Increasing evidence indicates that cancer stem cells (CSCs) and cancer stem-like cells form a special subpopulation of cells that are ubiquitous in tumors. These cells exhibit similar characteristics to those of normal stem cells in tissues; moreover, they are capable of self-renewal and differentiation, as well as high tumorigenicity and drug resistance. In prostate cancer (PCa), it is difficult to kill these cells using androgen signaling inhibitors and chemotherapy drugs. Consequently, the residual prostate cancer stem cells (PCSCs) mediate tumor recurrence and progression.

This review aims to provide a comprehensive and up-to-date overview of PCSCs, with a particular emphasis on potential therapeutic strategies targeting these cells.

After searching in PubMed and Embase databases using 'prostate cancer' and 'cancer stem cells' as keywords, studies related were compiled and examined.

In this review, we detail the origin and characteristics of PCSCs, introduce the regulatory pathways closely related to CSC survival and stemness maintenance, and discuss the link between epithelial-mesenchymal transition, tumor microenvironment and tumor stemness. Furthermore, we introduce the currently available therapeutic strategies targeting CSCs, including signaling pathway inhibitors, anti-apoptotic protein inhibitors, microRNAs, nanomedicine, and immunotherapy. Lastly, we summarize the limitations of current CSC research and mention future research directions.

A deeper understanding of the regulatory network and molecular markers of PCSCs could facilitate the development of novel therapeutic strategies targeting these cells. Previous preclinical studies have demonstrated the potential of this treatment approach. In the future, this may offer alternative treatment options for PCa patients.

Pulmonary fibrosis (PF) is always exacerbated by the comorbidity of lung adenocarcinoma (LUAD), and patients frequently died from the complications of PF instead of lung cancer. Although many studies have unveiled the mechanisms underlying PF exacerbation due to lung cancer resection and radiotherapy, the influence of lung cancer itself on PF remains enigmatic.

We cocultivated mouse pulmonary cells with mouse LUAD cells to explore the influence of LUAD on the pathogenesis and progression of PF. Additionally, a comorbidity model of PF with LUAD was established in mice via intratracheal injection of bleomycin (BLM) followed by in situ transplantation of LUAD cells. Furthermore, immunofluorescence, immunohistochemistry, and molecular analyses were employed to elucidate the mechanisms underlying the exacerbation of PF by the comorbidity of LUAD.

We found that PF was significantly exacerbated by LUAD. In the microenvironment of LUAD, the epithelial-mesenchymal transition (EMT) was predominantly activated in lung epithelial cells, while the transformation of lung fibroblasts into myofibroblasts was markedly induced. The TGF-β and GSK-3β pathways were differentially activated in lung epithelial cells and fibroblasts. Furthermore, clinical samples confirmed the involvement of these pathways in the process of PF exacerbation induced by LUAD in patients' lung lesions of PF with LUAD.

This study initially reveals that LUAD exacerbates PF by modulating epithelial cells and fibroblasts through TGF-β and GSK-3β pathways differentially. Practically, targeting the pathways of TGF-β and GSK-3β may promise a potential strategy for the prophylaxis of PF exacerbation in patients with LUAD.

This study aimed to explore the interaction between perceived stress, life satisfaction, heart rate variability (HRV), and immune-inflammatory markers in bladder cancer patients. We investigated how HRV moderates the relationship between psychological distress and levels of TNF-α and TGF-β cytokines. We hypothesized that high vagal nerve activity, as indicated by higher HRV, mitigates the impact of perceived stress and life dissatisfaction on inflammation.

The study included 73 patients with bladder cancer. HRV was determined from a 5-min ECG recording, focusing on the standard deviation of normal-to-normal interbeat intervals (SDNN). Psychological distress was measured using the Perceived Stress Scale (PSS), and life satisfaction was evaluated with the Life Satisfaction Questionnaire (LSQ). Serum concentrations of TNF-α and plasma levels of TGF-β were determined using sandwich ELISA.

We found evidence that HRV modulates the relation between perceived stress and inflammation. In patients with low HRV (SDNN <20 ms), PSS was positively correlated with serum level of TNF-α and negatively with the level of TGF-β, while life satisfaction was positively correlated with TGF-β. These relationships were not significant in patients with high HRV (SDNN ≥20 ms).

Our findings suggest that high vagal activity, as indicated by higher HRV, may mitigate the adverse effects of psychological distress on immune-inflammatory responses in patients with bladder cancer. Stress-related inflammation took place under conditions of low HRV, highlighting the potential role of autonomic regulation in cancer prognosis. Future research should further explore these relationships to develop interventions aimed at improving patient outcomes through stress management and enhanced vagal nerve activity to regulate inflammation in cancer.

Esophageal squamous cell carcinoma (ESCC) cells migrate from their initial site of origin, ultimately forming metastasis and causing death. The selective inhibition of ESCC cell movement has not been possible to date. Here we demonstrate that the small molecule therapeutic agent KBU2046 inhibits the characteristic migration and invasion of ESCC cells induced by chemokine gradients, having no effect on cell proliferation. After demonstrating that KBU2046 inhibits human ESCC metastasis in a murine model, we showed that it doesn't inhibit the in vitro efficacy of chemotherapeutic agents used clinically, going on to demonstrate maintenance of cisplatin efficacy when combined with KBU2046 in a murine model. Mechanistic studies demonstrated that KBU2046 inhibited epidermal growth factor (EGF)-mediated phosphorylation of receptor-interacting serine/threonine protein kinase 1 (RIPK1) on its Ser166 activation motif. RIPK1 was shown to be necessary for KBU2046 efficacy. However, this was shown to be dependent upon cell context, and was also shown to be dependent upon level of RIPK1 expression, both supporting the presence of additional therapeutically sensitive regulatory pathways. Mass spectrometry analysis of ESCC cells demonstrated that KBU2046 selectively altered the expression of proteins involved in cell motility. Integrin αV (ITGAV) is overexpressed in ESCC, was decreased by KBU2046, and its knockdown inhibited ESCC cell migration and invasion, which was necessary for KBU2046 efficacy. We demonstrate that ESCC's motility can be inhibited, and KBU2046 inhibits motility in an Integrin αV-dependent manner, and that combining anti-motility and cytotoxic agents is a high valuable therapeutic strategy for ESCC that should be further developed.

The transcriptional regulators SMAD2 and SMAD3 share the same primary signaling pathway in response to the cytokine TGFβ. However, whereas SMAD2 stimulates the differentiation of naive CD4+ T cells into proinflammatory T helper 17 cells (TH17 cells), SMAD3 stimulates the differentiation of anti-inflammatory regulatory T cells (Treg cells). Here, we report a dynamic SMAD2-specific posttranslational modification important for TH17 cell differentiation. SMAD2, but not SMAD3, was reversibly S-palmitoylated at cysteine-41 and cysteine-81 by the palmitoyltransferase DHHC7 and depalmitoylated by the acyl protein thioesterase APT2. As a result, SMAD2 was recruited to intracellular membranes where its linker region was phosphorylated, leading to its interaction with the transcriptional regulator STAT3. Nuclear translocation of the SMAD2-STAT3 complex induced the expression of their target genes that promoted TH17 cell differentiation. Perturbation of SMAD2-STAT3 binding by inhibiting the palmitoylation-depalmitoylation cycle suppressed TH17 cell differentiation and reduced disease severity in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Thus, the S-palmitoylation-depalmitoylation cycle mediated by DHHC7 and APT2 specifically regulates SMAD2, providing insights into the functional differences between SMAD2 and SMAD3 and the distinct role of SMAD2 in TH17 cell differentiation. The findings further highlight DHHC7 and APT2 as potential therapeutic targets for the treatment of TH17 cell-mediated inflammatory diseases, including MS.

Background: Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with a poor prognosis. Surgical removal of the primary tumor and regional lymph nodes (LNs) remains the fundamental treatment for OSCC, although 40% of patients are negative for LN metastasis. The epithelial-mesenchymal transition (EMT) plays a crucial role in OSCC progression by enabling epithelial cells to acquire mesenchymal traits, thereby facilitating migration and metastasis. Smad4, a tumor suppressor protein, is known to mediate EMT and is associated with poor prognosis and metastasis; however, its precise pro-metastatic role in OSCC via EMT remains unclear. Aims: We hypothesize that EMT and Smad4 could serve as practical diagnostic tools for personalized OSCC treatment. Methods: In this study, we analyzed 23 OSCC samples from Tzafon Medical Center, comparing the expression of Smad4 and EMT markers with clinical and histopathological data. Additionally, an OSCC cell model with and without Smad4 mutation was used to investigate tumor phenotypes, including proliferation and invasion, in relation to EMT markers. Results and Conclusion: Our findings reveal a strong correlation between EMT markers, Smad4 expression, and OSCC pathological staging, with the cell model further confirming the link between Smad4 and EMT markers. The combined influence of Smad4 and EMT markers on OSCC progression highlights their potential as diagnostic tools and as guides for personalized treatment strategies.

Hepatic fibrosis, characterized by the excessive deposition of the extracellular matrix, represents a common consequence of various chronic liver disorders. However, no specific drugs are available for antifibrotic therapy to date. SMAD2 is phosphorylated by transforming growth factor-β and subsequently binds to SMAD4 to generate a heteromeric complex, which then translocates into the nucleus and aggravates liver fibrosis. Herein, based on molecular docking simulation and structure-activity relationship study, we report the discovery of a novel cyclic peptide CMF9 that targets SMAD2 and potently interferes with the SMAD2-SMAD4 interaction. The subsequent in vivo and in vitro pharmacological studies demonstrated that CMF9 dramatically suppressed hepatic stellate cells activation and collagen synthesis, alleviating CCl4-induced hepatic inflammation and fibrosis. Overall, we first demonstrated that the novel cyclic peptide CMF9 could efficiently block the SMAD2-SMAD4 interaction via selectively inhibiting SMAD2 phosphorylation, providing a promising therapeutic strategy for targeting SMAD2 and an alternative candidate for the treatment of liver fibrosis.

Pseudopodia and invadopodia are dynamic, actin-rich membrane structures extending from the cell surface. While pseudopodia are found in various cell types, invadopodia are exclusive to tumor cells and play a key role in cancer progression. These specialized structures enable tumor cells to degrade the extracellular matrix, breach tissue barriers, and invade surrounding tissues and blood vessels, thus facilitating metastasis. Extensive research has elucidated the distinct structure of invadopodia, the signaling pathways driving their formation, and their interaction with the tumor microenvironment. Integrin- and Src kinase-mediated signaling pathways regulate invadopodia dynamics. This review explores the mechanisms underlying invadopodia stabilization and highlights recent insights into their regulation by the tumor microenvironment. Particular emphasis is placed on the role of cell surface signaling in modulating invadopodia activity and the intracellular targeting of matrix metalloproteinases (MMPs) in enhancing invasive potential. A deeper understanding of invadopodia-driven cancer cell migration and metastasis provides valuable implications for therapeutic development. These findings support the potential for receptor-mediated and molecularly targeted therapies to inhibit tumor metastasis, improve clinical outcomes, and enhance the efficacy of existing cancer treatments.

To recapitulate prostate cancer metastasis, DU145 cells were cultured in a hyaluronic acid-based, bio-orthogonally constructed, protease-degradable hydrogels. In the presence of a covalently conjugated integrin-binding peptide (GRGDSP), DU145 cells formed tumoroids and exhibited small protrusions. Upon addition of soluble transforming growth factor beta 1 (TGFβ1), cells underwent morphological changes to form extended interconnected cellular networks. Contrarily, in RGD-free hydrogels, cells maintained spherical structures even in the presence of TGFβ1. In RGD-conjugated hydrogels, TGFβ1 induced nuclear localization of SMAD2/3, upregulating a wide range of TGFβ1 target genes and proteins. Prolonged exposure to TGFβ1 led to matrix remodeling and induced epithelial-to-mesenchymal transition in DU145 cells, with loss of epithelial markers and gain of mesenchymal markers. A pharmacological inhibitor of TGFβRI/ALK5, SB-431542, attenuated TGFβ1-induced morphological changes, abrogated nuclear localization of SMAD2/3, and restored the expression of key epithelial markers. Our findings highlight the cooperative role of TGFβ1 signaling and integrin-binding peptide in the acquisition of an aggressive phenotype and the promotion of tumor progression.

TGF-β ligands suppress growth yet can paradoxically and potently promote cancer invasion and metastasis depending on downstream pathway mutational context, such as loss of Mothers against decapentaplegic homolog 4 (Smad4). Here, we characterised phenotypes and associated gene expression signatures in conditional murine intestinal adenoma with and without Smad4. Conditional Lgr5-CreERT2 activation in Apcfl/flSmad4fl/fl mice resulted in homozygote floxed alleles (ApcΔ/ΔSmad4Δ/Δ) and adenoma formation. The adenoma phenotype was discordant, with reduced small intestinal adenoma burden yet development of large non-metastatic caecal adenoma with nuclear localisation of phospho-Smad2/3. Derived ApcΔ/ΔSmad4Δ/Δ adenoma organoids resisted TGF-β1 dose dependent growth arrest and cell death (IC50 534 pM) compared to ApcΔ/ΔSmad4+/+ (IC50 24 pM). TGF-β1 (390 pM) altered adenoma bulk mRNA expression most significantly for Id1low and Spp1high in ApcΔ/ΔSmad4Δ/Δ. Single cell RNAseq of caecal adenoma identified expansion of Lgr5low, Pak3high and Id1low progenitor populations in ApcΔ/ΔSmad4Δ/Δ. Of the 76 Smad4 and TGF-β1 dependent genes identified in Apcfl/flSmad4fl/fl adenoma organoids, only 7 human equivalent genes were differentially expressed in SMAD4 mutated colorectal cancer (TCGA cohorts), including ID1low. SMAD4low, ID1low SPP1high and PAK3high all correlated with poorer survival. Murine adenoma identified Smad4 dependent gene expression signatures that require further evaluation as functional biomarker classifiers of SMAD4 mutated cancer subtypes.

N6-methyladenosine (m6A), one of the most prominent and reversible internal modifications of eukaryotic RNAs, has emerged as a critical regulator of gene expression in various cancers including oral squamous cell carcinoma (OSCC), wherein it shapes the tumor-specific epitranscriptomic gene-regulatory networks. METTL3, the primary m6A RNA methyltransferase, is significantly upregulated in OSCC cells leading to increased global m6A levels. Interestingly, METTL3 positively regulates miRNA biogenesis by modulating the processing of primary miRNAs in a m6A-dependent manner. We identified miR-146a-5p, an oncogenic miRNA as one of the METTL3-regulated miRNAs in OSCC. METTL3-depletion or inhibition of its catalytic activity leads to a reduction of miR-146a-5p and an appreciable accumulation of primary miR-146a in OSCC cells. Functional assays examining the effects of miR-146a-5p inhibition or overexpression confirm its oncogenic role in OSCC pathophysiology. Further, SMAD4, a central transducer in TGF-β signaling, was identified as a miR-146a-5p target. In OSCC cells, SMAD4-depletion exacerbates the oncogenic traits, whereas its overexpression exerts the opposite effect. Additionally, METTL3-depletion dysregulates SMAD4-regulated genes suggesting its potential involvement in SMAD4-dependent TGF-β signaling. Taken together, we report that METTL3, an oncogene regulates the expression of SMAD4, a tumor-suppressor via miR-146a-5p, thus unveiling a novel regulatory axis of METTL3/miR-146a-5p/SMAD4 in OSCC, which can potentially have therapeutic implications.

Gliomas are the most prevalent and aggressive neoplasms of the central nervous system, representing a major challenge for effective treatment and patient prognosis. This study identifies the proteasome subunit beta type-8 (PSMB8/LMP7) as a promising prognostic biomarker for glioma. Using a multiparametric radiomic model derived from preoperative magnetic resonance imaging (MRI), we accurately predicted PSMB8 expression levels. Notably, radiomic prediction of poor prognosis was highly consistent with elevated PSMB8 expression. Our findings demonstrate that PSMB8 depletion not only suppressed glioma cell proliferation and migration but also induced apoptosis via activation of the transforming growth factor beta (TGF-β) signaling pathway. This was supported by downregulation of key receptors (TGFBR1 and TGFBR2). Furthermore, interference with PSMB8 expression impaired phosphorylation and nuclear translocation of SMAD2/3, critical mediators of TGF-β signaling. Consequently, these molecular alterations resulted in reduced tumor progression and enhanced sensitivity to temozolomide (TMZ), a standard chemotherapeutic agent. Overall, our findings highlight PSMB8's pivotal role in glioma pathophysiology and its potential as a prognostic marker. This study also demonstrates the clinical utility of MRI radiomics for preoperative risk stratification and pre-diagnosis. Targeted inhibition of PSMB8 may represent a therapeutic strategy to overcome TMZ resistance and improve glioma patient outcomes.

Radio-immunotherapy has antitumor activity but also causes toxicity, which limits its clinical application. JS-201 is a dual antibody targeting PD-1 and TGF-β signaling. We investigated the antitumor effect of JS-201 combined with radiotherapy (RT) and the effect on radiation-induced lung injury (RILI). Different tumor models were established to detect the antitumor effects of the combination of JS-201 and RT, and RILI models were established to observe the effects of JS-201. Transcriptome sequencing showed that JS-201 optimized the tumor microenvironment by inhibiting extracellular matrix formation and angiogenesis. Combining JS-201 with RT further increased the inflammatory response and immune infiltration and showed great abscopal effects in Lewis lung cancer luciferase-positive models. Single-cell sequencing demonstrated that JS-201 reduced fibroblast proliferation by inhibiting the TGF-β/Smad pathway and the release of neutrophil extracellular traps mediated by ROS, thereby relieving radiation-induced pulmonary fibrosis. In conclusion, the JS-201 and RT combination enhances antitumor effects while mitigating acute and chronic RILI, and it may have potential for translational investigation as a cancer treatment strategy.

Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.

To investigate the expression of aquaporin 3 (AQP3) and transforming growth factor-β1 (TGF-β1) in the decidual tissue and serum of patients with missed abortion (MA) and explore their clinical significance, evaluating their potential as diagnostic biomarkers for MA.

A total of 40 MA patients (case group) and 40 induced abortion (IA) patients (control group) were included. Immunohistochemistry (IHC), Western blot (WB), and reverse transcription quantitative PCR (RT-qPCR) were used to detect the protein and mRNA expression of AQP3 and TGF-β1 in decidual tissue. Serum levels of AQP3 and TGF-β1 were measured by ELISA. The diagnostic efficacy was assessed using receiver operating characteristic (ROC) curve analysis.

The protein expression of AQP3 and TGF-β1 in the decidual tissue of the MA group was significantly higher than that of the IA group, with a 2.3-fold and 2.5-fold increase, respectively (p < 0.01), and their mRNA expression was also significantly upregulated (p < 0.01). Serum levels of AQP3 and TGF-β1 increased by 2.3-fold and 3.3-fold, respectively (p < 0.01). ROC analysis demonstrated that serum AQP3 (AUC = 0.887) and TGF-β1 (AUC = 0.949) exhibited high diagnostic accuracy for MA, with the combined detection achieving an AUC of 0.976, sensitivity of 92.5%, and specificity of 97.5%.

AQP3 and TGF-β1 are significantly overexpressed in the decidual tissue and serum of MA patients and may play a role in the pathogenesis of MA by regulating trophoblast function. The combined detection of these two biomarkers holds promise as potential diagnostic tools for MA, offering new directions for early clinical management.

Matrix metalloproteinase 3 (MMP-3) is a multifaceted enzyme that plays a critical role in the regulation of extracellular matrix (ECM) dynamics, influencing both normal physiological and pathological processes. In addition to its established role in ECM degradation, MMP-3 is gaining recognition for modulating cellular behaviors such as inflammation, migration, and proliferation. Recent research has uncovered its capacity to activate latent signaling molecules, release growth factors from the ECM and interact with various cell surface receptors, linking MMP-3 to the progression of various diseases, including inflammatory diseases, infection diseases, cardiovascular diseases, neurodegenerative disorders, and cancer. The review provides an overview of MMP-3's molecular regulation, emphasizing the mechanisms controlling its expression and activity. We discuss MMP3's involvement in both ECM-dependent and independent pathways, and its potential as a diagnostic, prognostic biomarker in various diseases. Additionally, we explore therapeutic strategies targeting MMP-3, summarizing ongoing efforts to develop specific inhibitors and modulate its activity in different pathologic conditions. Through this review, we aim to consolidate the diverse functions of MMP-3 and provide new insights into future research directions, particularly in translating these findings into clinical applications.

TGF-β is a pleiotropic cytokine with both stimulatory and inhibitory effects on immune cells, depending on the microenvironmental context. It targets mast cells (MCs) in different physio-pathological conditions, such as inflammation and cancer. Besides acting as a potent chemoattractant for MCs, TGF-β regulates many other aspects of MCs' physiology, including the secretion of many regulatory molecules. MCs secrete a variety of mediators, either pre-formed or newly synthesized, upon appropriate stimulation. CCL-2 chemokine and TNF cytokine act as potent chemoattractants for several immune cells and participate in the initiation of inflammatory responses by recruiting them to injured tissues. TGF-β regulates CCL-2 and TNF secretion in different cell types and under distinct cellular contexts. Here, we report that the treatment with TGF-β alone induces the secretion of both pre-formed and newly synthesized CCL-2 in the rat RBL-2H3 mast cells but not in mouse bone marrow-derived mast cells (BMMCs). TGF-β-induced CCL-2 secretion depends on rapid rearrangements of the actin cytoskeleton and, remarkably, on the early secretion of soluble TNF that triggers an autocrine TNF signaling. In conclusion, we found cooperation between TGF-β and TNF signaling pathways to promote the secretion of CCL-2 chemokine by MCs in a cell-context specific manner.

Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.

Transforming growth factor-beta (TGF-β) has long been known to be associated with early embryonic development and organogenesis, immune supervision, and tissue repair and homeostasis in adults. TGF-β has complex roles in fibrosis and cancer that may be opposing at different stages of these diseases. Under pathological conditions, overexpression of TGF-β causes epithelial-mesenchymal transition, deposition of extracellular matrix, and formation of cancer-associated fibroblasts, leading to fibrotic disease or cancer. Fibroblasts, epithelial cells, and immune cells are the most common targets of TGF-β, while fibrosis and cancer are the most common TGF-β-associated diseases. Given the critical role of TGF-β and its downstream molecules in fibrosis and progression of cancer, therapies targeting TGF-β signaling appear to be a promising strategy. Preclinical and clinical studies have investigated therapies targeting TGF-β, including antisense oligonucleotides, monoclonal antibodies, and ligand traps. However, development of targeted TGF-β therapy has been hindered by systemic cytotoxicity. This review discusses the molecular mechanisms of TGF-β signaling and highlights targeted TGF-β therapy for cancer and fibrosis as a therapeutic strategy for related diseases.

Epithelia contribute to the innate immune system through barrier formation and through signaling to immune cells. When the barrier is breached, epithelial cells undergo epithelial-to-mesenchymal transition (EMT) as part of the wound healing process. EMT is largely directed by signals from the stromal microenvironment, including transforming growth factor beta (TGFβ1), and antagonizes normal epithelial differentiation. How EMT and innate immunity may be connected molecularly has not been explored, although both processes are likely to occur simultaneously. Keratinocytes are the host cell type for human papillomaviruses (HPV), which can induce EMT in certain conditions but also depend on differentiation for their replication. We previously found that the innate immune factor interferon regulatory factor 3 (IRF3) inhibits epithelial differentiation and reduces the expression of HPV16 late genes. Here we report that IRF3 in the stroma compartment promotes an EMT-like pattern of gene expression in an HPV16-containing epithelium. The depletion of stromal IRF3 resulted in the downregulation of TGFβ1-related signaling in both the stroma and epithelium. IRF3 binds to the TGFB1 promoter in human foreskin fibroblasts and is necessary for TGFB1 mRNA production. Because an EMT-like state is unfavorable for differentiation-dependent HPV16, we observed that all EMT markers examined were reduced in the presence of episomal HPV16. Together, we show that stromal IRF3 can disrupt epithelial differentiation and act as an anti-HPV factor through the regulation of EMT, linking wound healing and immunity.

Distant metastasis remains a major reason for the high recurrence and mortality of colorectal cancer (CRC). However, the underlying molecular mechanisms driving metastasis in CRC remain poorly understood. In this study, we investigated the mechanisms underlying the inhibitory effects of lipocalin-2 (LCN2) on CRC metastasis.

We assessed the expression and clinical significance of LCN2 in human CRC specimens and CRC cell lines using, immunohistochemistry, and western blot analyses. We evaluated the migratory and invasive capabilities of CRC cells influenced by LCN2 using in vitro transwell assays and in vivo lung metastatic models. RNA sequencing and proteome analysis were employed to identify potential downstream targets of LCN2. Rescue experiments were conducted to further elucidate the potential mechanisms of LCN2 and its downstream effectors in CRC.

LCN2 exhibited high expression levels in human CRC tissues and an inverse correlation with N classification, advanced AJCC stages, and shorter overall survival. LCN2 expression independently predicted a more favorable outcome for CRC patients. Upregulation of LCN2 effectively suppressed CRC cell metastasis both in vitro and in vivo. Mechanistically, Transforming growth factor beta 1 (TGFB1) and C-X-C motif chemokine ligand 5 (CXCL5) were identified as downstream effectors of LCN2, with LCN2 inhibiting CRC metastasis through repression of the TGFB1/CXCL5 axis. Furthermore, either TGF-βR1 inhibitor SB431542 or CXCR2 antagonist SB225002 treatment moderately decreased the migratory and invasive capabilities of DLD-1-LV-shLCN2 cells, whereas the combination treatment of the two agents dramatically decreased the migratory and invasive capabilities of DLD-1-LV-shLCN2 cells.

This study underscores LCN2 as an independent protective factor and prognostic biomarker for CRC patients. Combined treatment with the SB431542 and the SB225002 significantly attenuated LCN2-related CRC metastasis. Targeting the LCN2/TGFB1/CXCL5 axis emerges as a promising therapeutic strategy for managing LCN2-related metastatic CRC.

Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated.

SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq.

Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells.

HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.

Endoplasmic reticulum stress (ERS) is an intracellular process in which improperly folded proteins lead to a cellular stress response. How endoplasmic reticulum stress contributes to the onset and progression of laryngeal squamous cell carcinoma remains unclear. Our research aimed to find an ERS signature to forecast the prognosis of laryngeal squamous cell carcinoma and to investigate its potential biological functions. LSCC sample data obtained from The Cancer Genome Atlas (TCGA) database were co-expressed with ERS- related genes, and then a prognostic signature on the basis of endoplasmic reticulum stress- related lncRNAs (ERS-related lncRNAs) was constructed by differential analysis and Cox regression analysis. Survival analysis, TMB, consensus cluster analysis, drug sensitivity analysis, immune analysis and clinical drug prediction were carried out on the model. Finally, the function of LHX1-DT was verified by in vitro experiments. From the TCGA-LSCC cohort, 35 significantly different ERS-related lncRNAs were identified. A prognostic signature consisting of three lncRNAs (AC110611.2, LHX1-DT, and AL157373.2) was identified. Kaplan-Meier analysis demonstrated the predictive ability of the model for overall survival. Calibration curves and receiver operating characteristic curves were validated and showed high predictive accuracy. Ultimately, the experimental results verified the expression of LHX1-DT in LSCC.

Amelogenesis is a highly regulated process involving multiple signaling pathways, among which the transforming growth factor-β1 (TGF-β1) signaling pathway plays a pivotal role in enamel formation. This review firstly elucidates the critical functions of TGF-β1 in regulating ameloblast behavior and enamel development, encompassing ameloblast proliferation, differentiation, apoptosis, enamel matrix protein synthesis, and mineralization. Secondly, based on emerging evidence, we further discuss potential interactions between TGF-β signaling and circadian regulation in enamel formation, although this relationship requires further experimental validation. Finally, future research directions are proposed to further investigate the relationship between TGF-β1 and the circadian clock in the context of amelogenesis.

The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.

Protein post-translational modifications (PTMs) refer to covalent and enzymatic alterations to folded or nascent proteins during or after protein biosynthesis to alter the properties and functions of proteins. PTMs are modified in a variety of types and affect almost all aspects of cell biology. PTMs have been reported to be involved in cancer progression by influencing multiple signaling pathways. The mechanism of action of histone PTMs in cancer has been extensively studied. Notably, evidence is mounting that PTMs of non-histone proteins also play a vital role in cancer progression. In this review, we provide a systematic description of main non-histone PTMs associated with cancer progression, including acetylation, lactylation, methylation, ubiquitination, phosphorylation, and SUMOylation, based on recent studies.

Transforming growth factor β (TGF-β) has important role in regulating the cellular processes including cell growth, differentiation, and migration. TGF-β exerts its effect by binding with transcellular membranes and kinases. Our findings demonstrate that TGF- β possess dual role as tumor suppressor and tumor promoter in different stages of cancer. TGF-β emerged as a promising anticancer agent that exhibits the apoptosis by acting on the suppressor of mothers against decapentaplegic (SMAD) and non-SMAD pathways. In this review we are focusing on the different types of TGF- β inhibitors active against skin cancer, breast cancer, colorectal cancer, lung cancer and ovarian cancer. TGF-β inhibitors includes ligand traps, monoclonal antibodies and receptor kinase inhibitors. In recent studies, TGF- β inhibitors have also been used in combination therapies in the treatment of cancer. The TGF-β has important role in vaccine therapy, Chemo and Radio Resistance in Cancer. TGF-β inhibitors present the novel therapeutic approach for the cancer therapy, highlighting the mechanism of action involved, clinical trials, challenges and exploring therapeutic opportunities. This will help to develop the novel TGF-β inhibitors as anticancer agents as well as help to resolve the problem of drug resistance by developing new drugs as anticancer agents.

As heart transplantation continues to be the gold standard therapy for end-stage heart failure, the imbalance between the supply of hearts, and the demand for them, continues to get worse. In the US alone, with less than 4,000 hearts suitable for transplant and over 100,000 potential recipients, this therapy is only available to a very few. The use of hearts Donated after Circulatory Death (DCD) and Donation after Brain Death (DBD) using ex vivo machine perfusion (EVMP) is a promising approach that has already increased the availability of suitable organs for heart transplantation. EVMP offers the promise of enabling the expansion of the overall number of heart transplants and lower rates of early graft dysfunction. These are realized through (1) safe extension of the time between procurement and transplantation and (2) ex vivo assessment of preserved hearts. Notably, ex vivo perfusion has facilitated the donation of DCD hearts and improved the success of transplantation. Nevertheless, DCD hearts suffer from serious preharvest ischemia/reperfusion injury (IRI). Despite these developments, only 40% of hearts offered for transplantation can be utilized. These devices do offer an opportunity to evaluate donor hearts for transplantation, resuscitate organs previously deemed unsuitable for transplantation, and provide a platform for the development of novel therapeutics to limit cardiac injury. Bone Morphogenetic Protein (BMP) signaling is a new target which holds the potential for ameliorating myocardial IRI. Recent studies have demonstrated that BMP signaling has a significant role in blocking the deleterious effects of injury to the heart. We have designed novel small peptide BMP mimetics that act via activin receptor-like kinase (ALK3), a type I BMP receptor. They are capable of (1) inhibiting inflammation and apoptosis, (2) blocking/reversing the epithelial-mesenchymal transition (EMT) and fibrosis, and (3) promoting tissue regeneration. In this review, we explore the promise that novel therapeutics, including these BMP mimetics, offer for the protection of hearts against myocardial injury during ex vivo transportation for cardiac transplantation. This protection represents a significant advance and a promising ex vivo therapeutic approach to expanding the donor pool by increasing the number of transplantable hearts.

Radiation induced lung injury, known as the main complication of thoracic radiation, remains to be a major resistance to tumor treatment. Based on the recent studies on radiation-induced lung injury, this review collated the possible mechanisms at the level of target cells and key pathways, corresponding prognostic models including predictors, patient size, number of centers, radiotherapy technology, construction methods and accuracy, and pharmacotherapy including drugs, targets, therapeutic effects, impact on anti-tumor treatment and research types. The research priorities and limitations are summarized to provide a reference for the research and management of radiation-induced lung injury.

Advanced colorectal cancer (CRC) continues to present with poor survival and treatment options remain limited. We have shown that increased activin A (activin) expression in the tumor microenvironment (TME) is associated with poor outcome in a cohort of stage III and IV CRC patients. Here, we hypothesized that activin promotes stage specific outcomes in CRC, enhancing metastasis and tolerance in late-stage CRC exclusively. We employed Digital Spatial Profiling (DSP) technology on a cohort of stage II and III CRC patient tissue samples obtained at the time of curative surgery to show that activin co-localization was associated with increased mitogenic signaling, proliferation, and immunosuppression in stage III, but not stage II, CRCs. Furthermore, we found strong linear correlations between markers of immunosuppression and signaling proteins in activin (+) areas, an effect that was not observed in activin (-) areas of tissue. Taken together these data suggest activin exerts pro-metastatic and immunosuppressive effects in stage III, but not stage II, CRC providing an attractive therapeutic target for advanced CRC.

Neutrophils play a crucial role in the innate immune response as a first line of defense in many diseases, including cancer. Tumor-associated neutrophils (TANs) can either promote or inhibit tumor growth in various steps of cancer progression via mutual interactions with cancer cells in a complex tumor microenvironment (TME). In this study, we developed and analyzed mathematical models to investigate the role of natural killer cells (NK cells) and the dynamic transition between N1 and N2 TAN phenotypes in killing cancer cells through key signaling networks and how adjuvant therapy with radiation can be used in combination to increase anti-tumor efficacy. We examined the complex immune-tumor dynamics among N1/N2 TANs, NK cells, and tumor cells, communicating through key extracellular mediators (Transforming growth factor (TGF-$ \beta $), Interferon gamma (IFN-$ \gamma $)) and intracellular regulation in the apoptosis signaling network. We developed several tumor prevention strategies to eradicate tumors, including combination (IFN-$ \gamma $, exogenous NK, TGF-$ \beta $ inhibitor) therapy and optimally-controlled ionizing radiation in a complex TME. Using this model, we investigated the fundamental mechanism of radiation-induced changes in the TME and the impact of internal and external immune composition on the tumor cell fate and their response to different treatment schedules.

This review provides a comprehensive overview of predictive biomarkers associated with metastasis in pancreatic cancer (PC), one of the most aggressive malignancies characterized by late-stage diagnosis and poor prognosis. Metastasis, particularly to the liver, lungs, and lymph nodes, significantly worsens patient outcomes by compromising organ function and promoting disease progression. Reliable biomarkers for predicting and detecting metastasis at early stages are critical for improving survival rates and guiding personalized therapies. This paper highlights both general and specific biomarkers, including genetic mutations, protein expression changes, and carbohydrate tumor markers such as CA19-9. Immunological factors, including PD-L1, inflammatory cytokines, and chemokines, further influence the metastatic process within the tumor microenvironment (TME). Specific biomarkers play pivotal roles in promoting metastasis through mechanisms such as epithelial-to-mesenchymal transition (EMT), tumor microenvironment remodeling, and immune evasion. Emerging markers such as circulating tumor cells (CTCs) and volatile organic compounds (VOCs) offer promising non-invasive tools for metastasis detection and monitoring. This review not only consolidates existing knowledge but also highlights the mechanisms through which specific biomarkers facilitate metastasis. Despite recent progress, challenges such as biomarker standardization, technical variability, and clinical validation remain, and addressing these hurdles is essential for integrating predictive biomarkers into clinical practice. Ultimately, this review contributes to advancing early detection strategies, personalized treatment options, and improved prognosis for PC patients.

Transforming growth factor β (TGF-β) is well known to play paradoxical roles in tumorigenesis as it has both growth-inhibitory and pro-metastatic effects. However, the underlying mechanisms of how TGF-β drives the opposing responses remain largely unknown. Here, we report that ERBB4, a member of the ERBB receptor tyrosine kinase family, specifically promotes TGF-β's metastatic response but not its anti-growth response. ERBB4 directly phosphorylates Tyr162 in the linker region of SMAD4, which enables SMAD4 to achieve a higher DNA-binding ability and potentiates TGF-β-induced gene transcription associated with epithelial-to-mesenchymal transition (EMT), cell migration, and invasion without affecting the genes involved in growth inhibition. These selective effects facilitate lung cancer metastasis in mouse models. This discovery sheds light on the previously unrecognized role of SMAD4 as a substrate of ERBB4 and highlights the selective involvement of the ERBB4-SMAD4 regulatory axis in tumor metastasis.

Liver fibrosis, a consequence of chronic liver injury, represents a major global health burden and is the leading cause of liver failure, morbidity, and mortality. The pathological hallmark of this condition is excessive extracellular matrix deposition, driven primarily by integrin-mediated mechanotransduction. Integrins, transmembrane heterodimeric proteins that serve as primary ECM receptors, orchestrate complex mechanosignaling networks that regulate the activation, differentiation, and proliferation of hepatic stellate cells and other ECM-secreting myofibroblasts. These mechanical signals create self-reinforcing feedback loops that perpetuate the fibrotic response. Recent advances have provided insight into the roles of specific integrin subtypes in liver fibrosis and revealed their regulation of key downstream effectors-including transforming growth factor beta, focal adhesion kinase, RhoA/Rho-associated, coiled-coil containing protein kinase, and the mechanosensitive Hippo pathway. Understanding these mechanotransduction networks has opened new therapeutic possibilities through pharmacological manipulation of integrin-dependent signaling.

The invasion and metastasis of pancreatic cancer (PC) are key factors contributing to disease progression and poor prognosis. This process is primarily driven by EMT, which has been the focus of recent studies highlighting the role of long non-coding RNAs (lncRNAs) as crucial regulators of EMT. However, the mechanisms by which lncRNAs influence invasive metastasis are multifaceted, extending beyond EMT regulation alone.

This review primarily aims to characterize lncRNAs affecting invasion and metastasis in pancreatic cancer. We summarize the regulatory roles of lncRNAs across multiple molecular pathways and highlight their translational potential, considering the implications for clinical applications in diagnostics and therapeutics.

The review focuses on three principal scientific themes. First, we primarily summarize lncRNAs orchestrate various signaling pathways, such as TGF-β/Smad, Wnt/β-catenin, and Notch, to regulate molecular changes associated with EMT, thereby enhancing cellular motility and invasivenes. Second, we summarize the effects of lncRNAs on autophagy and ferroptosis and discuss the role of exosomal lncRNAs in the tumor microenvironment to regulate the behavior of neighboring cells and promote cancer cell invasion. Third, we emphasize the effects of RNA modifications (such as m6A and m5C methylation) on stabilizing lncRNAs and enhancing their capacity to mediate invasive metastasis in PC. Lastly, we discuss the translational potential of these findings, emphasizing the inherent challenges in using lncRNAs as clinical biomarkers and therapeutic targets, while proposing prospective research strategies.

Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.