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The extracellular matrix (ECM) serves as signals that regulate specific cell states in tumor tissues. Increasing evidence suggests that extracellular biomechanical force signals are critical in tumor progression. In this study, we aimed to explore the influence of ECM-derived biomechanical force on breast cancer cell status. Experiments were conducted using 3D collagen, fibrinogen, and Matrigel matrices to investigate the role of mechanical force in tumor development. Integrin-cytoskeleton-AIRE and DDR-STAT signals were examined using RNA sequencing and western blotting. Data from 1358 patients and 86 clinical specimens were used for ECM signature-prognosis analysis. Our findings revealed that ECM-derived mechanical force regulated tumor stemness and cell quiescence in breast cancer cells. A mechanical force of ~45 Pa derived from the extracellular substrate activated integrin β1/3 receptors, stimulating stem cell signaling pathways through the cytoskeleton/AIRE axis and promoting tumorigenic potential and stem-like phenotypes. However, excessive mechanical force (450 Pa) could drive stem-like cancer cells into a quiescent state, with the removal of mechanical forces leading to vigorous proliferation in quiescent cancer stem cells. Mechanical force facilitated cell cycle arrest to induce quiescence, dependent on DDR2/STAT1/P27 signaling. Therefore, ECM-derived mechanical force governs breast cancer cell status and proliferative characteristics through stiffness alterations. We further established an ECM signature based on the fibrinogen/fibronectin/vitronectin/elastin axis, which efficiently predicts patient prognosis in breast cancer. Our findings highlight the vital role of ECM-derived mechanical force in governing breast cancer cell stemness/quiescence transition and suggest the novel use of ECM signature in predicting the clinical prognosis of breast cancer.

Introduction Colorectal cancer (CRC) is a malignancy characterized by strong associations with chronic inflammation. While tumor-infiltrating immune responses have been extensively studied, systemic alterations in innate immune cells, particularly monocytes and macrophages, remain underexplored. Interleukin-1β (IL-1β), a key pro-inflammatory cytokine, plays a pivotal role in both systemic inflammation and tumor microenvironment modulation. This study aimed to evaluate IL-1β secretion by monocyte-derived macrophages from CRC patients and assess its association with clinicopathological features. Methods Peripheral blood monocytes were isolated from 20 CRC patients and differentiated into macrophages in vitro using M-CSF. Macrophages were then stimulated with lipopolysaccharide (LPS) under three conditions: single stimulation, repeated stimulation, and no stimulation. IL-1β concentrations in culture supernatants were measured by ELISA. Patients were stratified by tumor grade and stage, and non-parametric statistical tests (Mann–Whitney U, Kruskal–Wallis) were used to assess differences in cytokine secretion across groups. Results Macrophage IL-1β secretion was significantly higher in patients with tumors extending beyond the muscularis propria compared to those with intact muscularis propria (median 30.33 vs 15.39 pg/mL, p = 0.0381). Patients with stage IV CRC exhibited a markedly greater fold increase in IL-1β secretion after LPS stimulation than those with stage I (9.08-fold vs 1.63-fold, p = 0.023). Although differences by tumor grade did not reach statistical significance, a trend toward increased IL-1β secretion was observed in higher-grade tumors. Conclusion Systemic IL-1β secretion by monocyte-derived macrophages is enhanced in CRC patients with advanced disease, suggesting tumor-driven reprogramming of innate immune responses. These findings support IL-1β as a potential biomarker of tumor progression and a candidate target for immunomodulatory strategies in CRC. Given the modest sample size (n = 20) and the ex vivo design, our conclusions are preliminary and hypothesis-generating. Validation in an independent, larger cohort is warranted.

Abstract In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas’ grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.

Background and Objectives: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. In addition, nonmalignant cells in the tumor microenvironment play critical roles in all the stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation. Aim: This study aims to explore the concept of the tumor microenvironment by conducting a critical review of previous studies on the topic. Materials and Methods: This review relies on evidence presented in previous studies related to the topic. The articles included in this review were obtained from different medical and health databases. Results and Discussion: The tumor microenvironment has received significant attention in the cancer literature, with a particular focus on its role in tumor development and progression. Previous studies have identified various components of the tumor microenvironment that influence malignant behavior and progression. In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells. Conclusion: The tumor microenvironment harbors cancer stem cells and other molecules that contribute to tumor development and progression. Consequently, targeting and manipulating the cells and factors in the tumor microenvironment during cancer treatment can help control malignancies and achieve positive health outcomes.

The establishing of the first cancer models created a new perspective on the identification and evaluation of new anti-cancer therapies in preclinical studies. Patient-derived xenograft models are created by tumor tissue engraftment. These models accurately represent the biology and heterogeneity of different cancers and recapitulate tumor microenvironment. These features have made it a reliable model along with the development of humanized models. Therefore, they are used in many studies, such as the development of anti-cancer drugs, co-clinical trials, personalized medicine, immunotherapy, and PDX biobanks. This review summarizes patient-derived xenograft models development procedures, drug development applications in various cancers, challenges and limitations.

The role of inflammation in the development of cancer was described as early as 19th century. Abundant evidence supports the preposition that various cancers are triggered by infection and chronic inflammatory disease whereas, evading immune destruction has been proposed as one of the new hallmarks of cancer. Changes of the tumor microenvironment have been closely correlated to cancer-mediated inflammation. Hyaluronan (HA), an important ECM component, has become recognized as an active participant in inflammatory, angiogenic, fibrotic, and cancer promoting processes. This review discusses how HA and specific HA-binding proteins participate in and regulate cancer-related inflammatory processes.

In recent years, the biological role of changes in physical factors in carcinogenesis and progression has attracted increasing attention. Matrix stiffness, also known as ECM stress, is a critical physical factor of tumor microenvironment and remains alternating during carcinogenesis as a result of ECM remodeling through activation of cancer-associated fibroblasts and extracellular collagen accumulation, crosslinking and fibrosis. Different content and density of extracellular collagen in ECM endows matrix with varying stiffness. Physical signals induced by matrix stiffness are transmitted to tumor cells primarily by the integrins receptor family and trigger a series of mechanotransduction that result in changes in tumor cell morphology, proliferative capacity, and invasive ability. Importantly, accumulating evidence revealed that changes in matrix stiffness in tumor tissues greatly control the sensitivity of tumor cells in response to chemotherapy, radiotherapy, and immunotherapy through integrin signaling, YAP signaling, and related signaling pathways. Here, the present review analyzes the current research advances on matrix stiffness and tumor cell behavior with a view to contributing to tumor cell growth and treatment, with the hope of improving the understanding of the biological role of matrix stiffness in tumors.

Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.

Background The prognostic management of bladder cancer (BLCA) remains a great challenge for clinicians. Recently, bulk RNA-seq sequencing data have been used as a prognostic marker for many cancers but do not accurately detect core cellular and molecular functions in tumor cells. In the current study, bulk RNA-seq and single-cell RNA sequencing (scRNA-seq) data were combined to construct a prognostic model of BLCA. Methods BLCA scRNA-seq data were downloaded from Gene Expression Omnibus (GEO) database. Bulk RNA-seq data were obtained from the UCSC Xena. The R package \"Seurat\" was used for scRNA-seq data processing, and the uniform manifold approximation and projection (UMAP) were utilized for downscaling and cluster identification. The FindAllMarkers function was used to identify marker genes for each cluster. The limma package was used to obtain differentially expressed genes (DEGs) affecting overall survival (OS) in BLCA patients. Weighted gene correlation network analysis (WGCNA) was used to identify BLCA key modules. The intersection of marker genes of core cells and genes of BLCA key modules and DEGs was used to construct a prognostic model by univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) analyses. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and chemotherapeutic drug sensitivity between the high and low-risk groups were also investigated. Results scRNA-seq data were analyzed to identify 19 cell subpopulations and 7 core cell types. The ssGSEA showed that all 7 core cell types were significantly downregulated in tumor samples of BLCA. We identified 474 marker genes from the scRNA-seq dataset, 1556 DEGs from the Bulk RNA-seq dataset, and 2334 genes associated with a key module identified by WGCNA. After performing intersection, univariate Cox, and LASSO analysis, we obtained a prognostic model based on the expression levels of 3 signature genes, namely MAP1B, PCOLCE2, and ELN. The feasibility of the model was validated by an internal training set and two external validation sets. Moreover, patients with high-risk scores are predisposed to experience poor OS, a larger prevalence of stage III-IV, a greater TMB, a higher infiltration of immune cells, and a lesser likelihood of responding favorably to immunotherapy. Conclusion By integrating scRNA-seq and bulk RNA-seq data, we constructed a novel prognostic model to predict the survival of BLCA patients. The risk score is a promising independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics.

Exosomal miRNAs have attracted much attention due to their critical role in regulating genes and the altered expression of miRNAs in virtually all cancers affecting humans (Sun et al. in Mol Cancer 17(1):14, 2018). Exosomal miRNAs modulate processes that interfere with cancer immunity and microenvironment, and are significantly involved in tumor growth, invasion, metastasis, angiogenesis and drug resistance. Fully investigating the detailed mechanism of miRNAs in the occurrence and development of various cancers could help not only in the treatment of cancers but also in the prevention of malignant diseases. The current review highlighted recently published advances regarding cancer-derived exosomes, e.g., sorting and delivery mechanisms for RNAs. Exosomal miRNAs that modulate cancer cell-to-cell communication, impacting tumor growth, angiogenesis, metastasis and multiple biological features, were discussed. Finally, the potential role of exosomal miRNAs as diagnostic and prognostic molecular markers was summarized, as well as their usefulness in detecting cancer resistance to therapeutic agents.