Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME) and play a crucial role in tumor progression. The biological properties of tumors, such as drug resistance, vascularization, immunosuppression, and metastasis are closely associated with CAFs. During tumor development, CAFs contribute to tumor progression by remodeling the extracellular matrix (ECM), inhibiting immune cell function, promoting angiogenesis, and facilitating tumor cell growth, invasion, and metastasis. Studies have shown that CAFs can promote endothelial cell proliferation by directly secreting cytokines such as vascular endothelial growth factor (VEGF) and fibroblast Growth Factor (FGF), as well as through exosomes. CAFs also secrete the chemokine stromal cell-derived factor 1 (SDF-1) to recruit endothelial progenitor cells (EPCs) into the peripheral blood and guide their migration to the tumor periphery. Additionally, CAFs can induce tumor cells to transform into "endothelial cells" that participate in vascular wall formation. However, the precise mechanisms remain to be further investigated. Due to their widespread presence in various solid tumors and their tumor-promoting function, CAFs are emerging as therapeutic targets. In this review, we summarize the specific mechanisms through which CAFs promote angiogenesis and outline current therapeutic strategies targeting CAF-induced vascularization, ongoing clinical trials targeting CAFs, and discuss potential future treatment approaches. We hope this will contribute to the advancement of CAF-targeted tumor treatment strategies.

Matrix stiffness affects the progression of nasopharyngeal carcinoma, but the underlying mechanism is still unknown. Here, we demonstrated that nasopharyngeal carcinoma tissues with distant metastasis contain large collagen deposits and strong matrix stiffness. First, we performed RNA-seq analysis of nasopharyngeal carcinoma cells cultured on polyacrylamide hydrogel systems and found that LPAR3 and COL8A1 are potential matrix stiffness markers. Based on in vivo and in vitro experiments, matrix stiffness mainly affected tumor metastasis rather than proliferation. Subsequently, we found that matrix stiffness triggers the formation of epithelial-mesenchymal transition by increasing the expression of LPAR3 in nasopharyngeal carcinoma, which is related to metastasis. In addition, matrix stiffness promotes the expression of COL8A1 secreted by nasopharyngeal carcinoma and is related to tumor angiogenesis. Simultaneous inhibition of LPAR3 and COL8A1 genes significantly reduced nasopharyngeal carcinoma invasion and metastasis. Based on the investigation, we confirmed that matrix stiffness governs the progression of nasopharyngeal carcinoma and that LPAR3 and COL8A1, as matrix stiffness related biomarkers, promote nasopharyngeal carcinoma metastasis by inducing epithelial-mesenchymal transition and angiogenesis. Overall, the in-depth exploration of matrix stiffness may provide a strategy for clinical treatment intervention and provide promising targets for clinical nasopharyngeal carcinoma treatment.

Tumor occurrence, development, invasion, and metastasis are regulated by multiple mechanisms. Among these, angiogenesis promotes tumor progression mainly by supplying tumor tissue and providing channels for tumor metastasis. Cancer stem cells (CSCs) are another important factor affecting tumor progression by involving in tumor initiation and development, while remaining insensitive to conventional antitumor treatments. Among treatment strategies for them, owing to the existence of alternative angiogenic pathways or the risk of damaging normal stem cells, the clinical effect is not ideal. Angiogenesis and CSCs may influence each other in this process. Tumor angiogenesis can support CSC self-renewal by providing a suitable microenvironment, whereas CSCs can regulate tumor neovascularization and mediate drug resistance to anti-angiogenic therapy. This review summarized the role of vascular niche formed by angiogenesis in CSC self-renewal and stemness maintenance, and the function of CSCs in endothelial progenitor cell differentiation and pro-angiogenic factor upregulation. We also elucidated the malignant loop between CSCs and angiogenesis promoting tumor progression. Additionally, we summarized and proposed therapeutic targets, including blocking tumor-derived endothelial differentiation, inhibiting pro-angiogenic factor upregulation, and directly targeting endothelial-like cells comprising CSCs. And we analyzed the feasibility of these strategies to identify more effective methods to improve tumor treatment.

Fibroblasts are important components in the tumor microenvironment and can affect tumor progression and metastasis. However, the roles of genetic variants of the fibroblast-related genes (FRGs) in the prognosis of non-small-cell lung cancer (NSCLC) patients have not been reported. Therefore, we investigated the associations between 26,544 single nucleotide polymorphisms (SNPs) in 291 FRGs and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In Cox regression multivariable analysis, we found that 661 SNPs were associated with NSCLC overall survival (OS). Then we validated these SNPs in another independent replication dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. Finally, we identified two independent SNPs (i.e., FER rs7716388 A>G and SULF1 rs11785839 G>C) that remained significantly associated with NSCLC survival with hazards ratios (HRs) of 0.87 (95% confidence interval [CI] = 0.77-0.98, p = 0.018) and 0.88 (95% CI = 0.79-0.99, p = 0.033), respectively. Combined analysis for these two SNPs showed that the number of protective alleles was associated with better OS and disease-specific survival. Expression quantitative trait loci analysis indicated that the FER rs7716388 G allele was associated with the up-regulation of FER mRNA expression levels in lung tissue. Our results indicated that these two functional SNPs in the FRGs may be prognostic biomarkers for the prognosis of NSCLC patients, and the possible mechanism may be through modulating the expression of their corresponding genes.

Fibroinflammation refers to the highly integrated fibrogenic and inflammatory responses mediated by the concerted function of fibroblasts and innate immune cells in response to tissue perturbation. This process underlies the desmoplastic remodelling of the tumour microenvironment and thus plays an important role in tumour initiation, growth and metastasis. More specifically, fibroinflammation alters the biochemical and biomechanical signalling in malignant cells to promote their proliferation and survival and further supports an immunosuppressive microenvironment by polarizing the immune status of tumours. Additionally, the presence of fibroinflammation is often associated with therapeutic resistance. As such, there is increasing interest in targeting this process to normalize the tumour microenvironment and thus enhance the treatment of solid tumours. Herein, we review advances made in unravelling the complexity of cancer-associated fibroinflammation that can inform the rational design of therapies targeting this.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer, with rectal cancer (RC) accounting for approximately 35 % of cases, posing a significant health burden. The early phase of R progression is characterized by the accumulation of genetic and epigenetic changes that promote cell growth. These rapidly dividing cells form a benign adenoma, which can eventually transform into malignant tumors and metastasize to other organs. Among the key molecular alterations, a mutation in the Wnt/β-catenin signaling pathway plays a crucial role. Additionally, BRAF mutation contributes to 8-10 % of CRC cases, while mutation in PIK3C pathways is responsible for 20-25 % of cases. The RC involves complex biological mechanisms. This review article highlights the pivotal role of mRNA in diagnosing and predicting the prognosis of RC, explores the various functions of non-coding RNAs (ncRNA,s), and examines the impact of RNA editing and modification on the progression of tumor genesis. Furthermore, we discuss the cellular signaling pathways and microenvironment interaction and pathways like PI3K/Akt/mTOR and Wnt/β-catenin. Advancements in molecular, RNA, and genetic research have evolved the treatment of cancer. Techniques like next-generation sequencing have tremendously opened the biological field of research. Along with this, techniques like CRISPR/Cas9 aid in the developing therapeutic strategies. Proteomics and metabolomics approach further contribute to novel research direction in oncology.

Meningeal lymphatic vessels (mLVs) play a critical role in clearing erythrocytes from the subarachnoid space and immune cells from the brain parenchyma following subarachnoid hemorrhage (SAH). However, the drainage function of mLVs is impaired during the acute stage after SAH and gradually recovers in the subacute phase. We aimed to investigate the meningeal transcriptional response post-SAH and elucidate the dynamic influence of meningeal microenvironment on meningeal lymphatic function.

We employed bioinformatics analysis of single-cell RNA sequencing and spatial transcriptomics to characterize the spatiotemporal dynamic changes in the early meningeal microenvironment post-SAH. In a mouse model of SAH, the early dynamic changes of the meningeal immune cells and the potential growth factor that promoted the early repair of the mLVs were further investigated and validated.

During the acute phase, myeloid cells early infiltrated the meninges and triggered inflammatory responses. In the subacute phase, the fibroblast population expanded significantly, contributing to tissue remodeling. The interplay between immune cells and fibroblasts regulated cell migration and phenotypic transition, potentially affecting the function of mLVs. Notably, placental growth factor (PGF) emerged as the most prominent ligand within the VEGF signaling pathway received by meningeal lymphatic endothelial cells (mLECs) post-SAH. This signaling event was associated with the early recovery of mLVs after acute immune responses.

Our study revealed a spatiotemporal transformation of the meningeal microenvironment from an "inflammatory response" phase to a "tissue remodeling" phase following SAH. Monocyte-derived macrophages and self-recruiting neutrophils contributed to impairment of mLVs in the acute stage, while PGF might serve as a key factor promoting early meningeal lymphatic function repair following the inflammatory response. These findings provided novel insights into the cellular dynamics underlying mLVs dysfunction and recovery post-SAH.

Competitive endogenous RNA (ceRNA) network modulation plays a crucial role in pathogenesis of colon adenocarcinoma (COAD). This study analyzed The Cancer Genome Atlas(TCGA) data to identify 151 copy number variation (CNV)-driven lncRNAs in COAD, constructing a ceRNA network (6 lncRNAs-14 miRNAs-68 mRNAs). Functional enrichment revealed their roles in muscle system processes , blood vessel development and extracellular matrix organization. Survival analysis linked LINC00941 amplification to poor prognosis. Two CNV-driven lncRNA-targeting drugs were identified, offering insights into COAD mechanisms and potential biomarkers.

Colorectal cancer (CRC) is the second most common malignant tumor in the world. With its increasing incidence and younger age trend, its impact on human health has been paid more and more attention. Currently, we have a variety of chemotherapy drugs that can be used to treat colorectal cancer. However, the drug resistance of colorectal cancer has become a significant factor affecting its cure rate. Some studies have reported that exosomes are related to the occurrence of drug resistance. However, the exact mechanism is not precise. Therefore, we focused on the role of cancer associated-fibroblast-derived (CAFs-derived) exosomes in colorectal progression. It was found that cancer cells transmit information through exosome interaction and induce chemotherapy resistance by promoting epithelial-mesenchymal transition (EMT), up-regulating the Wnt/β-catenin signaling pathway, transforming growth factor-β1 (TGF-β1) pathway, promoting angiogenesis and other possible molecular mechanisms. In addition, in terms of clinical significance and therapeutic strategies, we explore the clinical relevance of CAFs-derived exosomes in colorectal cancer patients and their potential as potential biomarkers for predicting chemotherapy response. We also provide a new possible direction for overcoming chemotherapy resistance in colorectal cancer by targeting CAFs-derived exosomes.

Heterogeneity is the malignancy feature of colorectal cancer (CRC), which augments the difficulty of CRC treatment. Consensus molecular subtypes (CMSs) classified CRC into 4 subtypes. CMS4 is the most aggressive subtype, characterized with epithelial mesenchymal transition (EMT) and angiogenesis activation. However, the mechanism of CMS4 formation still remains unclear. We aimed to investigate the role of phospholamban (PLN) on CMS4 formation.

Immunohistochemistry and Western blotting were used to detected PLN expressions. Transwell and wound-healing assays were used to evaluate migration and invasion of HCT116 and HT29. Tube formation assay was used to evaluate angiogenesis of HUVECs. GST pull-down was used to detected the interaction between PLN and AXIN2. The CAF-CT26 spleen co-transplantation mouse model was built to evaluate PLN's effects on CRC metastasis.

PLN knockdown reversed CAFs' conditional medium (CM)-induced EMT, cell migration, and angiogenesis (P < .01). PLN strongly bound to AXIN2, the main component of β-catenin degradation complex, and PLN knockdown increased β-catenin ubiquitination in CAFs (P < .01). PLN knockdown blocked GREM1 secretion (P < .01), and PLN overexpression-induced EMT, cell migration, and angiogenesis were blocked by anti-GREM1 neutralizing antibody (P < .01). Knockdown of BMP2 and VEGFR2 reversed CAFs' CM induced EMT and angiogenesis effects, respectively (P < .01). PLN knockdown attenuated CAFs mediated tumor promoting effects in vivo (P < .01).

PLN competitively binds with AXIN2 to increase β-catenin activity in CAFs. β-catenin signal induces GREM1 secretion, driving EMT and angiogenesis via BMP2 and VEGFR2, respectively. These findings demonstrate that PLN is a driver for CMS4 formation.

Immunoneoadjuvant therapy has gained significant attention due to its remarkable advancements in cancer treatment. This study aimed to investigate the molecular mechanisms underlying immunoneoadjuvant therapy through a comprehensive multiomics analysis of samples from a registered clinical trial cohort.

Preoperative samples were collected from 16 patients, and postoperative samples were obtained from 12 among them. RNA sequencing (RNA-seq) and Olink proteomics were employed to identify key genes before and after neoadjuvant treatment. The weighted coexpression network was constructed using Weighted gene co-expression network analysis (WGCNA). Furthermore, the proportion of infiltrated immune cells was calculated using xCell based on normalized expression data derived from RNA-seq.

Patients were stratified into T1 (good efficacy) and T2 (poor efficacy) groups based on Tumor Regression Grade (TRG) to neoadjuvant immunotherapy. Compared to the T2 group (TRG2 and TRG3), the T1 group (TRG0 and TRG1) showed significant differences in pathways related to inflammatory response and myeloid leukocyte activation. Furthermore, the T1 group exhibited elevated levels of CD8+ T cells and B cells. The top two factors with the highest area under the Receiver Operating Characteristic (ROC) curve were CD8a molecule (CD8A) (1.000) and C-C motif chemokine ligand 20 (CCL20) (0.967). Additionally, the expression of placenta growth factor (PGF) and TNF receptor superfamily member 21 (TNFRSF21) proteins significantly increased in the T1 group compared to the T2 group. High expression of CD8A and PGF were associated with favorable and poor prognosis in gastric cancer patients, respectively. Immunoinfiltration analysis revealed a positive correlation between CD8A and dendritic cell (DC) levels, while a negative correlation was observed with myeloid-derived suppressor cell (MDSC) levels.

Through multiomics analysis, we discovered that CD8A is linked to enhanced treatment response and tumor regression. In contrast, PGF appears to exert adverse effects on treatment outcomes, suggesting a complex interplay of factors influencing the efficacy of immunoneoadjuvant therapy in gastric cancer.

Colorectal cancer (CRC) is globally recognized as the third most frequently diagnosed malignancy and the second leading cause of cancer-related mortality. The etiology of CRC is multifactorial, arising from a complex interplay of genetic alterations, environmental exposures, and age-related physiological changes. Among the numerous signaling pathways that regulate cellular homeostasis, the Wnt/β-catenin signaling pathway not only plays a critical role in embryonic development and cell proliferation but also contributes to the initiation and progression of various malignancies, including CRC. Dysregulation of the Wnt/β-catenin signaling pathway is a hallmark of CRC, playing a pivotal role in regulating chemoresistance and driving invasive and metastatic behaviors. Traditional Chinese Medicine (TCM) is characterized by its multi-target and multi-pathway mechanisms. Extensive studies have demonstrated that TCM can inhibit the activity of CRC cells by targeting the Wnt/β-catenin signaling pathway and significantly alleviate symptoms in CRC animal models, demonstrating its potential therapeutic value for the treatment of CRC. This review primarily focuses on the literature published in the past 5 years, retrieved from databases such as PubMed, Web of Science, Scopus, MEDLINE, and Springer, concerning the targeting of the Wnt/β-catenin signaling pathway for the treatment of CRC. It highlights the research progress on TCM monomers (e.g., myricetin, genistein, baicalein), TCM formulations (e.g., Pai-Nong-San (PNS), Jian-Du-Xiao-Sheng Yin (JXY), Zuo-Jin-Wan (ZJW)), and small-molecule inhibitors (e.g., PCDHGA9, Cetuximab, PTK7). Furthermore, the experimental results and conclusions from these studies are thoroughly analyzed and discussed. Through a comprehensive review of the literature, we conclude that TCM exhibits multi-level, multi-target, and multi-faceted effects in the prevention and treatment of CRC. In-depth research into the mechanisms by which TCM targets the Wnt/β-catenin signaling pathway to prevent and treat CRC may provide novel insights into exploring the pathogenesis of CRC and developing new therapeutic agents for CRC.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous metastatic lymphoma that can be treated by targeting angiogenesis. Apolipoprotein C1 (APOC1) plays a significant role in the proliferation and metastasis of various malignant tumors; however, its role in DLBCL-particularly its effects on angiogenesis-remains largely unexplored. This study investigates the correlation between APOC1 expression and patient prognosis in DLBCL. Using APOC1 gene knockdown, apoptosis, migration, and invasion were assessed through flow cytometry, the EDU assay, wound healing, and Transwell assays. Additionally, human umbilical vein endothelial cells (HUVEC) angiogenesis was evaluated. Advanced techniques, such as immunofluorescence, TUNEL assay, and immunohistochemical labeling were employed to analyze the effects of APOC1 knockdown on the PI3K/AKT/mTOR signaling pathway and tumor formation in nude mice. Results showed that APOC1 is overexpressed in DLBCL tissues and cells, with high APOC1 levels associated with poor patient prognosis. In vitro experiments revealed that APOC1 knockdown increased apoptosis and inhibited cell proliferation, migration, invasion, HUVEC angiogenesis, and PI3K/AKT/mTOR signaling pathway protein expression in DLBCL cells. Similarly, in vivo studies demonstrated that APOC1 knockdown significantly reduced tumor growth, angiogenesis-related proteins, and phosphorylated PI3K/AKT/mTOR pathway proteins in nude mice. APOC1 knockdown promotes apoptosis and suppresses angiogenesis in DLBCL cells by inhibiting the PI3K/AKT/mTOR pathway.

Prostate cancer (PCa) ranks among the most prevalent cancers in men, noted for its high mortality rate and unfavorable prognosis. Estrogen-related genes (ERGs) are significantly associated with the progression of PCa. This investigation aims to comprehensively assess the prognosis of PCa based on ERGs and explore its underlying biological mechanisms. Univariate, multivariate, and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were conducted to identify prognostic signature genes and build a prognostic model. The model's predictive performance was assessed using Receiver Operating Characteristic (ROC) curve analysis. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed to investigate the underlying molecular mechanisms of PCa. Antitumor drugs with high sensitivity were predicted using the CellMiner database and the pRRophitic package. Additionally, miRNAs targeting the identified signature genes were predicted using the miRNet database. This study identified six ERGs as prognostic biomarkers for PCa: POU4F1, BMP2, PGF, GAS1, GNAZ, and FGF11. The findings indicated that individuals in the low-risk category exhibited improved prognostic results. Notably, PCa progression may be closely linked to the cell adhesion molecule pathway and epigenetic regulation. Additionally, hsa-let-7a-5p and hsa-miR-34a-5p were identified as potential therapeutic regulators for PCa treatment. In conclusion, this research offers novel perspectives into the progression of PCa, providing robust scientific support for the development of personalized treatment strategies for PCa patients.

Angiogenesis, as a core marker of cancer survival and growth, is integral to the processes of tumour growth, invasion and metastasis. In recent years, targeted angiogenesis treatment strategies have gradually become an important direction in cancer treatment. Single-cell sequencing technology can provide new insights into targeted angiogenesis by providing a deeper understanding of the heterogeneity of tumour endothelial cells and exploring the interactions between endothelial cells and surrounding cells in the tumour microenvironment. Here, we systematically review the research progress in endothelial cell pathophysiology and its endothelial‒mesenchymal transition and illustrate the heterogeneity of endothelial cells from a single-cell perspective. Finally, we examine the contributions of different cell types within the tumour microenvironment in relation to tumour angiogenesis, as well as the latest progress and strategies in targeted angiogenesis therapy, hoping to provide useful insights into the clinical application of antiangiogenic treatment. Furthermore, a summary of the present progress in the development of potential angiogenesis inhibitors and the ongoing clinical trials for combination therapies is provided. KEY POINTS: Angiogenesis plays a key role in tumour progression, invasion and metastasis, so strategies targeting angiogenesis are gradually becoming an important direction in cancer therapy. Interactions between endothelial cells and stromal cells and immune cells in the tumour microenvironment are significant in angiogenesis. The application of antiangiogenic immunotherapy and nanotechnology in antiangiogenic therapy provides a vital strategy for prolonging the survival of cancer patients.

Cancer-associated fibroblasts (CAFs) are key players in cancer development and therapy, and they exhibit multifaceted roles in the tumor microenvironment (TME). From their diverse cellular origins, CAFs undergo phenotypic and functional transformation upon interacting with tumor cells and their presence can adversely influence treatment outcomes and the severity of the cancer. Emerging evidence from single-cell RNA sequencing (scRNA-seq) studies have highlighted the heterogeneity and plasticity of CAFs, with subtypes identifiable through distinct gene expression profiles and functional properties. CAFs influence cancer development through multiple mechanisms, including regulation of extracellular matrix (ECM) remodeling, direct promotion of tumor growth through provision of metabolic support, promoting epithelial-mesenchymal transition (EMT) to enhance cancer invasiveness and growth, as well as stimulating cancer stem cell properties within the tumor. Moreover, CAFs can induce an immunosuppressive TME and contribute to therapeutic resistance. In this review, we summarize the fundamental knowledge and recent advances regarding CAFs, focusing on their sophisticated roles in cancer development and potential as therapeutic targets. We discuss various strategies to target CAFs, including ECM modulation, direct elimination, interruption of CAF-TME crosstalk, and CAF normalization, as approaches to developing more effective treatments. An improved understanding of the complex interplay between CAFs and TME is crucial for developing new and effective targeted therapies for cancer.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.

Ulcerative colitis (UC) is a chronic inflammatory disease of unknown cause, for which no curative treatments have been developed. Cytokines play an important role in the pathogenesis of UC, and therapies targeting specific cytokines have been successful in treating refractory UC. The purpose of this study was to measure mucosal cytokines in UC and identify those that contribute to nonrelapsing mucosal healing (MH) diagnosed by endoscopy.

This prospective, observational study included 163 patients with UC. The mucosa was evaluated by the Mayo Endoscopic Subscore (MES) and linked color imaging (LCI) at the time of endoscopy, and cytokine mRNA expression in biopsy tissue taken from the same site was quantified by real-time PCR and compared with endoscopic findings. The relationship between cytokine mRNA expression and endoscopic findings was investigated.

Cytokines such as IFNγ, IL-1β, IL-8, IL-17A, and IL-23 were significantly elevated in proportion to endoscopic severity of MES and LCI classification. Interestingly, we found differences in the expression of cytokines (eg, IL-22 and IL-33) between MES and LCI classification according to disease severity. Additionally, pathway analysis based on RNA sequencing comparing LCI-A and LCI-B in patients diagnosed as MES 0 revealed that IL-5 and IL-6 are involved in the finer differences in endoscopic mucosal redness.

This study is the first to report the correlation between mucosal cytokine expression and the pathogenesis of MH in UC and supports the contribution of specific cytokines as molecular markers of MH or in the pathogenesis of MH in UC.

The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays a critical role in cancer progression. It comprises various cell types, including immune cells, tumor cells, and stromal cells. Among these, cancer-associated fibroblasts (CAFs) represent a heterogeneous population with diverse origins, phenotypes, and functions. Activated CAFs secrete multiple factors that promote tumor growth, migration, angiogenesis, and contribute to chemoresistance. Additionally, CAFs secrete extracellular matrix (ECM) components, such as collagen, which form a physical barrier that hinders the penetration of chemotherapeutic and immunotherapeutic agents. This ECM also influences immune cell infiltration, impeding their ability to effectively target tumor cells. As a result, modulating the activity of CAFs has emerged as a promising strategy to enhance the efficacy of tumor immunotherapy. Nano-delivery systems, constructed from various nanomaterials with high targeting specificity and biocompatibility, offer a compelling approach to deliver therapeutic agents or immunomodulatory factors directly to CAFs. This modulation can alter CAF function, reduce their tumor-promoting effects, and thereby improve the outcomes of immunotherapy. This review provides an in-depth exploration of the origins, functions, and interactions of CAFs within the TME, particularly in the context of immune suppression. Furthermore, it discusses the potential applications of functional nanocarrifers in modulating CAFs and enhancing the effectiveness of tumor immunotherapy, highlighting the significant progress and potential of nanotechnology in this area.

Improved outcomes in HER2+ female breast cancer have resulted from chemotherapy and anti-HER2 therapies. However, HER2+ER+ cancers exhibit lower response rates. The phase 2 NA-PHER2 trial (NCT02530424) investigated chemo-free preoperative HER2 blockade (trastuzumab + pertuzumab) and CDK4/6 inhibition (palbociclib) with or without endocrine therapy (fulvestrant) in HER2+ER+ breast cancer. Clinical endpoints (i.e. Ki67 dynamics and pathological complete response) were previously reported. Here we report on the biomarker analysis, secondary objective of the study. Through RNA sequencing and tumour infiltrating lymphocytes (TIL) assessment in serial biopsies, we identified biomarkers predictive of pCR or Day14 Ki67 response and unveiled treatment-induced molecular changes. High immune infiltration and low ER signalling correlated with pCR, while TP53 mutations associated with high Day14 Ki67. Stratification based on Ki67 at Day14 and at surgery defined three response groups (Ki67 HighHigh, LowHigh, LowLow), with divergent tumour and stroma expression dynamics. The HighHigh group showed dysfunctional immune infiltration and overexpression of therapeutic targets like PAK4 at baseline. The LowLow group exhibited a Luminal A phenotype by the end of treatment. This study expands our understanding of drivers and dynamics of HER2+ER+ tumour response, towards treatment tailoring.

Cancer-associated fibroblast (CAF) cells play an important role in gastric malignancy. MiRNA dysregulation has been detected in CAF cells, which is related to the tumor progression ability of these cells. Therefore, this study aimed to evaluate the function of miRNA34a in CAF cells in gastric carcinoma.

We transiently transfected miRNA-34a mimic in CAF cells and examined the effect of the overexpressed miRNA on PD-L1 expression using real-time PCR. Next, we evaluated the role of transfected CAF-conditioned medium (CM) on the immune response and viability of gastric cancer cell lines.

We have shown that miRNA-34a significantly reduced PD-L1 expression in CAF cells (p < 0.05). However, the conditioned medium of transfected cells had no significant effect on the immune response. We also found that CM of miRNA-34a transfected CAF cells significantly suppressed gastric cancer cell line viability relative to the control group (P < 0.05).

We indicated that CM of miRNA-34a transfected CAF can reduce gastric cancer cell line proliferation. Additionally, miRNA-34a in these cells may improve immune response via PD-L1 reduction. Thus, miRNA-34a could be a potential therapeutic agent in gastric cancer treatment.

Not applicable.

Tenascin-C (TNC) is a secreted extracellular matrix protein that is highly expressed during embryonic development and re-expressed during wound healing, inflammation, and neoplasia. Studies in developmental models suggest that TNC may regulate the Wnt signaling pathway. Our laboratory has shown high levels of Wnt signaling and TNC expression in anaplastic thyroid cancer (ATC), a highly lethal cancer with an abysmal approximately 3- to 5-month median survival. Here, we investigated the role of TNC in facilitating ligand-dependent Wnt signaling in thyroid cancer. We used bulk RNA-sequencing from 3 independent multi-institutional thyroid cancer patient cohorts. TNC expression was spatially localized in patient tumors with RNA in situ hybridization. The role of TNC was investigated in vitro using Wnt reporter assays and in vivo with a NOD.PrkdcscidIl2rg-/- mouse ATC xenograft tumor model. TNC expression was associated with aggressive thyroid cancer behavior, including anaplastic histology, extrathyroidal extension, and metastasis. Spatial localization of TNC in patient tissue demonstrated a dramatic increase in expression within cancer cells along the invasive edge, adjacent to Wnt ligand-producing fibroblasts. TNC expression was also increased in areas of intravascular invasion. In vitro, TNC bound Wnt ligands and potentiated Wnt signaling. Finally, in an ATC mouse model, TNC increased Wnt signaling, tumor burden, invasion, and metastasis. Altogether, TNC potentiated ligand-driven Wnt signaling and promotes cancer cell invasion and metastasis in a mouse model of thyroid cancer. Understanding the role of TNC and its interaction with Wnt ligands could lead to the development of novel biomarkers and targeted therapeutics for thyroid cancer.

Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis.

This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution.

An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining.

In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI.

In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality.

The dynamic interactions between tumor endothelial cells (TECs) and the immune microenvironment play a critical role in the progression of non-small cell lung cancer (NSCLC). In general, endothelial cells exhibit diverse immunomodulatory properties, influencing immune cell recruitment, antigen presentation, and regulation of immune checkpoint expression. Understanding the multifaceted roles of TECs as well as assigning specific functional hallmarks to various TEC phenotypes offer new avenues for targeted development of therapeutic interventions, particularly in the context of advanced immunotherapy and anti-angiogenic treatments. This review provides insights into the complex interplay between TECs and the immune system in NSCLC including discussion of potential optimized therapeutic opportunities.

Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain.

Within the intricate milieu of colorectal cancer (CRC) tissues, cancer-associated fibroblasts (CAFs) act as pivotal orchestrators, wielding considerable influence over tumor progression. This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC, thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions. Through a comprehensive synthesis of current knowledge, this review delineates insights into CAFs-mediated modulation of cancer cell proliferation, invasiveness, immune evasion, and neovascularization, elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors. Additionally, recognizing the high level of heterogeneity within CAFs is crucial, as they encompass a range of subtypes, including myofibroblastic CAFs, inflammatory CAFs, antigen-presenting CAFs, and vessel-associated CAFs. Innovatively, the symbiotic relationship between CAFs and the intestinal microbiota is explored, shedding light on a novel dimension of CRC pathogenesis. Despite remarkable progress, the orchestrated dynamic functions of CAFs remain incompletely deciphered, underscoring the need for continued research endeavors for therapeutic advancements in CRC management.

Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.

Liver fibrosis is a disease with a high prevalence worldwide. The development of hepatic fibrosis results from a combination of factors within the liver, such as extracellular matrix (ECM) deposition, hepatic stellate cells (HSCs) activation, collagen cross-linking, and inflammatory response. Heterogeneity in fibrotic liver is the result of a combination of heterogeneity in the intrahepatic microenvironment as well as heterogeneous expression of fibrosis-associated enzymes and cells, complicating the study of the mechanisms underlying the progression of liver fibrosis. The role of this heterogeneity on the crosstalk between cells and matrix and on the fibrotic process is worth exploring. In this paper, we will describe the phenomenon and mechanism of heterogeneity of liver matrix and intrahepatic cells in the process of hepatic fibrosis and discuss the crosstalk between heterogeneous factors on the development of fibrosis. The elucidation of heterogeneity is important for a deeper understanding of the pathological mechanisms of liver fibrosis as well as for clinical diagnosis and targeted therapies.

Colorectal cancer (CRC) remains the third leading cause of cancer-related death worldwide. Here, we aimed to uncover the mechanism underlying the transcription factor fifth Ewing variant protein (FEV) in CRC. Transcriptome differential expression in human CRC and adjacent tissues was analyzed using GSE143939, GSE142279, GSE196006, and GSE200427 datasets, and the intersecting genes were screened by comparing them with the list of transcription factors in the Human TFBD database, followed by KEGG enrichment analysis. FEV expression was significantly reduced in CRC, and upregulation of FEV inhibited cell growth and tumor progression in CRC. The highly expressed genes in CRC were mainly enriched to the Wnt signaling pathway, and WNT2 is the core initiator of the Wnt signaling pathway. Two binding sites for FEV are present on the WNT2 promoter. WNT2 promoted the proliferation, migration, and invasion of CRC cells. FEV repressed WNT2 transcription by binding to the WNT2 promoter. Collectively, our data revealed that a novel FEV/WNT2 axis is critical for CRC progression. Strategies targeting this specific signaling axis might be developed to treat patients with CRC.

The online version contains supplementary material available at 10.1007/s10616-024-00643-0.

Tenascin-C (TNC) is a secreted extracellular matrix protein that is highly expressed during embryonic development and re-expressed during wound healing, inflammation, and neoplasia. Studies in developmental models suggest that TNC may regulate the Wnt signaling pathway. Our lab has shown high levels of Wnt signaling and TNC expression in anaplastic thyroid cancer (ATC), a highly lethal cancer with an abysmal ~3-5 month median survival. Here, we investigated the role of TNC in facilitating ligand-dependent Wnt signaling in thyroid cancer. We utilized bulk RNA-sequencing from three independent multi-institutional thyroid cancer patient cohorts. TNC expression was spatially localized in patient tumors with RNA in situ hybridization. The role of TNC was investigated in vitro using Wnt reporter assays and in vivo with a NOD.PrkdcscidIl2rg-/- mouse ATC xenograft tumor model. TNC expression was associated with aggressive thyroid cancer behavior, including anaplastic histology, extrathyroidal extension, and metastasis. Spatial localization of TNC in patient tissue demonstrated a dramatic increase in expression within cancer cells along the invasive edge, adjacent to Wnt ligand-producing fibroblasts. TNC expression was also increased in areas of intravascular invasion. In vitro, TNC bound Wnt ligands and potentiated Wnt signaling. Finally, in an ATC mouse model, TNC increased Wnt signaling, tumor burden, invasion, and metastasis. Altogether, TNC potentiated ligand driven Wnt signaling and promotes cancer cell invasion and metastasis in a mouse model of thyroid cancer. Understanding the role of TNC and its interaction with Wnt ligands could lead to the development of novel biomarkers and targeted therapeutics for thyroid cancer.

The WNT/β-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/β-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT 'On' or 'Off' mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/β-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/β-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/β-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/β-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/β-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/β-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/β-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/β-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/β-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.

Esophageal cancer (EC) continues to pose a significant health risk. Cancer-associated fibroblasts (CAFs), an essential part of the tumor microenvironment (TME), are viewed as potential therapeutic targets. However, their role in tumor mechanisms specific to esophageal cancer remains to be elucidated. This study identified MMP14+ CAFs and MMP14- CAFs using immunofluorescence staining. The cytotoxic activity of CD8 T cells was assessed via western blot and ELISA. Using a transwell test, the migratory potential of MMP14+ CAFs was evaluated. Using flow cytometry, apoptosis was found in the esophageal squamous cell carcinoma cell line KYSE30. To determine the important tsRNAs released by MMP14+ CAFs, tsRNA-seq was used. Two subgroups of EC receiving PD-1 immunotherapy were identified by our research: MMP14+ CAFs and MMP14- CAFs. MMP14+ CAFs showed improved migratory capacity and released more inflammatory factors linked to cancer. Through exosomes, these CAFs may prevent anti-PD-1-treated CD8 T cells from being cytotoxic. Furthermore, exosomal tsRNA from MMP14+ CAFs primarily targeted signaling pathways connected with cancer. Notably, it was discovered that tsRNA-10522 plays a critical role within inhibiting CD8 T cell tumor cell death. The tumor cell killing of CD8 T cells by exosomal tsRNA-10522 is inhibited by a subgroup of cells called MMP14+ CAFs inside the EC microenvironment during PD-1 immunotherapy. This reduces the effectiveness of PD-1 immunotherapy for EC. Our findings demonstrate the inhibitory function of MMP14+ CAFs within EC receiving PD-1 immunotherapy, raising the prospect that MMP14+ CAFs might serve as predictive indicators in EC receiving PD-1 immunotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent pancreatic cancer and represents one of the most aggressive human neoplasms. Typically identified at advance stage disease, most PDAC tumors are unresectable and resistant to standard therapies. The immunosuppressive microenvironment in PDAC impedes tumor control but a greater understanding of the complex stromal interactions within the tumor microenvironment (TME) and the development of strategies capable of restoring antitumor effector immune responses could be crucial to fight this aggressive tumor and its spread. Natural Killer (NK) cells play a crucial role in cancer immunosurveillance and represent an attractive target for immunotherapies, both as cell therapy and as a pharmaceutical target. This review describes some crucial components of the PDAC TME (collagens, soluble factors and fibroblasts) that can influence the presence, phenotype and function of NK cells in PDAC patients tumor tissue. This focused overview highlights the therapeutic relevance of dissecting the complex stromal composition to define new strategies for NK cell-based immunotherapies to improve the treatment of PDAC.