Viewing the hallmarks as a sequence of adaptations captures the "why" behind the "how" of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.

Mesenchymal stem cells (MSCs), due to their tumor-targeting homing properties, are present in the tumor microenvironment (TME) and influence the biological behaviors of tumors. The purpose of this paper is to establish a signature based on the MSC secretome to predict the prognosis and treatment of bladder cancer (BLCA).

The presence of MSCs in BLCA was validated through flow cytometry and multiplex fluorescence immunohistochemistry (mFIHC), and the relationships between MSCs and clinical characteristics were explored. Unsupervised clustering analysis was performed on BLCA according to the differential proteins detected in MSC-conditioned medium (MSCCM) using a cytokine array. Using the TCGA-BLCA, GSE32548, and GSE32894 datasets as background data, a risk signature was constructed according to the differential proteins in MSCCM through machine learning. For the risk groups with high and low prognoses, we calculated Kaplan-Meier (K-M) curves. Additionally, we explored the relationships between the signature and the tumor immune landscape, response to immunotherapy, and chemotherapy drugs.

Both flow cytometry and mFIHC confirmed the presence of MSCs in bladder tumors, and clinical samples revealed correlations between MSCs and the pathological grade, T stage, and Ki67 in BLCA. Based on differential proteins and unsupervised clustering analysis, BLCA patients were divided into two groups, and significant differences were found between these groups in terms of TME, immune response, and clinical treatments. Using machine learning, a signature was constructed with the combination algorithm Stepcox (both) + plsRcox, revealing significant survival differences between the high- and low-risk MSC groups. Regression analyses, along with ROC curves, further demonstrated that risk score independently predict the prognosis of patients with high predictive performance. Moreover, there were notable differences between the high- and low-risk groups in terms of the TME scores, immune infiltration, and immune checkpoints. For BLCA immunotherapy, the low-risk group suggested better efficacy, while conventional chemotherapy drugs such as gemcitabine and cisplatin might be less effective in the low-risk group.

The signature based on MSC secreted protein profiles could effectively predict the prognosis of BLCA and provided valuable guidance for treatment and drug resistance.

Inflammasomes are multi-protein complexes that detect pathogenic and damage-associated molecular patterns, activating caspase-1, pyroptosis, and the maturation of pro-inflammatory cytokines such as IL-1β and IL-18Within the tumor microenvironment, inflammasomes like NLRP3 play critical roles in cancer initiation, promotion, and progression. Their activation influences the crosstalk between innate and adaptive immunity by modulating immune cell recruitment, cytokine secretion, and T-cell differentiation. While inflammasomes can contribute to tumor growth and metastasis through chronic inflammation, their components also present novel therapeutic targets. Several inhibitors targeting inflammasome components- such as sensor proteins (e.g., NLRP3, AIM2), adaptor proteins (e.g., ASC), caspase-1, and downstream cytokines- are being explored to modulate inflammasome activity. These therapeutic strategies aim to modulate inflammasome activity to enhance anti-tumor immune responses and improve clinical outcomes. Understanding the role of inflammasomes in cancer immunity is crucial for developing interventions that effectively bridge innate and adaptive immune responses for better therapeutic outcomes.

To investigate the role of Biglycan(BGN) in the progression and metastasis of clear cell renal cell carcinoma(ccRCC).

Based on multiple public databases, we investigated the expression level of BGN in ccRCC, its clinical significance, and its association with immune cells. Real-time fluorescence quantitative polymerase chain reaction(PCR) was employed to validate BGN expression in tumor and adjacent normal tissues from ten patients. We utilized RNA sequencing results for further analysis, including differential gene analysis, GO-KEGG analysis, and GSEA analysis, to identify the signaling pathways through which BGN exerts its effects. BGN knockdown cells(786-0 and Caki-1) were generated through lentiviral transfection to examine the impact of BGN on ccRCC. Cell proliferation, migration, and invasion were assessed using CCK8, colony formation, wound healing, Transwell migration, and invasion assays, respectively.

Our findings from database analysis and PCR revealed a significant upregulation of BGN expression in kidney cancer tissues compared to normal tissues. Further analysis demonstrated a correlation between high BGN expression and ccRCC progression and immune infiltration. In vitro experiments confirmed that BGN silencing effectively inhibited cell proliferation, migration, and invasion of ccRCC. Mechanistically, these effects may be mediated through the MAPK signaling pathway.

BGN potentially plays a pivotal role in the progression and metastasis of ccRCC, possibly acting through the MAPK signaling pathway. Therefore, BGN holds promise as a potential therapeutic target for ccRCC.

The negatively charged aminophospholipid, phosphatidylserine (PS), is typically restricted to the inner leaflet of the plasma membrane under normal, healthy physiological conditions. PS is irreversibly externalized during apoptosis, where it serves as a signal for elimination by efferocytosis. PS is also reversibly and transiently externalized during cell activation such as platelet and immune cell activation. These events associated with physiological PS externalization are tightly controlled by the regulated activation of flippases and scramblases. Indeed, improper regulation of PS externalization results in thrombotic diseases such as Scott Syndrome, a defect in coagulation and thrombin production, and in the case of efferocytosis, can result in autoimmunity such as systemic lupus erythematosus (SLE) when PS-mediated apoptosis and efferocytosis fails. The physiological regulation of PS is also perturbed in cancer and during viral infection, whereby PS becomes persistently exposed on the surface of such stressed and diseased cells, which can lead to chronic thrombosis and chronic immune evasion. In this review, we summarize evidence for the dysregulation of PS with a main focus on cancer biology and the pathogenic mechanisms for immune evasion and signaling by PS, as well as the discussion of new therapeutic strategies aimed to target externalized PS. We posit that chronic PS externalization is a universal and agnostic marker for diseased tissues, and in cancer, likely reflects a cell intrinsic form of immune escape. The continued development of new therapeutic strategies for targeting PS also provides rationale for their co-utility as adjuvants and with immune checkpoint therapeutics.

Keloids represent a challenging clinical problem because of their unpredictable and often refractory nature to treatment. This study aimed to identify the key changes in gene expression in the formation of keloid and provide potential biomarker candidates for clinical treatment and drug target discovery. Keloids and normal skin samples were analyzed for gene expression, and datasets from the Gene Expression Omnibus database were also analyzed. Differentially expressed genes (DEGs) were identified and analyzed using bioinformatics techniques, including gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. A protein-protein interaction network of the DEGs was created using the Search Tool for the Retrieval of Interacting Genes database. The gene set enrichment analysis was performed on keloid and normal skin tissue from clinical samples. The enriched functions and pathways identified included collagen-containing extracellular matrix (ECM), ECM, and external encapsulating structure. Ten hub genes were identified, along with one differentially expressed microRNA, miR-22-5p. miRNA target gene prediction was performed using miRPathDB 2.0 and Targetscan database. Among the hub genes, RUNX2, IGF1, EGF, and PPARGC1A were predicted targets of miR-22-5p. Validation at the tissue level highlighted RUNX2 as a crucial DEG in keloid tissue. These findings shed light on the molecular mechanisms of keloid formation and offer candidate therapeutic targets, suggesting that modulation of the miR-22-5p/RUNX2 axis may be a promising avenue for keloid diagnosis and treatment, thus laying a foundation for improved clinical management of keloid disorders.

The highly nuanced transition from an inflammatory process to tumorigenesis is of great scientific interest. While it is well known that environmental stimuli can cause inflammation, less is known about the oncogenic modifications that chronic inflammation in the tissue microenvironment can bring about, as well as how these modifications can set off pro-tumorigenic processes. It is clear that no matter where the environmental factors come from, maintaining an inflammatory microenvironment encourages carcinogenesis. In addition to encouraging angiogenesis and metastatic processes, sustaining the survival and proliferation of malignant transformed cells, and possibly altering the efficacy of therapeutic agents, inflammation can negatively regulate the antitumoral adaptive and innate immune responses. Because chronic inflammation has multiple pathways involved in tumorigenesis and metastasis, it has gained recognition as a marker of cancer and a desirable target for cancer therapy. Recent advances in our knowledge of the molecular mechanisms that drive cancer's progression demonstrate that inflammation promotes tumorigenesis and metastasis while suppressing anti-tumor immunity. In many solid tumor types, including breast, lung, and liver cancer, inflammation stimulates the activation of oncogenes and impairs the body's defenses against the tumor. Additionally, it alters the microenvironment of the tumor. As a tactical approach to cancer treatment, these findings have underscored the importance of targeting inflammatory pathways. This review highlights the role of inflammation in cancer development and metastasis, focusing on its impact on tumor progression, immune suppression, and therapy resistance. It examines current anti-inflammatory strategies, including NSAIDs, cytokine modulators, and STAT3 inhibitors, while addressing their potential and limitations. The review emphasizes the need for further research to unravel the complex mechanisms linking inflammation to cancer progression and identify molecular targets for specific cancer subtypes.

ASS1(argininosuccinate synthase 1) is a rate-limiting enzyme in the urea cycle, catalyzing the synthesis of argininosuccinate from citrulline and aspartate to ultimately produce arginine and support cellular metabolism. Increasing evidence suggests that ASS1 is commonly dysregulated in the tumor microenvironment, promoting tumor cell metastasis and infiltration. With a deeper understanding of tumor metabolic reprogramming in recent years, the impact of ASS1 dysregulation on abnormal tumor metabolism has attracted growing interest among researchers. In tumors with lacked or downregulated expression of ASS1, tumor cells become 'addicted' to exogenous arginine. Several strategies for arginine deprivation have been developed and entered clinical trials for treating such tumors. Therefore, we focus on elucidating the commonalities and characteristics of ASS1 dysregulation in tumors, as well as its implications for diagnosis, treatment, and prognosis. The mechanisms by which ASS1 gene dysregulation leads to metabolic abnormalities in tumor cells vary across different types of tumors. Extensive experimental studies have demonstrated that overexpression or low expression of ASS1 exhibits varying effects-either inhibitory or stimulatory proliferation-on tumor cells across different types. Restoring its expression can inhibit proliferation in some tumors lacking or downregulating ASS1 but can promote metastasis and infiltration in others (e.g., resistance to arginine deprivation therapy). Additionally, the expression level of ASS1 dynamically changes during tumorigenesis and progression. Finally, this review discusses the diagnostic, therapeutic, and prognostic value of ASS1 in future clinical practice.

Tumour-associated microbiota are integral components of the tumour microenvironment (TME). However, previous studies on intratumoral microbiota primarily rely on bulk tissue analysis, which may obscure their spatial distribution and localized effects. In this study, we applied in situ spatial-profiling technology to investigate the spatial distribution of intratumoral microbiota in breast cancer and their interactions with the local TME. Using 5R 16S rRNA gene sequencing and RNAscope FISH/CISH on patients' tissue, we identified significant spatial heterogeneity in intratumoral microbiota, with Fusobacterium nucleatum (F. nucleatum) predominantly localized in tumour cell-rich areas. GeoMx digital spatial profiling (DSP) revealed that regions colonized by F. nucleatum exhibit significant influence on the expression of RNAs and proteins involved in proliferation, migration and invasion. In vitro studies indicated that co-culture with F. nucleatum significantly stimulates the proliferation and migration of breast cancer cells. Integrative spatial multi-omics and co-culture transcriptomic analyses highlighted the MAPK signalling pathways as key altered pathways. By intersecting these datasets, VEGFD and PAK1 emerged as critical upregulated proteins in F. nucleatum-positive regions, showing strong positive correlations with MAPK pathway proteins. Moreover, the upregulation of VEGFD and PAK1 by F. nucleatum was confirmed in co-culture experiments, and their knockdown significantly reduced F. nucleatum-induced proliferation and migration. In conclusion, intratumoral microbiota in breast cancer exhibit significant spatial heterogeneity, with F. nucleatum colonization markedly altering tumour cell protein expression to promote progression and migration. These findings provide novel perspectives on the role of microbiota in breast cancer, identify potential therapeutic targets, and lay the foundation for future cancer treatments. KEY POINTS: Intratumoral Fusobacterium nucleatum exhibits significant spatial heterogeneity within breast cancer tissues. F. nucleatum colonization alters the expression of key proteins involved in tumour progression and migration. The MAPK signalling pathway is a critical mediator of F. nucleatum-induced breast cancer cell proliferation and migration. VEGFD and PAK1 are potential therapeutic targets to mitigate F. nucleatum-induced tumour progression.

The arachidonic acid (AA) pathway promotes tumor progression by modulating the complex interactions between cancer and immune cells within the microenvironment. In this Review, we summarize the knowledge acquired thus far concerning the intricate mechanisms through which eicosanoids either promote or suppress the antitumor immune response. In addition, we will discuss the impact of eicosanoids on immune cells and how they affect responsiveness to immunotherapy, as well as potential strategies for manipulating the AA pathway to improve anticancer immunotherapy. Understanding the molecular pathways and mechanisms underlying the role played by AA and its metabolites in tumor progression may contribute to the development of more effective anticancer immunotherapies.

Mesenchymal stem/stromal cells (MSCs) have garnered attention for their potential in cancer therapy due to their ability to home to tumor sites. Engineered MSCs have been developed to deliver therapeutic proteins, microRNAs, prodrugs, chemotherapy drugs, and oncolytic viruses directly to the tumor microenvironment, with the goal of enhancing therapeutic efficacy while minimizing off-target effects. Despite promising results in preclinical studies and clinical trials, challenges such as variability in delivery efficiency and safety concerns persist. Ongoing research aims to optimize MSC-based cancer eradication and immunotherapy, enhancing their specificity and efficacy in cancer treatment. This review focuses on advancements in engineering MSCs for tumor-targeted therapy.

CAR T cell therapies often lack specificity, leading to issues ranging from inadequate antigen targeting to off-tumor toxicities. To counter that lack of specificity, we expanded tumor targeting capabilities with universal CAR and spatially defined CAR T cell engagement with targets through a combination of synthetic biology and biomaterial approaches. We developed a novel framework, called "In situ Mobilization: Polymer Activated Cell Therapies" (IMPACT) for polymer-mediated, anatomical control of IF-THEN gated CAR T cells. With IMPACT, a regulated payload such as a BiTE or tumor-targeting CAR will only be expressed after engineered cells engage a tumor-localizing polymer ("IF" condition). In this first demonstration of IMPACT, we engineered CAR T cells to respond to fluorescein that is displayed by an injectable polymer that binds to and is retained in fibrin deposits in tumor microenvironments. This interaction then drives selective and conditional expression of a protein within tumors ("THEN" condition). Here, we develop the polymer and CAR T cell infrastructure of IMPACT and demonstrate tumor-localized CAR T cell activation in a murine tumor model after the intravenous administration of polymer and engineered T cells.

Tumors can exert a far-reaching influence on the body, triggering systemic responses that contribute to debilitating conditions like cancer cachexia. To characterize the mechanisms underlying tumor-host interactions, we utilized a BioID-based proximity labeling method to identify proteins secreted by Ykiact adult Drosophila gut tumors into the bloodstream/hemolymph. Among the major proteins identified are coagulation and immune-responsive factors that contribute to the systemic wasting phenotypes associated with Ykiact tumors. The effect of innate immunity factors is mediated by NFκB transcription factors Relish, dorsal, and Dif, which in turn upregulate the expression of the cachectic factors Pvf1, Impl2, and Upd3. In addition, Ykiact tumors secrete Eiger, a TNF-alpha homolog, which activates the JNK signaling pathway in neighboring non-tumor cells, leading to cell death. The release of damage-associated molecular patterns (DAMPs) from these dying cells presumably amplifies the inflammatory response, exacerbating systemic wasting. Targeting the inflammatory response, the JNK pathway, or the production of cachectic factors could potentially alleviate the debilitating effects of cancer cachexia.

The elevation of IQGAP3 expression in diverse cancers indicates a key role for IQGAP3 in carcinogenesis. Although IQGAP3 was established as a proliferating stomach stem cell factor and a regulator of the RAS-ERK pathway, how it drives cancer growth remains unclear.

We define the function of IQGAP3 in gastric cancer (GC) development and progression.

We studied the phenotypic changes caused by IQGAP3 knockdown in three molecularly diverse GC cell lines by RNA-sequencing. In vivo tumorigenesis and lung metastasis assays corroborated IQGAP3 as a mediator of oncogenic signalling. Spatial analysis was performed to evaluate the intratumoral transcriptional and functional differences between control tumours and IQGAP3 knockdown tumours.

Transcriptomic profiling showed that IQGAP3 inhibition attenuates signal transduction networks, such as KRAS signalling, via phosphorylation blockade. IQGAP3 knockdown was associated with significant inhibition of MEK/ERK signalling-associated growth factors, including TGFβ1, concomitant with gene signatures predictive of impaired tumour microenvironment formation and reduced metastatic potential. Xenografts involving IQGAP3 knockdown cells showed attenuated tumorigenesis and lung metastasis in immunodeficient mice. Accordingly, immunofluorescence staining revealed significant reductions of TGFβ/SMAD signalling and αSMA-positive stromal cells; digital spatial analysis indicated that IQGAP3 is indispensable for the formation of two phenotypically diverse cell subpopulations, which played crucial but distinct roles in promoting oncogenic functions.

IQGAP3 knockdown suppressed the RAS-TGFβ signalling crosstalk, leading to a significant reduction of the tumour microenvironment. In particular, IQGAP3 maintains functional heterogeneity of cancer cells to enhance malignant growth. IQGAP3 is thus a highly relevant therapy target in GC.

Marjolin ulcer is a malignant degeneration of previously injured skin, long-established scars, and wounds. This malignant transformation is most implicated in full-thickness burns; however, it may be associated with vaccination sites, pressure sores, venous stasis, and many other conditions causing chronic scar or wound formation. These lesions are aggressive and carry a poor prognosis. FDG PET/CT is an excellent diagnostic aid to differentiate these lesions from benign inflammation, to evaluate the primary malignant site and its extent and depth, and to evaluate metastasis.Metabolic activity has been noted to be significantly higher in Marjolin ulcer than in benign conditions.

Postradiotherapy nasopharyngeal necrosis with granulation mass (PRNN-GM) is a rare subtype of postradiotherapy nasopharyngeal necrosis (PRNN). It is characterized by the formation of isolated granulomatous tissue masses or masses combined with PRNN. However, the relationship between clinical features and survival outcomes in PRNN-GM remains unclear.

This retrospective study systematically evaluated 33 pathologically diagnosed PRNN-GM patients treated at three medical centres from January 2010 to May 2024. The clinical features, endoscopic and imaging characteristics, treatment methods, and survival outcomes of the patients were analysed.

Among the 33 patients, 27 were male and 6 were female, with a mean age of 52 years (±10.9 years). Internal carotid artery exposure was observed in 5 patients. Nineteen patients underwent surgical treatment, whereas 14 received conservative management. Internal carotid artery exposure (OR = 6.863, 95 % CI: 1.196-39.385) and surgical treatment (OR = 0.130, 95 % CI: 0.026-0.659) were identified as independent prognostic factors influencing survival outcomes (P < 0.05).

Patients with PRNN-GM who have internal carotid artery exposure and do not undergo surgical treatment tend to have a poorer prognosis.

Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation.

Using single-cell RNA sequencing, we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multiparameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics were used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and nontumor cells within the metastatic microenvironment.

Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. Single-cell RNA sequencing demonstrated that the surrounding lung stroma adopts a chronic, nonresolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, the metastasis-associated lung demonstrated marked fibrosis, likely because of the accumulation of pathogenic, profibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis.

Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a prometastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the antifibrotic tyrosine kinase inhibitor (TKI) nintedanib. Our data shed light on the non-cell-autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.

Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein alpha (FAP) are abundant in tumor microenvironments and represent an emerging target for PET cancer imaging. While different quinolone-based small molecule agents have been developed for whole-body imaging, there is a scarcity of well-validated fluorescent small molecule imaging agents to better study these cells in vivo. Here, we report the synthesis and characterization of a series of fluorescent FAP imaging agents based on the common quinolone azide inhibitor. Our data show excellent performance of some synthesized FAP Targeting Fluorescent probes (FTFs) for both topical application and intravenous delivery to label CAF populations in solid tumors. These results suggest that FTF can be used to study CAF biology and therapeutic targeting in vivo.

Thyroid cancer progression from curable well-differentiated thyroid carcinoma to highly lethal anaplastic thyroid carcinoma is distinguished by tumor cell de-differentiation and recruitment of a robust stromal infiltrate. Combining an integrated thyroid cancer single-cell sequencing atlas with spatial transcriptomics and bulk RNA-sequencing, we define stromal cell subpopulations and tumor-stromal cross-talk occurring across the histologic and mutational spectrum of thyroid cancer. We identify distinct inflammatory and myofibroblastic cancer-associated fibroblast (iCAF and myCAF) populations and perivascular-like populations. The myCAF population is only found in malignant samples and is associated with tumor cell invasion, BRAF V600E mutation, lymph node metastasis, and disease progression. Tumor-adjacent myCAFs abut invasive tumor cells with a partial epithelial-to-mesenchymal phenotype. Tumor-distant iCAFs infiltrate inflammatory autoimmune thyroid lesions and anaplastic tumors. In summary, our study provides an integrated atlas of thyroid cancer fibroblast subtypes and spatial characterization at sites of tumor invasion and de-differentiation, defining the stromal reorganization central to disease progression.

Renal cell cancer (RCC) is the most common and highly malignant subtype of kidney cancer. Mesenchymal stromal cells (MSCs) are components of tumor microenvironment (TME) that influence RCC progression. The impact of RCC-secreted small non-coding RNAs (sncRNAs) on TME is largely underexplored. Here, we comprehensively analysed the composition of exosomal sncRNAs secreted by RCC cells to identify those that influence MSCs.

Exosomal sncRNAs secreted by RCC cells and normal kidney cells were analyzed using RNAseq, followed by qPCR validation. MSCs were treated by conditioned media (CM) derived from RCC cells and transfected with piRNA, followed by the analysis of proliferation, viability, migration and immunocytochemical detection of piRNA. Expression of MSCs genes was evaluated using microarray and qPCR. TCGA data were analyzed to explore the expression of sncRNAs in RCC tumors.

RNAseq revealed 40 miRNAs, 71 tRNAs and four piRNAs that were consistently secreted by RCC cells. qPCR validation using five independent RCC cell lines confirmed that expressions of miR-10b-3p and miR-125a-5p were suppressed, while miR-365b-3p was upregulated in exosomes from RCC cells when compared with normal kidney proximal tubules. The expression of miR-10b-3p and miR-125a-5p was decreased, whereas the expression of miR-365b-3p was increased in RCC tumors and correlated with poor survival of patients. Expressions of tRNA-Glu, tRNA-Gly, and tRNA-Val were the most increased, while tRNA-Gln, tRNA-Leu, and tRNA-Lys were top decreased in RCC exosomes when compared with normal kidney cells. Moreover, hsa_piR_004153, hsa_piR_016735, hsa_piR_019521, and hsa_piR_020365 were consistently upregulated in RCC exosomes. piR_004153 (DQ575660.1; aliases: hsa_piRNA_18299, piR-43772, piR-hsa-5938) was the most highly expressed in exosomes from RCC cells when compared with normal kidney cells. Treatment of MSCs with RCC CM resulted in upregulation of piR_004153 expression. Transfection of MSCs with piR_004153 stimulated their migration and viability, and altered expression of 35 genes, including downregulation of FGF2, SLC7A5, and WISP1. Immunocytochemistry confirmed the nuclear localization of piR_004153 transfected in MSCs.

RCC cells secrete multiple sncRNAs, including piR_004153 which targets MSCs, alters expression of FGF2, SLC7A5, and WISP1, and stimulates their motility and viability. To our knowledge, this is the first study showing that cancer-derived piRNA can enhance MSC migration.

Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/β-catenin, TGF-β, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, characterized by aggressive growth and a dismal prognosis. Interleukin-33 (IL-33) and its receptor ST2 have emerged as regulators of glioma growth, but their exact function in tumorigenesis has not been deciphered. Indeed, previous studies on IL-33 in cancer have yielded somewhat opposing results as to whether it is pro- or anti-tumorigenic.

IL-33 expression was assessed in a GBM tissue microarray and public databases. As in vivo models we used orthotopic xenografts of patient-derived GBM cells, and syngenic models with grafted mouse glioma cells.

We analyzed the role of IL-33 and its receptor ST2 in nonmalignant cells of the glioma microenvironment and found that IL-33 levels are increased in cells surrounding the tumor. Protein complexes of IL-33 and ST2 are mainly found outside of the tumor core. The IL-33-producing cells consist primarily of oligodendrocytes. To determine the function of IL-33 in the tumor microenvironment, we used mice lacking the ST2 receptor. When glioma cells were grafted to ST2-deficient mouse brains, the resulting tumors exhibited a more invasive growth pattern, and are associated with poorer survival, compared to wild-type mice. Tumors in ST2-deficient hosts are more invasive, with increased expression of extracellular matrix remodeling enzymes and enhanced tumor angiogenesis. Furthermore, the absence of ST2 leads to a more immunosuppressive environment.

Our findings reveal that glia-derived IL-33 and its receptor ST2 participate in modulating tumor invasiveness, tumor vasculature, and immunosuppression in glioma.

Globally, people widely recognize cancer as one of the most lethal diseases due to its high mortality rates and lack of effective treatment options. Ongoing research into cancer therapies remains a critical area of inquiry, holding significant social relevance. Currently used treatment, such as chemotherapy, radiation, or surgery, often suffers from other problems like damaging side effects, inaccuracy, and the lack of ability to clear tumors. Conventional cancer therapies are usually imprecise and ineffective and usually develop resistance to treatments and cancer recurs. Cancer patients need fresh and innovative treatment that can reduce side effects while maximizing effectiveness. In recent decades several breakthroughs in these, and other areas of medical research, have paved the way for new avenues of fighting cancer including more focused and more effective alternatives. This study reviews exciting possibilities for mesenchymal stem cells (MSCs), nanomaterials, and microbial agents in the modern realm of cancer treatment. Nanoparticles (NPs) have demonstrated surprisingly high potential. They improve drug delivery systems (DDS) significantly, enhance imaging techniques remarkably, and target cancer cells selectively while protecting healthy tissues. MSCs play a double role in tissue repair and are a vehicle for novel cancer treatments such as gene treatments or NPs loaded with therapeutic agents. Additionally, therapies utilizing microbial agents, particularly those involving bacteria, offer an inventive approach to cancer treatment. This review investigates the potential of nanomaterials, MSCs, and microbial agents in addressing the shortcomings of conventional cancer therapies. We will also discuss the challenges and limitations of using these therapeutic approaches.

Various therapeutic strategies have been developed to treat Pancreatic Cancer (PaCa). Unfortunately, most efforts have proved unfruitful, as the poor prognosis observed in this disease has only attained little improvement in the past 40 years. Recently, deeper understanding of the immune system and its interaction with malignant tumors have allowed significant advances in immunotherapy. Consistent with this, some of the most promising approaches are those that involve T-cell redirection to the tumor site, such as bispecific T-cell engagers (BiTEs). These recombinant antibodies bridge cytotoxic T-cells to tumor cells, inducing target cell-dependent polyclonal T-cell activation/proliferation, which in turn results in elimination of bound tumor cells. Blinatumomab, an anti-CD19 BiTE, received FDA approval in 2014 for Precursor B-cell Acute Lymphoblastic Leukemia. In the past decade, it has demonstrated impressive clinical benefit in patients with B-cell leukemias; and other T-cell engagers have been FDA-approved for hematological malignancies and other diseases, yet limited effect has been observed with other BiTEs against solid cancers, including PaCa. Nevertheless, on May 2024, Tarlatamab, an anti-DLL3 BiTE was approved by the FDA for extensive small cell lung cancer, becoming the first BiTE for solid tumors. In this review, the generation of BiTEs, therapeutic features, manufacturing issues as well as the remaining challenges and novel strategies of BiTE therapy in the context of PaCa, including the lessons we can learn from the use of BiTEs on other types of cancer will be explored.

C-X-C motif chemokine ligand 12 (CXCL12; Stromal Cell-Derived Factor 1 [SDF-1]), most notably known for its role in embryogenesis and hematopoiesis, has been implicated in tumor pathophysiology and neovascularization. However, its cell-specific role and mechanism of action have not been well characterized. Previous work by our group has demonstrated that hypoxia-inducible factor (HIF)-1 modulates downstream CXCL12 expression following ischemic tissue injury. By utilizing a conditional CXCL12 knockout murine model, we demonstrate that endothelial-specific deletion of CXCL12 (eKO) modulates ischemic tissue survival, altering tissue repair and tumor progression without affecting embryogenesis and morphogenesis. Loss of endothelial-specific CXCL12 disrupts critical endothelial-fibroblast crosstalk necessary for stromal growth and vascularization. Using murine parabiosis with novel transcriptomic technologies, we demonstrate that endothelial-specific CXCL12 signaling results in downstream recruitment of non-inflammatory circulating cells, defined by neovascularization modulating genes. These findings indicate an essential role for endothelial-specific CXCL12 expression during the neovascular response in tissue injury and tumor progression.

Cancer is a complex and multifaceted group of diseases characterized by highly intricate mechanisms of tumorigenesis and tumor progression, which complicates diagnosis, prognosis, and treatment. In recent years, targeted therapies have gained prominence by focusing on specific mutations and molecular features unique to each tumor type, offering more effective and personalized treatment options. However, it is equally critical to explore the genetic commonalities across different types of cancer, which has led to the rise of pan-cancer studies. These approaches help identify shared therapeutic targets across various tumor types, enabling the development of broader and potentially more widely applicable treatment strategies. This review aims to provide a comprehensive overview of key concepts related to tumors, including tumorigenesis processes, the tumor microenvironment, and the role of extracellular vesicles in tumor biology. Additionally, we explore the molecular interactions and mechanisms driving tumor progression, with a particular focus on the pan-cancer perspective. To achieve this, we conducted an in silico analysis using publicly available datasets, which facilitated the identification of both common and divergent genetic and molecular patterns across different tumor types. By integrating these diverse areas, this review offers a clearer and deeper understanding of the factors influencing tumorigenesis and highlights potential therapeutic targets.

Although the age of the genome gave us much insight about how our organs fail with disease, it also suggested that diseases do not arise from mutations alone; rather, they develop as we age. In this Review, we examine how wound healing might act to ignite disease. Wound healing works well when we are younger, repairing damage from accidents, environmental assaults, and battles with pathogens. Yet, with age and accumulation of mutations and tissue damage, the repair process can devolve, leading to inflammation, fibrosis, and neoplastic signaling. We discuss healthy wound responses and how our bodies might misappropriate these pathways in disease. Although we focus predominantly on epithelial-based (lung and skin) diseases, similar pathways might operate in cardiac, muscle, and neuronal diseases.

Integrins are cellular transmembrane receptors that physically connect the cytoskeleton with the extracellular matrix. As such, they are positioned to mediate cellular responses to microenvironmental cues. Importantly, integrins also regulate their own microenvironment through secreted factors, also known as the integrin-mediated secretome. Epidermal integrins, or integrins expressed by keratinocytes of the skin epidermis, regulate the cutaneous microenvironment through the contribution of matrix components, via proteolytic matrix remodeling, or by mediating factors like cytokines and growth factors that can promote support for nearby but distinct cells of the stroma, such as immune cells, endothelial cells, and fibroblasts. This role for integrins is enhanced during both pathological and repair tissue remodeling processes, such as tumor growth and progression and wound healing. This review will discuss examples of how the epithelial integrin-mediated secretome can regulate the tissue microenvironment. Although different epithelial integrins in various contexts will be explored, emphasis will be given to epidermal integrins that regulate the secretome during wound healing and cutaneous tumor progression. Epidermal integrin α3β1 is of particular focus as well, since this integrin has been revealed as a key regulator of the keratinocyte secretome.

Inflammation is one of the hallmarks of cancer and is associated with tumor growth. Tumor endothelial cells (TECs) demonstrate inflamed phenotypes. Endothelial inflammation initiates thrombus formation, which is the second cause of cancer-related deaths. Epigallocatechin-3-O-gallate (EGCG), a natural compound in green tea, has demonstrated an anti-inflammatory effect. However, the tumor progression inhibition effect of EGCG by targeting TEC inflammation remains unclear. This study addresses the anti-tumor effect of EGCG, especially its anti-inflammatory role in TECs.

In vitro, the effect of EGCG on TECs were studied using real-time quantitative PCR and immunofluoresence to analyza gene and protein expression. In vivo, a cyclic RGD liposome delivery system (MEND) was employed to efficiently deliver EGCG to TECs in tumor-bearing mice.

In vitro, EGCG significantly reduces inflammatory cytokine expression, including tumor necrosis factor-α, interleukin-6, IL-8, and IL-1β through NF-κB signaling inhibition. Additionally, von Willebrand factor reduction in TECs, which is involved in platelet adhesion and thrombosis formation, was analyzed. Our results revealed that EGCG-MEND significantly inhibited TEC inflammation and thrombus formation in tumors. Additionally, EGCG-MEND improved tumor immunity by reducing programmed death-ligand 1 expression and promoting high endothelial venule formation by recruiting CD8+ T cells.

Our results indicate the anti-tumor potential of EGCG-MEND in normalizing the inflammatory immune microenvironment and inhibiting thrombosis by targeting TEC.

Electrophysiology typically deals with the electrical properties of excitable cells like neurons and muscles. However, all other cells (non-excitable) also possess bioelectric membrane potentials for intracellular and extracellular communications. These membrane potentials are generated by different ions present in fluids available in and outside the cell, playing a vital role in communication and coordination between the cell and its organelles. Bioelectric membrane potential variations disturb cellular ionic homeostasis and are characteristic of many diseases, including cancers. A rapidly increasing interest has emerged in sorting out the electrophysiology of cancer cells. Compared to healthy cells, the distinct electrical properties exhibited by cancer cells offer a unique way of understanding cancer development, migration, and progression. Decoding the altered bioelectric signals influenced by fluctuating electric fields benefits understanding cancer more closely. While cancer research has predominantly focussed on genetic and molecular traits, the delicate area of electrophysiological characteristics has increasingly gained prominence. This review explores the historical exploration of electrophysiology in the context of cancer cells, shedding light on how alterations in bioelectric membrane potentials, mediated by ion channels and gap junctions, contribute to the pathophysiology of cancer.

Wound healing represents a complex and evolutionarily conserved process across vertebrates, encompassing a series of life-rescuing events. The healing process runs in three main phases: inflammation, proliferation, and maturation/remodelling. While acute inflammation is indispensable for cleansing the wound, removing infection, and eliminating dead tissue characterised by the prevalence of neutrophils, the proliferation phase is characterised by transition into the inflammatory cell profile, shifting towards the prevalence of macrophages. The proliferation phase involves development of granulation tissue, comprising fibroblasts, activated myofibroblasts, and inflammatory and endothelial cells. Communication among these cellular components occurs through intercellular contacts, extracellular matrix secretion, as well as paracrine production of bioactive factors and proteolytic enzymes. The proliferation phase of healing is intricately regulated by inflammation, particularly interleukin-6. Prolonged inflammation results in dysregulations during the granulation tissue formation and may lead to the development of chronic wounds or hypertrophic/keloid scars. Notably, pathological processes such as autoimmune chronic inflammation, organ fibrosis, the tumour microenvironment, and impaired repair following viral infections notably share morphological and functional similarities with granulation tissue. Consequently, wound healing emerges as a prototype for understanding these diverse pathological processes. The prospect of gaining a comprehensive understanding of wound healing holds the potential to furnish fundamental insights into modulation of the intricate dialogue between cancer cells and non-cancer cells within the cancer ecosystem. This knowledge may pave the way for innovative approaches to cancer diagnostics, disease monitoring, and anticancer therapy.

This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.

Modulated electro-hyperthermia (mEHT) is unique due to its combination of thermal and non-thermal effects.

This report summarizes the literature on the effects of mEHT observed in vitro and in vivo.

The thermal and electrical heterogeneity of tissues allows the radiofrequency signal to selectively target malignant tissue. The applied modulation appears to activate various apoptotic pathways, predominantly leading to immunogenic cell death (ICD). ICD promotes the release of damage-associated molecular patterns, potentially producing tumour-specific antigen-presenting cells. This abscopal-type effect may target distant metastases while treating the primary tumour locally. This immune memory effect is like vaccination mechanisms.

The application of mEHT has the potential to expand from local to systemic disease, enabling the simultaneous treatment of micro- and macro-metastases.

Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell-ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, may inhibit tumor progression and enhance the efficacy of combination treatment with immune checkpoint inhibitors (ICIs), chemotherapy, or immunotherapy. In this review, we combine the results of different approaches targeting extracellular matrix elements in melanoma in preclinical and clinical studies. The identified limitations of many approaches, including side effects, low selectivity, and toxicity, indicate the need for further studies to optimize therapy. Nevertheless, significant progress in expanding our understanding of tumor biology and the development of targeted therapies holds great promise for the early approaches developed several decades ago to inhibit metastasis through ECM targeting.

Malignant cells flourish within a specialized environment known as the tumor microenvironment (TME) [...].

The adult mammary gland is maintained by lineage-restricted progenitor cells through pregnancy, lactation, involution, and menopause. Injury resolution, transplantation-associated mammary gland reconstitution, and tumorigenesis are unique exceptions, wherein mammary basal cells gain the ability to reprogram to a luminal state. Here, we leverage newly developed cell-identity reporter mouse strains, and time-resolved single-cell epigenetic and transcriptomic analyses to decipher the molecular programs underlying basal-to-luminal fate switching in vivo. We demonstrate that basal cells rapidly reprogram toward plastic cycling intermediates that appear to hijack molecular programs we find in bipotent fetal mammary stem cells and puberty-associatiated cap cells. Loss of basal-cell specifiers early in dedifferentiation coincides with activation of Notch and BMP, among others. Pharmacologic blockade of each pathway disrupts basal-to-luminal transdifferentiation. Our studies provide a comprehensive map and resource for understanding the coordinated molecular changes enabling terminally differentiated epithelial cells to transition between cell lineages and highlights the stunning rapidity by which epigenetic reprogramming can occur in response to disruption of tissue structure.

Aging is associated with stereotyped changes in the tissue microenvironment that increase susceptibility to diseases of the elderly, including organ fibrosis and cancer. From a tissue perspective, fibrosis and cancer can both be viewed as non-healing wounds with pathogenic activation of tissue repair pathways in the stroma. If fibrosis and cancer represent an example of the convergent evolution of maladaptive stromal responses in distinct pathologies, what are the analogous cell types that might emerge in both diseases that share similarities in identity and function? In this review, we explore how senescent fibroblasts form a nexus that connects the aging organ with both fibrosis and cancer. The advent of single cell sequencing, coupled with improved detection of cell types with senescent traits in vivo, have allowed us to identify senescent fibroblasts with similar identities in both fibrosis and cancer that share pro-fibrotic programs. In addition to their ability to reorganize the extracellular matrix in diseased states, these pro-fibrotic senescent fibroblasts can also promote epithelial reprogramming and immune rewiring, which drive disease progression in fibrosis and cancer. Finally, the identification of common pathogenic cell types in fibrosis and cancer also presents a therapeutic opportunity to target both diseases with a shared approach.