Cell Communication and Signaling最新文献

Tumor innervation, the infiltration of nerves into the tumor microenvironment (TME), is increasingly recognized as a novel hallmark driving cancer progression and is associated with poor patient prognosis across various solid malignancies. This process is orchestrated by a complex, bidirectional crosstalk. Cancer and stromal cells release neurotrophic factors that induce axonogenesis or neurogenesis. In turn, the infiltrating nerves, particularly sensory nerves, secrete neurotransmitters, neuropeptides or form pseudo-synapse with tumor cells to facilitate cancer hallmarks, including sustained proliferation, invasion, metastasis, modulation of the anti-tumor immune response, and cancer plasticity. However, the specific contributions and underlying mechanisms of sensory nerve innervation in orchestrating malignancy remain incompletely elucidated. This review aims to synthesize the current understanding of the multifaceted roles of sensory neurons within the TME, detailing their intricate interactions with cancer and stromal cells, and highlighting the emerging therapeutic strategies that target the sensory nerve-tumor axis.

Background: Tumor cells have the capacity to develop coordinated resistance mechanisms that promote their survival and progression through the acquisition of multidrug resistance (MDR). This phenotype is the consequence of global cellular changes caused by antineoplastic drugs and may include modifications in the secretome, which influence the antitumoral immune response and the fate of resistant cells.

Results: In this study, we determined the cytokine secretion profile of human leukemic cells sensitive and resistant to several antineoplastic drugs. We also analyzed the p38 MAPK signaling pathway and its involvement in the regulation of both cytokine production and resistance. For this purpose, we generated a human leukemic model that consists of pre-B parental leukemic cells and their derived sublines resistant to several drugs (daunomycin, DNM; cisplatin, CDDP; methotrexate, MTX); an additional transfected subline with inducible expression of P-glycoprotein (P-gp) was obtained. We observed drastic differences in the cytokine secretion profiles of parental and P-gp-transfected cells and resistant sublines. Thus, whereas sensitive and transfected cells exhibit a cytokine regulatory profile, drug-resistant cells are characterized by a predominant inflammatory pattern that is similar in the three drug-resistant sublines, regardless of the drug that has induced the resistant phenotype. In parallel, we observed changes in the p38 MAPK activation profile in DNM-resistant versus DNM-sensitive cells after incubation under stress conditions (DNM at 0.1 µM or hypothermia). Furthermore, the use of a p38 MAPK pharmacological inhibitor decreases not only the IC₅₀ value in DNM-resistant cells but also the cytokine secretion levels in parental and DNM-resistant cells, demonstrating that p38 signaling is a link between resistance and cytokine production in human leukemic cells.

Conclusions: Together, our results suggest that cytotoxic drug-based treatments can modify the cytokine secretory pattern of pre-B leukemic cells, leading to a resistant phenotype through a mechanism that involves p38 MAPK activation. Defining the specific cytokine signatures and associated signaling circuits could provide valuable prognostic markers and aid in optimizing treatment strategies for refractory and/or relapsed patients.

With the development of next-generation sequencing methods, the presence of flora has been detected in otherwise sterile tumour tissues, and intratumoural flora has a role in tumour diagnosis suggesting prognosis due to its heterogeneous nature. Studies have shown that intratumoural flora may contribute to cancer development and progression by inducing DNA damage, affecting immune system homeostasis, influencing signalling pathways, affecting barrier effects, and the effects of intratumoural flora metabolites on the organism. Moreover, intratumoural bacteria have been combined with various therapies to play a role in the clinical management of upper gastrointestinal tumours. In addition, immune cells act as either promoters or suppressors of tumours, and there are various crosstalks between intratumoral bacteria and immune cells; intratumoral bacteria enhance anti-tumour immunity through mechanisms such as T and NK cell activation and intratumoral microbiota-derived antigen presentation, and also reduce anti-tumour immune responses and promote cancer progression through the promotion of anti-inflammatory environments, T-cell inactivation and immunosuppression. In recent studies, intratumoral bacteria have been combined with nano-engineering to target not only the tumour tissue but also the tumour microenvironment. In this review, we summarise the roles and mechanisms played by intratumoural flora in cancer development, metastasis and therapy, and hope to provide ideas for follow-up studies.

Exosomes are key mediators of communication between tumor cells and the tumor microenvironment(TME); however, the mechanisms underlying exosome-mediated crosstalk between tumor cells and macrophages remain largely unclear. This study investigated the effect of exosomal RAB10 on macrophage polarization and tumor growth. Mechanistically, RAB10 delivered by breast cancer cells binds to the interferon receptor IFNAR1 and inhibits JAK1/STAT1 pathway phosphorylation, thereby impeding M1 polarization and promoting M2 polarization. RAB10 expression was significantly upregulated in drug-resistant breast cancer cells and was correlated with poor patient prognosis. In vitro assays confirmed that RAB10 enhances cancer cell proliferation. In vivo knockdown of RAB10 suppressed tumor growth and reduced the expression of markers related to proliferation (Ki67, PCNA), invasion (MMP2), and epithelial-mesenchymal transition (Snail, Vimentin). Single-cell RNA sequencing revealed a marked decrease in the proportion of macrophages in the TME following RAB10 knockdown. This phenotypic shift increases the secretion of immunosuppressive factors such as PDL1, leading to reduced activity of CD8⁺ T cells. Animal studies further confirmed that combined targeting of RAB10 and PD-L1 produces a synergistic inhibitory effect on tumor growth. This study demonstrated that breast cancer cells can transfer RAB10 to macrophages via exosomes. RAB10 interacts with IFNAR1 to suppress the JAK1/STAT1 signaling pathway, thereby inhibiting M1 polarization and promoting M2 polarization of macrophages. Inhibition of RAB10, especially in combination with PD-L1 blockade, offers a promising strategy to enhance anti-tumor immunity and overcome therapeutic resistance in breast cancer.

Background: Cisplatin (CP)-induced nephrotoxicity is a major clinical concern. Emerging evidence has revealed the critical role of PANoptosis, a coordinated cell death pathway, and neutrophil extracellular traps (NETs) in renal tubular damage. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has been recognized as a potential modulator of inflammation and cell survival; however, its regulatory function and mechanism in acute kidney injury (AKI), especially CP-induced AKI, particularly concerning NETs and PANoptosis, remain poorly understood. This study investigates the central role of PPARγ and explores the therapeutic potential of its novel activator, O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1L), in this context.

Methods: Cultured renal tubular epithelial cells (mTECs) as well as a CP-induced AKI mouse model (20 mg/kg, 72 h) and renal ischemia-reperfusion injury (IRI) model​ were used. PPARγ heterozygous knockout mice, NET inhibitors (DNase I and GSK484), and pharmacological interventions (including the novel PPARγ agonist HD-1L and rosiglitazone [ROSI]) were used. The molecular mechanisms were assessed using western blotting, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and cellular thermal shift assays (CETSA). PPARγ activity, NET markers (MPO, Cit-H3, and dsDNA), PANoptosis-related proteins (p-MLKL, GSDMD-N, and cleaved caspase-3), and reactive oxygen species (ROS) levels were quantified.

Results: CP triggered robust PANoptosis in the renal tissues, accompanied by elevated NETs and ROS-dependent NETosis. PPARγ activation significantly suppressed ROS production in neutrophils, thereby reducing NET formation. Mechanistically, NETs facilitate the release of cytoplasmic dsDNA, activate the AIM2 inflammasome, and promote PANoptosome assembly. Genetic PPARγ heterozygous knockout exacerbated renal injury and abolished protective effects, confirming the central role of PPARγ. HD-1L-induced activation of PPARγ reduced markers of PANoptosis and improved renal function in CP-AKI models. Furthermore, PPARγ agonism similarly protected against renal injury and suppressed the NETosis-PANoptosis axis in the IRI model.

Conclusion: PPARγ is a pivotal checkpoint in CP-AKI by inhibiting ROS-NETosis-driven AIM2-mediated PANoptosis. This protective mechanism is also applicable to IRI-induced AKI, highlighting its broad relevance. HD-1L confers renoprotection through PPARγ activation, providing a novel therapeutic strategy against AKI.