Microenvironment Of Cancer Cells Research Articles

Calculus bovis hijacks the tumor microenvironment in liver cancer cells in a multifaceted approach: A falling row of dominoes.

Calculus bovis (C. bovis) is widely used in traditional Chinese medicine due to its anti-tumor effects. C. bovis shifts liver cancer tumor microenvironment towards regression by hindering tumor-associated macrophages polarization. Huang et al have demonstrated in their study that C. bovis inhibits M2-tumour-associated macrophages (TAM) polarization by halting the Wnt/β-catenin pathway. The mechanism of action by which C. bovis exerts its anti-tumor effects is multifaceted and includes network pharmacology, transcriptomics and molecular docking. In vitro assays demonstrated that C. bovis-containing serum inhibited M2-TAMs polarization in human hepatocellular carcinomas cells. C. bovis was found to have 22 active components of which 11 were detected in the bloodstream. The anti-neoplastic activity of C. bovis lies in suppressing M2-TAM polarization by modulation of the Wnt/B-catenin pathway. In vitro and in vivo experiments have shown that C. bovis suppresses M2-TAM polarization and halts the Wnt signaling pathway. The inhibitory effect of C. bovis on M2-TAM was reversed by SKL2001, a Wnt agonist, which highlights C. bovis's selectivity and specificity. C. bovis inhibits M2-TAM polarization by modulating the Wnt/ β-catenin pathway, thus impeding liver cancer growth. Owing to the "cross-talk" between transforming growth factor-β (TGF-β) signaling pathways, this paper highlights the potential significance of C. bovis in controlling the tumor microenvironment not only through hindering the polarization of M2-TAMs via the Wnt signaling pathway, but also by downregulating TGF-β. Therefore, C. bovis serves as an igniter to fuel a cascade of signaling events that culminates in the regression of the tumor microenvironment by compromising oncogenesis and angiogenesis. TGF-β is also known for its pro-fibrotic properties. Therefore, C. bovis may play a pivotal role in treating liver fibrosis by downregulating TGF-β, thus hindering oncogenesis, angiogenesis and liver fibrosis. Hence, the "domino effect".

Liposomal Encapsulation of Chlorambucil with a Terpyridine-Based, Glutathione-Targeted Optical Probe Facilitates Cell Entry and Cancer Cell Death.

The nitrogen mustard alkylating agent chlorambucil (CBL) is a critical component of chemotherapeutic regimens used in the treatment of chronic lymphocytic leukemia. The cancer cell-killing actions of CBL are limited by glutathione (GSH) conjugation, a process catalyzed by the GSH transferase hGSTA1-1 that triggers CBL efflux from cells. In the cancer cell microenvironment, intracellular GSH levels are elevated to counterbalance oxidative stress generated due to the high glycolytic demand. As many chemotherapeutic drugs trigger cell death through mechanisms that depend on reactive oxygen species (ROS), antioxidant capacity in cancer cells also represents a barrier to anticancer therapies. Here, we demonstrate that a heightened GSH content in cancer cells can also be exploited for cell-selective drug delivery. We successfully synthesized a malononitrile conjugate terpyridine-based derivative L1, which specifically reacts with GSH in the presence of other biologically relevant amino acids including cysteine (Cys) and homocysteine (Hcy). The significant change in the electronic spectra of L1 in the presence of GSH confirmed GSH detection, which was further corroborated by density functional theory calculations. We next encapsulated CBL into L1-containing, anthracene-functionalized, and 10,12-pentacosadiynoic acid (PCDA)- and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based liposomes (Lip-CBL-L1). We established successful CBL encapsulation and release from L1-containing liposomes in GSH-enriched cancer cells in vitro. Both Lip-CBL-L1 and the L1-lacking Lip-CBL control displayed cell-killing activity. However, human triple-negative breast cancer cells MDAMB231, human lung cancer cells A549, and murine leukemic WEHI cells were more sensitive to the cytotoxic effects of Lip-CBL-L1 compared to the nonmalignant cells (AC16 and HEK293). Indeed, in these cancer cell lines, Lip-CBL-L1 induced greater ROS generation compared to that of Lip-CBL. Together, our results provide initial evidence of the feasibility of exploiting the unique oxidant environment of cancer cells for optimized drug delivery.

Engineered Reactive Oxygen Species (ROS)-Responsive Artificial H+/Cl- Ion Channels for Targeted Cancer Treatment.

Reactive oxygen species (ROS)-responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS-responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H+/Cl- ion channels activatable by elevated ROS levels in cancer cells. ROS-induced decaging of the phenylboronate group triggers the rapid release of the channel-forming units, leading to self-assembly of the H-bonded cascades facilitating the synergistic transport of H+ and Cl- ions, with H+/Cl- ion transport selectivity of 7.7. Upon activation, ROS-C-Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC50 of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H+/Cl- co-transport, ROS-C-Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds.

Engineered Reactive Oxygen Species (ROS)‐Responsive Artificial H+/Cl− Ion Channels for Targeted Cancer Treatment

Reactive oxygen species (ROS)‐responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS‐responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H+/Cl‐ ion channels activatable by elevated ROS levels in cancer cells. ROS‐induced decaging of the phenylboronate group triggers the rapid release of the channel‐forming units, leading to self‐assembly of the H‐bonded cascades facilitating the synergistic transport of H+ and Cl‐ ions, with H+/Cl‐ ion transport selectivity of 7.7. Upon activation, ROS‐C‐Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC50 of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H+/Cl‐ co‐transport, ROS‐C‐Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds.

Abstract B031: Lean adipocyte-derived lipid decreases metastatic potential of breast cancer cells

Abstract Obesity rates are increasing globally, making it of critical importance to study obesity-linked diseases. Breast cancer is the most common cancer in women, and obesity is associated with both increased incidence and metastatic progression of breast cancer. Metastasis formation depends on a cancer cell leaving the primary site, migrating through the bloodstream, and establishing new growth in a distant site. Both metastasizing cell-intrinsic and metastatic site-dependent factors can help to regulate the effectiveness of this process; however, it is unknown whether obesity-linked metastasis depends on changes to the metastasizing cell and/or changes to the distant metastatic site. This study aims to characterize how the lean versus obese tumor microenvironment impacts breast cancer metastasis and identify adipocyte-derived molecules that modulate the metastatic potential of breast cancer cells. We and others have shown that obesity leads to increased metastasis formation in mouse models of orthotopic breast cancer. However, my preliminary data show that an obese metastatic site is not sufficient to increase metastasis formation in an intravenous injection model of metastasis, emphasizing the importance of the primary tumor microenvironment in programming breast cancer cells for metastasis. Cancer cell stemness helps to mediate metastasis formation and can be assessed in vitro with the mammosphere assay. Importantly, my data demonstrate that a secreted lipid from lean, but not obese, adipocytes potently inhibits the ability of breast cancer cells to form mammospheres. Furthermore, this inhibition induces a G1/S cell cycle arrest. Together, these data suggest that lean adipocytes in the breast cancer tumor microenvironment act in a paracrine manner to decrease the metastatic potential of breast cancer cells. My work demonstrates the role of adipocytes in the regulation of metastasis in breast cancer and provides important insight into the role of the tumor microenvironment in mediating metastasis in lean versus obese conditions. Citation Format: Abigail E. Jackson, Keren I Hilgendorf. Lean adipocyte-derived lipid decreases metastatic potential of breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B031.

Sennoside A represses the malignant phenotype and tumor immune microenvironment of non-small cell lung cancer cells by inhibiting the TRAF6/NF-κB pathway.

Non-small cell lung cancer (NSCLC) is a prominent cause of cancer death worldwide. Sennoside A (SA) is the primary anthraquinone active component from Rheum officinale Baill and exerts antitumor functions in multiple human tumors. This research aimed to elucidate the function and mechanism of SA in NSCLC. SA functions in NSCLC were determined using Cell Counting Kit-8 (CCK-8) assay, Terminal deoxynucleotidyl transferase dUTP nick-end labeling analysis, Transwell assay, Enzyme-Linked Immunosorbent Assay (ELISA), and Western blot. Meanwhile, the SA mechanism in NSCLC was examined with Western blot, immunofluorescence assay, CCK-8 assay, Transwell analysis, and ELISA. Furthermore, SA functions in NSCLC growth in vivo were assessed by the establishment of a tumor xenograft model, hematoxylin-eosin staining, analysis of NSCLC tissue apoptosis, and immunohistochemistry assays. Functionally, less than 200µM SA had no significant effect on normal human bronchial epithelial cell BEAS-2B cell viability. Furthermore, H460 cell viability was decreased when the SA dose was greater than or equal to 25µM (IC50 = 53.34µM). A549 cell viability was reduced when the SA dose was greater than or equal to 12.5µM (IC50 = 48.21µM). Also, SA repressed NSCLC cell proliferation and boosted cell apoptosis. SA restrained NSCLC cell invasion and tumor microenvironment. Mechanically, SA weakened NSCLC cell proliferation, invasion, and tumor microenvironment, yet this impact was abolished after transfecting pcDNA3.1-TRAF6, which indicated that SA repressed NSCLC cell proliferation, invasion, and tumor microenvironment through inactivating TRAF6/NF-κB. Moreover, SA reduced subcutaneous tumor volume and promoted NSCLC tissue apoptosis in vivo. SA repressed NSCLC cell proliferation, invasion, and tumor microenvironment through inactivating TRAF6/NF-κB.

PH and Redox Dual-Responsive Nanoparticle with Enhanced Dendritic Cell Maturation for Cancer Therapy.

Type I interferons (IFNs) are essential for activating dendritic cells (DCs) and presenting tumor-associated antigens to T cells. IFNs are primarily produced from DCs among immune cells. A combination of chemotherapy and metalloimmunotherapy induces IFN production by activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, chemotherapeutic agents deplete DC populations, suppressing immunostimulatory activities, despite their potent anticancer activities. Furthermore, an optimal ratio between chemotherapeutic agents and metal for activating DCs at the highest level has not been reported, and evidence for ensuring DC survival is lacking. In this study, we hypothesized that there is an optimal ratio to yield the highest DC maturation and anticancer activity with minimal DC depletion. To demonstrate it, we have designed a pH and redox dual-responsive nanoparticle, MnO2@BSA@DOX (MD), to prevent DCs from depleting and activate the cGAS-STING pathway both in cancer cells and DCs, inducing considerable levels of IFNs and maturation. MD consists of a core-layer structure, a manganese dioxide (MnO2) core, and a cross-linked layer with bovine serum albumin (BSA) and doxorubicin (DOX), with a specific ratio of DOX to manganese. MD exhibits structure-based selectivity between cancer cells and DCs by targeting the extracellular pH of the tumor microenvironment and intracellular redox reactions in cancer cells. Among various formulations, the 1:1 ratio shows the highest maturation with no significant depletion. Moreover, it induces distinct cytotoxicity in cancer cells through apoptosis and cGAS-STING activation, leading to increased calreticulin expression and enhanced DC phagocytosis. Consequently, it results in superior tumor suppression and prolonged survival with the high accumulation of MD in the tumor and no observed systemic toxicities, highlighting its potential as a therapeutic agent in cancer treatments.

Enterococcus faecalis co-cultured with oral cancer cells exhibits higher virulence and promotes cancer cell survival, proliferation, and migration: an in vitro study.

Introduction. Enterococcus faecalis is a common pathogen associated with many oral diseases and is often isolated from oral cancer patients. However, limited information is available on its key virulence gene expression in oral cancer cell microenvironment and cancer cell behaviour in co-culture studies.Hypothesis. E. faecalis overexpresses virulence genes when co-cultured with oral cancer cells and possibly alters the tumour microenvironment, promoting oral cancer proliferation and survival.Aim. To investigate altered virulence gene expression in E. faecalis and oral cancer cell behaviour using in vitro co-culture experiments.Methodology. Cal27 cells were co-cultured with E. faecalis and assessed for their cell proliferation, apoptosis, migration and clonogenicity using standard cell culture assays. The levels of reactive oxygen species (ROS) and inflammatory cytokines, along with proliferative, angiogenic and apoptotic biomarker expressions, were also assessed. E. faecalis adherence to cancer cells was demonstrated by the gentamicin protection assay. Real time-PCR was used to analyse the expression of virulence genes.Results. Co-culture of Cal27 cells with E. faecalis showed significantly higher cell proliferation, migration and clonogenicity compared to the control (P<0.01). A significant increase in the levels of ROS and inflammatory cytokines and overexpression of Ki67, vascular endothelial growth factor, extracellular signal-regulated kinase 1/2, phosphoinositide 3 kinase and Akt was observed in the co-culture group. E. faecalis also downregulated p53 and Bax genes while upregulated Bcl-2. The virulence genes GelE, Asa and Ace were overexpressed in E. faecalis co-cultured with Cal27 cells.Conclusion. The results from this study indicate the possible risks of E. faecalis infection in oral cancer. An effective antibiotic strategy against E. faecalis to prevent complications associated with oral diseases, including cancer, is needed.

Influence of Nanomedicine as a Smart Weapon on Multidrug Resistance in Cancer Therapy.

Cancer is the leading cause of death worldwide. The effectiveness of chemotherapy in cancer patients is still significantly hampered by Multidrug Resistance (MDR). Tumors exploit the MDR pathways to invade the host and limit the efficacy of chemotherapeutic drugs that are delivered as single drugs or combinations. Further, overexpression of ATP-binding Cassette transporter (ABC transporter) proteins augments the efflux of chemotherapeutic drugs and lowers their intracellular accumulation. Recent progress in the development of nanotechnology and nanocarrier-based drug delivery systems has shown a better perspective with respect to the improvement of cancer chemotherapy. Nanoparticles/nanomaterials are designed to target the immune system and tumor microenvironment of cancer cells for a variety of cancer treatments in order to improve bioavailability and reduce toxicity. This review elucidates the successful use of nanomaterials for cancer therapy and addressing the MDR and throws some light on the present obstacles impeding their translation to clinical use.

Clarifying new molecular subtyping and precise treatment of melanoma based on disulfidptosis-related lncRNA signature

Disulfidptosis, the newest form of programmed cell death, is closely associated with the immune microenvironment of cancer cells. Long non-coding RNA (lncRNA) has also been found to play a crucial role in melanoma. However, the role of disulfidptosis-related lncRNA in melanoma remains unclear. Through bioinformatic analysis of the transcriptional, clinical, and pathological data from the TCGA-SKCM (The Cancer Genome Atlas—Skin cutaneous melanoma) database, we established a 2-Disulfidptosis-related lncRNA (DRL) prognostic model and a novel molecular subtype for melanoma. The survival and ROC curves of the 2-DRL prognostic model demonstrated its strong efficacy in predicting the prognosis of melanoma. The high-risk group of melanoma exhibited a significant decrease in ESTIMATEScore, ImmuneScore, and StromalScore, indicative of pronounced immune suppression and exhaustion. Subgroup C2 of melanoma displayed an immune-activated state, while subgroups C1 and C3 showed immune suppression and exhaustion, potentially leading to poorer prognosis. Subgroup C1 demonstrated better sensitivity to Zoledronate, UMI-77, Nilotinib, and Cytarabine. Subgroup C2 exhibited greater sensitivity to Ribociclib, XAV939, Topotecan, and Ruxolitinib. Subgroup C3 showed higher sensitivity to VX-11e, Ulixertinib, Trametinib, and Afatinib. This study revealed the immune microenvironment status and targeted drug sensitivity in melanoma patients with different risk scores and molecular subtypes, offering valuable guidance for clinical treatment and identifying significant DRL targets for future in-depth research.

The study on 4D culture system of squamous cell carcinoma of tongue

Traditional cell culture methods often fail to accurately replicate the intricate microenvironments crucial for studying specific cell growth patterns. In our study, we developed a 4D cell culture model-a precision instrument comprising an electromagnet, a force transducer, and a cantilever bracket. The experimental setup involves placing a Petri dish above the electromagnet, where gel beads encapsulating magnetic nanoparticles and tongue cancer cells are positioned. In this model, a magnetic force is generated on the magnetic nanoparticles in the culture medium to drive the gel to move and deform when the magnet is energized, thereby exerting an external force on the cells. This setup can mimic the microenvironment of tongue squamous cell carcinoma CAL-27 cells under mechanical stress induced by tongue movements. Electron microscopy and rheological analysis were performed on the hydrogels to confirm the porosity of alginate and its favorable viscoelastic properties. Additionally, Calcein-AM/PI staining was conducted to verify the biosafety of the hydrogel culture system. It mimics the microenvironment where tongue squamous cell carcinoma CAL-27 cells are stimulated by mechanical stress during tongue movement. Electron microscopy and rheological analysis experiments were conducted on hydrogels to assess the porosity of alginate and its viscoelastic properties. Calcein-AM/PI staining was performed to evaluate the biosafety of the hydrogel culture system. We confirmed that the proliferation of CAL-27 tongue squamous cells significantly increased with increased matrix stiffness after 5 d as assessed by MTT. After 15 d of incubation, the tumor spheroid diameter of the 1%-4D group was larger than that of the hydrogel-only culture. The Transwell assay demonstrated that mechanical stress stimulation and increased matrix stiffness could enhance cell aggressiveness. Flow cytometry experiments revealed a decrease in the number of cells in the resting or growth phase (G0/G1 phase), coupled with an increase in the proportion of cells in the preparation-for-division phase (G2/M phase). RT-PCR confirmed decreased expression levels of P53 and integrinβ3 RNA in the 1%-4D group after 21 d of 4D culture, alongside significant increases in the expression levels of Kindlin-2 and integrinαv. Immunofluorescence assays confirmed that 4D culture enhances tissue oxygenation and diminishes nuclear aggregation of HIF-1α. This device mimics the microenvironment of tongue cancer cells under mechanical force and increased matrix hardness during tongue movement, faithfully reproducing cell growthin vivo, and offering a solid foundation for further research on the pathogenic matrix of tongue cancer and drug treatments.

Exploring the potential of nanoparticles as a drug delivery system for cancer therapy: A review

In this review, we discuss the use of organic nanoparticles such as liposomes, polymeric nanoparticles, dendrimers, and inorganic nanoparticles such as gold nanoparticles and mesoporous silica nanoparticles in drug delivery in chemotherapy for cancer therapy. Another strategy is the use of nanoparticle vehicles for drug delivery through the natural openings on tumor vessels called fenestrations. Both of these can be functionalized to attach angiotensin to lymphocytes or any certain part of the cancer cell membrane, microenvironment, or cytoplasmic or nuclear receptor sites, and therefore a high concentration of drug delivery to targeted cancer cells is achieved, but with less or no toxicity to normal tissue. The potential advantages evident in this technology are useful approaches to established high-concentration drug treatment of cancer tissues without harming normal cells. Some features of a nanoparticle-based drug delivery system include the durability of the vehicle, biocompatibility, permeation, and ability to target specific types of cells. Organic and inorganic nanoparticles have developed this kind of drug-carrier system. Particulate systems are also still being explored for cancer drug resistance mechanisms, and their function in immunotherapy is expanding.

Design, synthesis and application of polarity- and pH-sensitive dual-responsive small molecule fluorescent probe for early cancer diagnosis

Cancer is one of the deadliest and most complex diseases globally. It is well known that cancer cells exhibit a unique intracellular microenvironment characterized by low pH and low polarity compared to normal cells. Thus, dual-responsive fluorescent probe are more suitable for such complex and variable physiological environments than single-response probe. In this study, we designed and synthesized a dual-responsive fluorescent probe, CCT, which responds to both pH and polarity based on intramolecular charge transfer (ICT) and photoelectron transfer (PET) mechanisms.We synthesized probe CCT by combining naphthylimide, a coumarin unit, and morpholine through a six-step process. The PET mechanism between morpholine and naphthylimide renders probe CCT pH-sensitive. Additionally, the direct linkage of the polarity-sensitive units, coumarin and naphthylimide, creates a larger polarity-sensitive system. When both low pH and low polarity conditions are present, the fluorescence intensity of probe CCT is significantly higher than under separate conditions. This increased fluorescence intensity matches the low pH and low polarity microenvironment of cancer cells, facilitating bioimaging.Fluorescence imaging results demonstrate that probe CCT effectively distinguishes between cancer and normal cells, suggesting its potential as a powerful tool for early cancer diagnosis.

Quantitative atlas of collagen hydrogels reveals mesenchymal cancer cell traction adaptation to the matrix nanoarchitecture

Collagen-based hydrogels are commonly used in mechanobiology to mimic the extracellular matrix. A quantitative analysis of the influence of collagen concentration and properties on the structure and mechanics of the hydrogels is essential for tailored design adjustments for specific in vitro conditions. We combined focused ion beam scanning electron microscopy and rheology to provide a detailed quantitative atlas of the mechanical and nanoscale three-dimensional structural alterations that occur when manipulating different hydrogel's physicochemistry. Moreover, we study the effects of such alterations on the phenotype of breast cancer cells and their mechanical interactions with the extracellular matrix. Regardless of the microenvironment's pore size, porosity or mechanical properties, cancer cells are able to reach a stable mesenchymal-like morphology. Additionally, employing 3D traction force microscopy, a positive correlation between cellular tractions and ECM mechanics is observed up to a critical threshold, beyond which tractions plateau. This suggests that cancer cells in a stable mesenchymal state calibrate their mechanical interactions with the ECM to keep their migration and invasiveness capacities unaltered. Statement of significanceThe paper presents a thorough study on the mechanical microenvironment in breast cancer cells during their interaction with collagen based hydrogels of different compositions. The hydrogels’ microstructure were obtained using state-of-the-art 3D microscopy, namely focused ion beam-scanning electron microscope (FIB-SEM). FIB-SEM was originally applied in this work to reconstruct complex fibered collagen microstructures within the nanometer range, to obtain key microarchitectural parameters. The mechanical microenvironment of cells was recovered using Traction Force Microscopy (TFM). The obtained results suggest that cells calibrate tractions such that they depend on mechanical, microstructural and physicochemical characteristics of the hydrogels, hence revealing a steric hindrance. We hypothesize that cancer cells studied in this paper tune their mechanical state to keep their migration and invasiveness capacities unaltered.

Increase in GPIHBP1 expression in advanced stage colorectal cancer indicates poor immune surveillance.

Glycosylphosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) plays a crucial role in fatty acid metabolism, which is involved in the progression of colorectal cancer (CRC). The aim of this study was to determine the expressional variations of GPIHBP1 in CRC at different stages and to verify whether this protein affects the shaping of the immune microenvironment of cancer cells. Variations of GPIHBP1 messenger RNA (mRNA) levels were first analysed using The Cancer Genome Atlas (TCGA) database. Protein levels of GPIHBP1 in cancer nest cells, stromal cells or surrounding normal tissues from 68 patients with CRC were checked by immunohistochemistry. Infiltration of immune cells such as macrophages, myeloid-derived suppressor cells (MDSCs), CD8+ and CD56+ cells was parallelly stained in the same tissues. Ectopic GPIHBP1 expressed colonic tumour cells were transplanted into the back of mice. Tumour growth and immune cell infiltrations were also observed. Compared with those in healthy tissues, GPIHBP1 mRNA and protein levels decreased in the patients with CRC at Dukes A-B stage but gradually increased in the patients at Dukes C-D stage. GPIHBP1 in foci or stroma was positively correlated with recruited macrophages or MDSCs and negatively correlated with recruited CD8+, CD56+ or granzyme+ cells. The mice injected with GPIHBP1 overexpression cells bore large tumours. Histological analysis confirmed the infiltration of many macrophages and MDSCs but less CD8+ T or CD56+ cells. The increased expression of GPIHBP1 is involved in the progression of CRC. High GPIHBP1 level of advanced CRC indicates efficient immune evasion in tumour microenvironment.

CDK4/6 inhibition enhances T-cell immunotherapy on hepatocellular carcinoma cells by rejuvenating immunogenicity

Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC.Graphical abstract

Impact of iron oxide alginate berbamine nanocomposites on the pre-metastatic microenvironment of human bladder cancer cells through ROS-mediated mitochondrial depolarization

The main objective of the current study was to synthesize, characterize, and application of an anticancer agent based on iron oxide nanoparticles (NPs) synthesized in the presence of berbamine and alginate to modulate the pre-metastatic ecological niche of human bladder cancer cells by inducing ROS-mediated mitochondrial depolarization. The environmentally friendly synthesized nanoparticles were analyzed using SEM and TEM imaging, VSM, XRD, DLS, Zeta sizing, photoluminescence, EDX, and UV–Vis spectroscopy techniques. The findings indicated that the nanoparticles were smaller than 100 nm, displayed consistent spherical morphology, and were evenly monodispersed in size. We observed that the hydrodynamic size of the synthesized NPs was around 247.8 nm and the zeta potential was −32.1 mV. EDX analysis showed that the fabricated NPs composed of Iron (70.9 % of Mass) and O (29.1 % of Mass). The XRD analysis showed that the pattern of the NPs is matched with JCPDS card number 82–1533. The VSM analysis revealed that the NPs displayed superparamagnetic properties when exposed to a magnetic field. Results from the anticancer investigations demonstrated that the NPs caused a dose and time-dependent lethal impact on T24 cells, while showing no significant toxicity on SV-HUC-1 cells, highlighting their biocompatibility. The anticancer mechanism was evaluated using acridine orange/ethidium bromide, DCFH-DA, JC-1 staining, and wound-healing/scratch assay. The results demonstrated that the cells underwent apoptosis instead of necrosis, attributed to ROS-triggered mitochondrial depolarization. Additionally, the nanoparticles inhibited the cells' migratory capabilities. These results suggest that the environmentally friendly produced iron nanoparticles have promising potential as a strong anticancer treatment.

Targeted pH-responsive delivery of rosmarinic acid via phenylboronic acid functionalized mesoporous silica nanoparticles for liver and lung cancer therapy

Currently, chemotherapy is one of the most practiced approaches for the treatment of cancers. However, existing chemotherapeutic drugs have poor aqueous solubility, poor selectivity, higher systematic toxicity, and poor target accumulation. In this study, we designed and synthesized a boronic acid/ester-based pH-responsive nano-valve that specifically targets the microenvironment in cancer cells. The nano-valve comprises phenylboronic acid-coated mesoporous silica nanoparticles (B-MSN) loaded with polyphenolic compound Rosmarinic acid (ROS-B-MSN). The nano-valve was further coated with lignin (LIG) to achieve our desired LIG-ROS-BMSN nano-valve for targeted chemotherapy against Hep-G2 and NCI-H460 cell lines. The structure and properties of NPs were characterized by Fourier-transformed infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM) in combination with EDX, and Dynamic light scattering (DLS). The outcomes revealed that the designed LIG-ROS-BMSN were in the nanorange (144.1 ± 0.70 nm), had negative Zeta potential (-15.7 ± 0.46 mV) and had a nearly spherical morphology. In vitro, drug release investigations showed a controlled pH-dependent release profile under mild acidic conditions that could enhance the targeted chemotherapeutic response against cancer in mild acidic environments. The obtained LIG-ROS-BMSN nano valve achieved significantly lower IC50 values of (1.70 ± 0.01 μg/mL and 3.25 ± 0.14 μg/mL) against Hep-G2 and NCI-H460 cell lines as compared to ROS alone, which was (14.0 ± 0.7 μg/mL and 29.10 ± 0.25 μg/mL), respectively. The cellular morphology before and after treatment was further confirmed via inverted microscopy. The outcomes of the current study imply that our designed LIG-ROS-BMSN nanovalve is a potential carrier for cancer chemotherapeutics.

Propolis polyphenol nanosheet for synergistic cancer chemo-photothermal therapy

Two-dimensional (2D) carbon-based nanostructures hold great promise as near-infrared (NIR) photothermal materials, yet their widespread use has been hindered by labor-intensive and costly fabrication processes. Here, a novel, cost-effective approach is presented to produce photothermal materials derived from the polyphenolic fraction of propolis (PFP) for the first time. The method involves the pyrolysis of PFP under a neutral atmosphere, resulting in the formation of 2D PFP-based nanosheets (PFPNS) measuring 50–100 nm in size with efficient photothermal properties. Then, a layer-by-layer nanohybrid structure comprising PFPNS, polydopamine (PDA), mesoporous silica (MS), and polyethyleneimine (PEI) layers (PFPNS@PDA@MS-PEI) was designed as a versatile platform for drug delivery. Specifically, the anticancer drug doxorubicin (DOX) was loaded onto the nanohybrid (PFPNS@PDA@MS(DOX)-PEI) for targeted delivery to cancerous cells. Each layer of the nanohybrid serves a distinct purpose, enhancing functionality and efficacy. The NIR-responsive PFPNS@PDA component facilitates accelerated drug release and induces hyperthermic effects on cancer cells upon NIR irradiation. The MS structure enables high drug loading capacity (approximately 83.3%), while the pH-responsive PEI layer promotes cellular uptake and facilitates drug release within the acidic microenvironment of cancer cells. Combining NIR irradiation with chemotherapy results in a synergistic effect, leading to the eradication of 67% of MCF-7 breast cancer cells. The demonstrated efficacy, coupled with the non-toxic nature of the nanohybrid, positions it as a promising candidate for synergistic chemo-photothermal therapy of tumor tissues.

LncRNAs in Immune and Stromal Cells Remodel Phenotype of Cancer Cell and Tumor Microenvironment.

Emerging studies suggest that long non-coding RNAs (lncRNAs) participate in the mutual regulation of cells in tumor microenvironment, thereby affecting the anti-tumor immune activity of immune cells. Additionally, the intracellular pathways mediated by lncRNAs can affect the expression of immune checkpoints or change the cell functions, including cytokines secretion, of immune and stromal cells in tumor microenvironment, which further influences cancer patients' prognosis and treatment response. With the in-depth research, lncRNAs have shown great potency as a new immunotherapy target and predict immunotherapy response. The research on lncRNAs provides us with a new insight into developing new immunotherapy drugs and predicting the outcome of immunotherapy. With development of RNA sequencing technology, amounts of lncRNAs were found to be dysregulated in immune and stromal cells rather than tumor cells. These lncRNAs function through ceRNA network or regulating transcript factor activity, thus leading abnormal differentiation and activation of immune and stromal cells. Here, we review the function of lncRNAs in the immune microenvironment and focus on the alteration of lncRNAs in immune and stromal cells, and discuss how these alterations affect tumor growth, metastasis and treatment response.