both patients and mice. Our in vitro and in vivo models further confirmed that CCL2 has a functional role in brain metastasis. Given their aggressive nature, we sought additional immune checkpoints for rationale combination therapy. Among the promising candidates were the adhesion molecule P-selectin, which we have recently shown to play a key role in the crosstalk with microglia cells and the co-inhibitory receptor PD-1, the main target of currently approved immunotherapies. Finally, combining CCL2 inhibition with immunomodulators targeting either PD-1/PD-L1 or P-selectin/P-Selectin Ligand-1 axes in our human 3D tumouroid models and in vivo presented more favourable outcomes than each monotherapy. Taken together, we propose that CCL2-CCR2/CCR4 is a key pathway promoting breast cancer brain metastases and a promising target for an immunotherapeutic combination approach.

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.

Colorectal cancer (CRC) is a leading global cancer with high mortality, especially in metastatic cases, with limited therapeutic options. The tumor microenvironment (TME), a network comprising various immune cells, stromal cells and extracellular (ECM) components plays a crucial role in influencing tumor progression and therapy outcome. The genetic heterogeneity of CRC and the complex TME complicates the development of effective, personalized treatment strategies. The prognosis has slowly improved during the past decades, but metastatic CRC (mCRC) is common among patients and is still associated with low survival. The therapeutic options for CRC differ from those for mCRC and include surgery (mostly for CRC), chemotherapy, growth factor receptor signaling pathway targeting, as well as immunotherapy. Malignant CRC cells are established in the TME, which varies depending on the primary or metastatic site. Herein, we review the role and interactions of several ECM components in 3D models of CRC and mCRC tumor cells, with an emphasis on how the TME affects tumor growth and treatment. This comprehensive summary provides support for the development of 3D models that mimic the interactions within the TME, which will be essential for the development of novel anticancer therapies.

Metastasis remains a primary cause of cancer-related mortality, with its intricate mechanisms continuing to be uncovered through advancing research. Among the various regulatory processes involved, RNA modification has emerged as a critical epitranscriptomic mechanism influencing cancer metastasis. N6-methyladenosine (m6A), recognized as one of the most prevalent and functionally significant RNA modifications, plays a central role in the regulation of RNA metabolism. In this review, we explore the multifaceted role of m6A in the different stages of cancer metastasis, including epithelial-mesenchymal transition, invasion, migration, and colonization. In addition to summarizing the current state of our understanding, we offer insights into how m6A modifications modulate key oncogenic pathways, highlighting the implications of recent discoveries for therapeutic interventions. Furthermore, we critically assess the limitations of previous studies and propose areas for future research, including the potential for targeting m6A as a novel approach in anti-metastatic therapies. Our analysis provides a comprehensive understanding of the regulatory landscape of m6A in metastasis, offering directions for continued exploration in this rapidly evolving field.

Malignant tumors represent a significant worldwide health challenge, with elevated morbidity and mortality rates necessitating enhanced early identification and individualized treatment. Liposomes, as biomimetic lipid-based nanovesicles, have developed as a multifaceted platform for detecting and treating malignant tumors due to their excellent biocompatibility, stability, and membrane fusion properties. Circulating tumor markers, such as circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating tumor proteins (CTPs), and circulating tumor nucleic acids (ctNAs), play a key role in early cancer diagnosis, disease progression monitoring, and personalized therapy. Liposome-based platforms enable effective molecular recognition, targeted detection, and signal amplification by targeting circulating tumor biomarkers, significantly increasing the potential for early tumor diagnosis and treatment. This review systematically summarizes advancements in the study of liposomes concerning circulating tumor markers, including applications in targeted recognition, early detection, and disease diagnosis, while discussing present problems and prospective applications of existing technology.

Renal cell carcinoma (RCC) is among the most frequently occurring types of cancer, and its metastasis is a major contributor to its elevated mortality. Before the primary tumor metastasizes to secondary or distant organs, it remodels the microenvironment of these sites, creating a pre-metastatic niche (PMN) conducive to the colonization and growth of metastatic tumors. RCC releases a variety of biomolecules that induce angiogenesis, alter vascular permeability, modulate immune cells to create an immunosuppressive microenvironment, affect extracellular matrix remodeling and metabolic reprogramming, and determine the organotropism of metastasis through different signaling pathways. This review summarizes the principal processes and mechanisms underlying the formation of the premetastatic niche in RCC. Additionally, we emphasize the significance and potential of targeting PMNs for the prevention and treatment of tumor metastasis in future therapeutic approaches. Finally, we summarized the currently potential targeted strategies for detecting and treating PMN in RCC and provide a roadmap for further in-depth studies on PMN in RCC.

Platelets, traditionally recognized for their role in hemostasis, have emerged as pivotal players in cancer biology. They actively contribute to tumor proliferation, angiogenesis, immune evasion, and metastasis and thus play a significant role in cancer progression. Tumor-educated platelets (TEPs) acquire protumorigenic phenotypes through RNA, protein, and receptor profile alterations driven by interactions with tumors and their microenvironment. These modifications enable TEPs to enhance tumor growth and dissemination and to play a critical role throughout the metastatic process. Moreover, TEPs are promising biomarkers that can easily be analyzed in liquid biopsies. Since they dynamically mirror tumor activity through transcriptomic and proteomic changes, their analysis offers a non-invasive method for determining cancer detection and diagnosis, patient prognosis, therapy monitoring, and personalization of treatment. Their demonstrated accuracy in identifying cancer types and predicting treatment responses underscores their ability to provide real-time insights into tumor biology, including in urological malignancies. Their diagnostic potential and their accessibility as blood-sourced biomarkers position TEPs as transformative tools in advancing personalized oncology. Here, we focus on the role of TEPs in urological tumors, exploring their applications in early cancer detection, disease monitoring, and the design of tailored therapeutic strategies.

Membrane-intercalating conjugated oligoelectrolytes (MICOEs), a class of phospholipid bilayer mimics, demonstrate an exceptional ability to spontaneously integrate into biological membranes through a combination of electrostatic and hydrophobic interactions. This unique property makes them promising candidates for membrane imaging applications. Over the past decade, MICOEs have been successfully applied to imaging and tracking a wide range of biological membranes, including microbial membranes, mammalian plasma membranes, intracellular membranes, extracellular vesicles, and artificial liposomes. Recent advancements have shed light on the imaging mechanisms of MICOEs and highlighted their potential as fluorescent probes, with a focus on structural optimization to enhance their performance. Building on these developments, this review will explore the intercalation mechanisms of MICOEs, analyze the structure-activity relationships governing their molecular design and imaging capabilities, and discuss the future challenges and emerging opportunities for their application as advanced membrane dyes.

The relationship between patterns of RNA modifications and gastric cancer (GC) liver metastasis (GCLM) remains unclear. Here, by single-cell sequencing, clinical sample analysis, and mouse model studies, an abnormal increase in the expression of the RNA acetyltransferase N-acetyltransferase 10 (NAT10) in liver metastatic GC cells is identified. NAT10-mediated N4-acetylcytidine modification of CXCL2 and KLF5 mRNA increases their stability. Then, secreted CXCL2 is found to promote the infiltration and polarization of M2-like macrophages to produce oncostatin M, which transcriptionally activates NAT10 expression via STAT3 signaling. In addition, organoid models confirm that NAT10 promotes the adhesion of GC cells to hepatocytes. Mechanistically, KLF5 transcriptionally activates ITGαV, facilitating GC cell attachment to hepatocytes. Intriguingly, high expression of NAT10/KLF5 axis is associated with poor prognosis of GC patients and targeting this axis significantly reduces GCLM in preclinical murine models. Collectively, these findings suggest the clinical significance of NAT10 in developing targeted therapies for GC patients with liver metastasis.

Elevated levels of reactive oxygen species (ROS) in cancer cells, arising from their altered metabolism, represent a distinctive therapeutic target. Here, we introduce the first example of bisboronic esters as potent agents for rapidly disrupting redox homeostasis, selectively inducing oxidative stress to eliminate cancer cells. Structure-activity relationship studies revealed that both the electronic and steric factors significantly influence their cytotoxicity, with the most effective compounds achieving IC50 values as low as 0.63 μM. Confocal imaging confirmed the rapid intracellular depletion of ROS, leading to a severe metabolic imbalance and efficient cancer cell death. This study highlights the potential of boronate-based therapeutics for redox-targeted cancer therapy, which may provide a promising foundation for the development of innovative anticancer strategies.

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.

The distinctive physiological and physical properties of 3D cultures that mimic tumor microenvironments in vivo make them more suitable for assessing the efficacy of drugs and nanoparticles compared to 2D culture models. Therefore, this study aims to examine and contrast how liposomes interact with cell cultures in both 2D and 3D models. Hanging drop technique was used to generate 3D spheroids. Cellular toxicity of Doxorubicin and Doxil®-liposomes was tested using an MTT assay. Cellular uptake of Doxil®-liposomes was investigated in 3D and 2D cell culture models using flow cytometry and confocal microscopy. Finally, migration and invasion assays were used to investigate the Doxil®-liposomes interaction with the two models 2D model and 3D model, respectively. Our findings show that cells were able to form spheroid structures when a specific cell ratio was maintained. Flow cytometry analysis revealed that 2D cells exhibited higher Doxil®-liposome uptake than 3D cells. The data obtained from confocal and fluorescent microscopy supported the findings of the flow cytometry analysis. Furthermore, the MTT assay showed that Doxil®-liposomes induced less metabolic-disruption compared to free Doxorubicin. Our results also demonstrated that Doxil®-liposomes interacted more loosely with the 3D model than 2D cells, which was further confirmed by measurements of the total migration and invasion areas. Therefore, a 3D model replicating the in vivo conditions of tumor structure and extracellular matrix to assess the delivery of liposomal-nanoparticles to spheroids through a collagen matrix can be more informative and recapitulate the in vivo microenvironment than the 2D model.

Rationale: Advances in cancer therapies have significantly improved patient survival; however, tumors enriched in cancer stem cells (CSCs) have poor treatment responses. CSCs are a key source of tumor heterogeneity, contributing to therapeutic resistance and unfavorable patient outcomes. In the tumor microenvironment (TME), cell-in-cell (CIC) structures, where one cell engulfs another, have been identified as markers of poor prognosis. Despite their clinical relevance, the mechanisms underlying CIC formation across different tumor cell subpopulations remain largely unknown. Elucidating these processes could provide novel insights and therapeutic opportunities to address aggressive, treatment-resistant cancers. Method: Fluorescent mCherry-carrying colorectal cancer stem cells (CRCSCs) were expanded as spheroids in serum-free media and cocultured with either parental cancer cell-expressing Venus fluorescent protein or CFSE dye-stained immune cells (T cells, M1/M2 macrophages, neutrophils, and NK cells) or treated with EGFR- or PD-L1-targeting antibodies to assess the formation of CIC structures. Genes potentially crucial for the formation of CIC structures were knocked down or overexpressed, and their effects on CIC formation were evaluated. The clinical relevance of the in vitro findings was confirmed through analysis of formalin-fixed, paraffin-embedded (FFPE) human colorectal cancer (CRC) specimens. Results: CRCSCs have a strong predilection for serving as the outer cell in a CIC structure and forming homotypic CIC structures predominantly with parental CRC cells. The frequency of CIC structure formation increased when the cells were exposed to anti-PD-L1 antibody treatment. Both the outer CRCSC in a CIC structure and CRCSCs released from a homotypic CIC structure showed enhanced resistance to the cytotoxicity of NK-92MI cells. Restoration of Stathmin1 (STMN1) expression but not RAC1 knockdown in CRCSCs reduced the homotypic CIC frequency, disrupted the outer cell fate in CIC structures, and increased cell susceptibility to NK-92MI cytotoxicity. In CRC patients, CIC structures are associated with poor tumor differentiation, negative STMN1 expression, and poor prognosis. Conclusion: CSCs play a crucial role in informing CIC structures in CRC. CIC structure formation partially depends on low STMN1 expression and confers a survival advantage under NK cytotoxicity. Targeting this pathway may significantly improve immunotherapy's efficacy for CRC patients.

Fc receptor γ subunit (FcRγ) activation plays a crucial role in cancer carcinogenesis. Here, we aimed to uncover the impact of FcRγ on circulating tumor cells (CTC) colonization and the underlying mechanism. FcRγ deficient (FcRγ-/-) mice were used to investigate the functional effects of FcRγ in cancer metastasis, and the results demonstrated that FcRγ deficiency significantly promotes metastasis. The tumor metastasis effect, antiplatelet, platelet or neutrophil infusion experiments were conducted with FcRγ deficient (FcRγ-/-) mice and wild type mice (WT), bearing B16F10 or LCC tumor cells. Blood routine test, flow cytometry, immunofluorescent staining and in vivo image were applied for analysis. Platelet adhesion and neutrophil chemotaxis were analyzed by flow cytometry and ELISA in vitro. Platelet adoptive model was used for mimicing early colonization stage. Our results indicated FcRγ deficiency significantly promoted tumor metastasis accompanied with increased number of platelet and neutrophil in the lung. Further investigation showed that FcRγ-/- platelet infusion, rather than FcRγ-/- neutrophils, promoted CTC colonization. While platelet inhibitor Aspirin abrogated the platelet-mediated infiltration of neutrophil in the lung. Mechanistically, platelet FcRγ deficiency facilitated the adhesion of platelets and cancer cells and increased secretion of CXCL5 and CXCL7 which triggered the platelet-induced neutrophil recruitment. In sum, our study indicates that FcRγ is a restrainer in controlling cancer metastasis through regulating the adhesion of platelets and cancer cells and recruiting more neutrophils, which provides a potential target for anti-metastatic therapies. The level of FcRγ expression in platelets could act as a novel biomarker for cancer metastasis.

This review focuses on recent advancements in the effective use of mesoporous bioactive glasses (MBG) in the treatment of bone cancer, focusing on Osteosarcoma (OS). Bone cancers are rare but are associated with significant morbidity and mortality; often, aggressive treatment is required. Conventional treatments such as surgery, radiation, and chemotherapy are often not enough. This is because surgery cannot completely remove the tumor, without creating a critical size which are defects larger than 2 cm that cannot be repaired by physiological mechanisms. As a result, patients often face the additional burden of radiation and chemotherapy. Scientists have been exploring new treatments, including hyperthermia-targeted therapy, polymeric nanoparticles, and stem cell therapy. This could potentially negatively impact healthy tissues and organs. MBG offers a promising alternative to chemotherapeutic agents and ions for disease treatment as it acts as a multifunctional drug delivery system (DDS). In addition, MBG can also be engineered into scaffolds to facilitate local delivery of growth factors and drugs, thus promoting the efficiency of bone healing and restoration. Therefore, the current review highlights various MBG types reported in the past decade and explores potential future paths to enhance their use in bone cancer treatment while also giving insight on the already commercially available BGs that are used in different bone-related disease.

Epithelial tissues serve as critical barriers in metazoan organisms, maintaining structural integrity and facilitating essential physiological functions. Epithelial cell polarity regulates mechanical properties, signaling, and transport, ensuring tissue organization and homeostasis. However, the barrier function is challenged by cell turnover during development and maintenance. To preserve tissue integrity while removing dying or unwanted cells, epithelial tissues employ cell extrusion. This process removes both dead and live cells from the epithelial layer, typically causing detached cells to undergo apoptosis. Transformed cells, however, often resist apoptosis, leading to multilayered structures and early carcinogenesis. Malignant cells may invade neighboring tissues. Loss of cell polarity can lead to multilayer formation, cell extrusion, and invasion. Recent studies indicate that multilayer formation in epithelial cells with polarity loss involves a mixture of wild-type and mutant cells, leading to apical or basal accumulation. The directionality of accumulation is regulated by mutations in polarity complex genes. This phenomenon, distinct from traditional apical or basal extrusion, exhibits similarities to the endophytic or exophytic growth observed in human tumors. This review explores the regulation and implications of these phenomena for tissue biology and disease pathology.

Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.

Lymph node metastasis (LNM) significantly affects the prognosis and clinical management of breast cancer (BC) patients. This systematic review and meta-analysis aim to identify microRNAs (miRNAs) associated with LNM in BC and evaluate their potential diagnostic and prognostic value. Following PRISMA guidelines, a comprehensive literature search was conducted in PubMed, Web of Science, and SCOPUS databases, to assess the role of miRNAs in LNM BC. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to evaluate the quality of included studies. A total of 84 miRNAs were identified as differentially expressed in BC patients with LNM. Of these, a meta-analysis was performed in two microRNAs that were present in at least 3 different articles with a coherent expression direction: miR-155 and miR-34a. The meta-analysis returned a pooled a Log2 fold change of 1.50 for miR-155 (upregulated) and -0.53 for miR-34a (downregulated) with no evidence of publication bias, and a low risk of bias and applicability concerns. To conclude, this study names miR-155 and miR-34a as potential diagnostic biomarkers for LNM in BC, although further experimental validation is necessary to confirm these findings and develop non-invasive diagnostic tools for clinical use.

This review article delves into the multifaceted role of lactylation modification in antitumor therapy, revealing the complex interplay between lactylation modification and the tumor microenvironment (TME), metabolic reprogramming, gene expression, and immunotherapy. As an emerging epigenetic modification, lactylation has a significant impact on the metabolic pathways of tumor cells, immune evasion, gene expression regulation, and sensitivity to chemotherapy drugs. Studies have shown that lactylation modification significantly alters the development and therapeutic response of tumors by affecting metabolites in the TME, immune cell functions, and signaling pathways. In the field of immunotherapy, the regulatory role of lactylation modification provides a new perspective and potential targets for tumor treatment, including modulating the sensitivity of tumors to immunotherapy by affecting the expression of immune checkpoint molecules and the infiltration of immune cells. Moreover, research progress on lactylation modification in various types of tumors indicates that it may serve as a biomarker to predict patients' responses to chemotherapy and immunotherapy. Overall, research on lactylation modification provides a theoretical foundation for the development of new tumor treatment strategies and holds promise for improving patient prognosis and quality of life. Future research will further explore the application potential of lactylation modification in tumor therapy and how to improve treatment efficacy by targeting lactylation modification.

Lung cancer is prevalent worldwide and is a major cause of cancer-related mortality. Despite being the primary model for immunotherapy research, the response rates of lung cancer patients to immunotherapy are unsatisfactory. Furthermore, research on immunogenic cell death (ICD) in lung cancer is limited, which limits the development of strategies that combine ICD-related therapies with immunotherapy. In this study, we compiled and summarized 69 genes associated with ICD and developed an IRS. Across seven independent datasets, the IRS was identified as an independent prognostic factor. IRS was positively associated with multiple tumor proliferation pathways and negatively associated with immune-related pathways. Additionally, IRS negatively correlated with the infiltration of various immune cells, supporting its association with survival outcomes. Based on the correlation between IRS and immune activity, we validated the ability of IRS to predict immunotherapy efficacy across seven immunotherapy datasets and demonstrated that patients who respond to immunotherapy tend to have a lower IRS. Moreover, utilizing single-cell RNA sequencing, we revealed the role of mast cells in the TME with the highest IRS. Through interactions with various receptors on macrophages, endothelial cells, and tumor cells, mast cells promote tumor progression, providing a comprehensive explanation for poor prognosis and lack of response to immunotherapy in patients with high IRS. Our study offers new guidance for combination therapies in lung adenocarcinoma patients and elucidated the mechanism by which mast cells contribute to cancer development within the TME.

Chimeric antigen receptor T cell (CAR T) therapy has been successfully used to treat hematological malignancies. Nonetheless, its application to solid tumors remains challenging. Our previous analysis of the ongoing clinical trial (NCT03874897) demonstrated promising results in patients with advanced CLDN18.2-positive gastric cancer who received CT041 CAR T treatment. Here, we collected peripheral blood and ascites from five patients from the clinical trial 3 and 7 days (d) after CT041 infusion. Patients with a high proportion of naïve-like T cells were more likely to benefit from CT041 treatment. We found that high expression of CLDN18 in ascites epithelial cells correlated with a favorable prognosis, whereas ascites epithelial cells with high MYC expression and strong interactions between tumor cells and T cells were adverse prognostic factors for CT041 treatment. These findings may provide theoretical evidence for the screening of populations that can benefit from CAR T therapy and improve the efficacy of CAR T therapy.

The tumor microenvironment (TME) is pivotal in non-small cell lung cancer (NSCLC) progression, influencing drug resistance and immune cell behavior through complex ligand-receptor (LR) interactions. This study developed an epithelial LR-related prognostic risk score (LRrisk) to identify biomarkers and targets in NSCLC. We identified twenty epithelial LRs with significant prognostic implications and delineated three molecular NSCLC subtypes with distinct outcomes, pathological characteristics, biological pathways, and immune profiles. The LRrisk model was constructed using twelve differentially expressed ligand-receptor interaction-related genes (LRGs), with a focus on POPDC3 (popeye domain-containing protein 3), which was overexpressed in NSCLC cells. Functional assays revealed that POPDC3 knockdown reduced cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while its overexpression promoted cancerous activities. In vivo, POPDC3 silencing hindered, and its overexpression accelerated the growth of NSCLC xenografts in nude mice. Additionally, high expression levels of POPDC3 in NSCLC tissues were associated with enhanced CD4+ T cell infiltration and increased PD-1 expression within the TME. Moreover, ectopic POPDC3 overexpression in C57BL/6 J mouse Lewis lung carcinoma (LLC) xenografts enhanced CD4+ T cell infiltration and PD-1 expression in the TME. This research establishes a robust epithelial LR-related signature, highlighting POPDC3 as a critical facilitator of NSCLC progression and a potential therapeutic target.

In cancer patients, prognostic markers are needed to improve the management and clinical course of both the cancer itself and surgery therefor. Elevated systemic inflammatory markers are associated with morbidity and mortality in most cancer types. In this study, we aimed to determine the prognostic value of inflammatory markers such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) in patients undergoing cytoreductive surgery for ovarian cancer. The data of 188 patients who underwent surgery for ovarian cancer between December 2022 and December 2023 were retrospectively analyzed. Receiver operating characteristic (ROC) curves were constructed to evaluate the correlation between complications and the inflammatory prognostic factors NLR, PLR, and LMR. Optimal cutoff values were determined as the points where the Youden index (sensitivity + specificity - 1) was maximal. Patients were compared according to the presence of complications. As a result of the ROC curve analysis, patients were divided as high and low NLR and PLR groups. The difference of preoperative and postoperative inflammatory prognostic factors was compared according to the presence of complications. In this study in which a total of 90 patients were evaluated, the cutoff value for NLR was 2.04 (areas under the ROC curve: 0.655; P < .05) and the cutoff value for PLR was 145.3 (areas under the ROC curve: 0.740; P < .05) according to the presence of complications. In the group with complications, lymphopenia and thrombocytosis were more common preoperatively, while patients were more anemic postoperatively (P < .05). Patients in the high NLR group were younger and received less neoadjuvant chemotherapy. In the high PLR group, the number of patients receiving neoadjuvant chemotherapy was lower, and although the patients were more anemic and lymphopenic, higher rates of neutrophilia and thrombocytosis were observed. The analysis of preoperative and postoperative NLR, PLR, and LMR differences revealed an increase in NLR and PLR values and a decrease in LMR values (P < .05). The preoperative systemic inflammatory biomarkers NLR and PLR may be considered as prognostic predictors of poor postoperative outcomes. Therefore, consideration of these biomarkers may have an important role in clinical course management.

In cancer metastasis, tumor cells condition distant tissues to create a supportive environment, or metastatic niche, by driving the activation of cancer-associated fibroblasts (CAFs). These CAFs remodel the extracellular matrix, creating a microenvironment that supports tumor growth and compromises immune cell function, enabling cancer cells to evade immune detection. Consequently, targeting the activation of CAFs has been proposed as a therapeutic strategy to hinder metastatic spread. Our objective was to develop the first in vitro phenotypic screening assay capable of assessing this activation process.

Human primary lung fibroblasts were co-cultured with highly invasive breast cancer cells (MDA-MB-231) to identify changes in the expression of selected genes using RT-qPCR. An In-Cell ELISA (ICE)-based assay using human lung fibroblasts, MDA-MB-231 cells and human monocytes (THP-1 cells) was developed to measure the activation of CAFs. Another ELISA assay was used to measure released osteopontin.

When lung fibroblast were co-cultured with MDA-MB-231 cells, among the 10 selected genes, the genes for osteopontin (SPP1), insulin like growth factor 1 (IGF1), periostin (POSTN) and α-smooth muscle actin (α-SMA, ACTA2) elicited the greatest fold change (55-, 37-, 8- and 5-fold respectively). Since osteopontin, IGF-1 and periostin are secreted proteins and α-SMA is an intracellular cytoskeleton protein, α-SMA was chosen to be the readout biomarker for the ICE assay. When fibroblasts were co-cultured with MDA-MB-231 cells and monocytes in the 96 well ICE assay, α-SMA expression was increased 2.3-fold yielding a robust Z' of 0.56. A secondary, low throughput assay was developed by measuring the release of osteopontin which showed a 6-fold increase when fibroblasts were co-cultured with MDA-MB-231 cells and monocytes.

This phenotypic assay is the first to measure the activation of CAFs in a 96-well format, making it suitable for medium-to high-throughput screening of potential therapeutic compounds. By focusing on observable cellular phenotypic changes rather than targeting specific molecular pathways, this assay allows for a broader and unbiased identification of compounds capable of modulating CAF activation.

Comprehensive genomic profiling (CGP) testing is used worldwide for personalized cancer treatment. Unstained slides from formalin-fixed paraffin-embedded (FFPE) blocks are required for tissue-based CGP testing. However, the use of low quality FFPE specimens can result in testing failure or invalid results. Although several previous studies have indicated that the quality of genomic testing is affected by various factors, the factor(s) that has the greatest influence on CGP testing has not been well studied in real-world data. Thus, we conducted a large-scale multi-institutional study in Hiroshima, Japan to investigate the factors associated with quality check status in FoundationOne CDx CGP testing using real-world data from 1,204 participants from an area with a population of approximately 2.7 million. This study revealed low percentage of tumor nuclei in FFPE specimen, long-term storage of FFPE block, and pancreatic cancer as independent risk factors for qualified status. Of the three factors, percentage of tumor nuclei had the largest effect on quality check status, while the magnitudes of the effects of storage time of FFPE or pancreatic cancer were minor. Collectively, our real-world data indicate that tumor purity is the most important factor for successful CGP, and we would suggest greater than 35% as an ideal percentage of tumor nuclei for CGP submission.

Hemostasis is a mechanism that stops bleeding from an injured vessel, involves multiple interlinked steps, culminating in the formation of a "clot" sealing the damaged area. Moreover, it has long been recognized that inflammation also provokes the activation of the coagulation system. However, there has been an increasing amount of evidence revealing the immune function of the hemostasis system. This review collects and analyzes the results of the experimental studies and data from clinical observations confirming the inflammatory function of hemostasis. Here, we summarize the latest knowledge of the pathways in immune system activation under the influence of coagulation factors. The data analyzed allow us to consider the components of hemostasis as receptors recognizing «foreign» or damaged «self» or/and as «self» damage signals that initiate and reinforce inflammation and affect the direction of the adaptive immune response. To sum up, the findings collected in the review allow us to classify the coagulation factors, such as Damage-Associated Molecular Patterns that break down the conventional concepts of the coagulation system.

Histone deacetylation represents a significant epigenetic mechanism that involves the removal of acetyl groups from histones, subsequently influencing gene transcription. Overexpression of histone deacetylases (HDACs) is prevalent across various cancer types, positioning HDAC inhibitors as broadly applicable therapeutic agents. These inhibitors are known to enhance tumor immune antigenicity, potentially slowing tumor progression. Furthermore, the tumor microenvironment, which is intricately linked to cancer development, acts as a mediator in the proliferation of numerous cancers and presents a viable target for oncological therapies. This paper primarily explores how HDAC inhibitors can regulate cancer progression via the tumor microenvironment and suppress tumor growth through multiple pathways, in addition to examining the synergistic effects of combined drug therapies involving HDAC inhibitors.