Tumor Research Articles

A Sustained H2/Fluorouracil-Releasing Suppository for High-efficacy and Low-Toxicity Hydrogenochemotherapy of Colon Cancer.

To attenuate the intestinal toxicity of chemotherapeutic drugs from rectal suppositories and enhance their chemotherapeutic outcome is greatly significant, but maintains a challenge. In this work, a new strategy of local synergistic hydrogenochemotherapy is proposed to attenuate side effects and enhance therapeutic efficacy based on the anti-cancer selectivity and normal cells-protecting effect of H2, and construct a novel anti-cancer formulation of rectal suppository (5-FU/CSN@FAG) by fatty acid glycerides (FAG) encapsulating 5-fluorouracil (5-FU, a first-line drug for colorectal cancer treatment) and cerium silicide nanoparticles (CSN) with a sustained hydrolytic H2 release behavior which is synchronous with 5-FU release. The 3-week treatment with the suppository once a day can not only completely eradicate colon tumors without tumor recurrence after suppository administration withdrawal, but also efficiently protect the intestinal tract from chemotherapeutic damage. Mechanistically, H2 generated by CSN reduces the toxicity of 5-FU to normal cells in the intestinal tract by scavenging over-expressed reactive oxygen species and correcting energy metabolism, and also assists 5-FU to promote the apoptosis of colon tumor cells by inhibiting their respiration through a CO signaling pathway. High biosafety and therapeutic validity endow the developed suppository with a high potential for clinical translation.

A Novel 167-Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKBα Ubiquitination.

Intrahepatic cholangiocarcinoma (ICC), a formidable challenge in oncology, demands innovative biomarkers and therapeutic targets. This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6-167aa in ICC. CircPCSK6 is significantly downregulated in both ICC patients and mouse primary ICC models, and its lower expression is linked to adverse prognosis, highlighting its pivotal role in ICC pathogenesis. Functionally, this study elucidates the regulatory effect of circPCSK6-167aa on IκBα ubiquitination within the NF-κB pathway, which is mediated by its competitive binding to the E3 ligase RBBP6. This complex interaction leads to reduced activation of the NF-κB pathway, thereby curbing tumor cell proliferation, migration, invasion, stemness, and hepatic-lung metastasis in vivo. This groundbreaking discovery expands the understanding of circRNA-driven tumorigenesis through atypical signaling pathways. Additionally, this investigation identified EIF4A3 as a detrimental regulator of circPCSK6, exacerbating ICC malignancy. Importantly, by leveraging patient-derived xenograft (PDX), organoids, and organoid-derived PDX models, higher levels of circPCSK6-167aa enhance sensitivity to gemcitabine, indicating its potential to improve the effectiveness of chemotherapy. These insights emphasize the therapeutic promise of targeting circPCSK6-167aa, offering vital biological insights and clinical directions for developing cutting-edge therapeutic approaches, thus revealing innovative strategies and targets for future treatments.

Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies.

Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood-brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound 1, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound 1 induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound 1 also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound 1, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.

Artificial Intelligence (AI) and Liquid Biopsy Transforming Early Detection of Liver Metastases in Gastrointestinal Cancers.

Liver metastases from Gastrointestinal (GI) cancers present significant challenges in oncology, often signaling poor prognosis. Traditional detection methods like imaging and tissue biopsies have limitations in sensitivity, specificity, and tumor heterogeneity represen-tation. The advent of artificial intelligence (AI) in healthcare, driven by advancements in ma-chine learning, algorithms, and data science, offers a promising frontier for early detection and management of liver metastases. This review explores the integration of AI and liquid biopsy technologies as transformative tools in the proactive detection of liver metastases aris-ing from GI malignancies. Liquid biopsy, a non-invasive method, analyzes circulating tumor cells (CTCs), cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA) in bodily fluids. It provides a compre-hensive overview of tumor heterogeneity and enables real-time monitoring of tumor evolu-tion and treatment response. Despite its advantages, liquid biopsy faces challenges such as low sensitivity for early-stage metastases, reduced detectability due to liver filtration, and technical limitations. AI enhances the potential of liquid biopsies by improving diagnostic accuracy through ad-vanced algorithms like Convolutional Neural Networks (CNNs) and Natural Language Pro-cessing (NLP). These AI models analyze complex biomedical data, offering higher sensitivity and specificity in cancer detection. The synergy between AI and liquid biopsies promises early detection, better disease monitoring, and personalized treatment strategies. This review underscores the significant advancements AI and liquid biopsy technologies bring to oncological precision medicine, particularly in improving overall survival (OS) and disease-free survival (DFS) for patients with GI cancer metastases. As we transition into the era of precision medicine, the integration of these technologies holds the potential to redefine cancer care and patient management.

Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression.

Glioblastoma (GBM) is an aggressive form of brain cancer that is highly resistant to therapy due to significant intra-tumoral heterogeneity. The lack of robust in vitro models to study early tumor progression has hindered the development of effective therapies. Here, this study develops engineered GBM organoids (eGBOs) harboring GBM subtype-specific oncogenic mutations to investigate the underlying transcriptional regulation of tumor progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon xenotransplantation into immunodeficient mice, eGBOs form tumors that recapitulate the transcriptional and spatial landscape of human GBM samples. Integrative single-cell trajectory analysis of both eGBO-derived tumor cells and patient GBM samples reveal the dynamic gene expression changes in developmental cell states underlying tumor progression. This analysis of eGBOs provides an important validation of engineered cancer organoid models and demonstrates their utility as a model of GBM tumorigenesis for future preclinical development of therapeutics.

Resolution of oncogene-induced senescence markers in HPV-infected cervical cancer tissue

BackgroundOncogene-Induced Senescence (OIS) is a form of senescence that occurs as a consequence of oncogenic overstimulation and possibly infection by oncogenic viruses. Whether senescence plays a role in the pathogenesis of cervical cancer (CC) is not well understood. Moreover, whether cervical epithelial cells that are part of the premalignant cervical intraepithelial neoplasia (CIN), exhibit markers of OIS in Human Papillomavirus (HPV)-infected tissue, has not been investigated.MethodsWe utilized a set of patient-derived premalignant and malignant tissue samples to investigate the protein (Ki67 and Lamin B1) and gene (TP53, IL1A, CCL2, and MMP9) expression of several OIS-associated biomarkers using immunohistochemistry (IHC) and qRT-PCR, respectively. Furthermore, we characterized the HPV status of all tissue samples.ResultsMost of the CC samples (34/37) were positive for HPV, mainly HPV-16 which was observed in 62.2% of the CC samples. Among CINs, HPV infection was found in 60.2% of the 32 samples with HPV-16 as the dominant genotype in 58.5% of the CINs. IHC analysis revealed a significant increase in the expression levels of both Ki67 and Lamin B1 proteins in CC tissue compared to CIN. On average, 93% of tumor cells were positive for Ki67 in comparison to only 25% of premalignant cells in CIN samples. Similarly, Lamin B1 expression was observed in 89% of tumor cells in malignant tissue on average, compared to 60% in CIN samples. Importantly, Lamin B1 expression was elevated in nonmalignant cervical tissue suggesting that its downregulation is more predominant in the premalignant state. Furthermore, RT-PCR revealed a significant decrease in the expression of TP53, IL1a, CCL2, and MMP9 markers in CC samples compared to CINs. Specifically, 84% of CC samples showed reduced TP53 expression, 90% showed reduced IL1a expression, 74% showed reduced CCL2 expression, and 76% showed reduced MMP9 expression when compared with their premalignant baseline. Infection of HPV was confirmed in 61% of the tumor tissues while only 25% of the CINs were positive for HPV.ConclusionThis work shall provide an opportunity to further examine the role of OIS in the process of HPV-driven CC development.

Microneedle patch-involved local therapy synergized with immune checkpoint inhibitor for pre- and post-operative cancer treatment.

The metastasis and recurrence of cancer post-surgery remain the major reasons for treatment failures. Herein, a photo-immune nanoparticle decorating with M1 macrophage membrane (BD@LM) is designed based on the inflammatory environment after surgical resection. By loading photosensitizer black phosphorus quantum dots (BPQDs) and chemotherapeutics doxorubicin (DOX) in BD@LM nanoparticles, an effective chemophototherapy-mediated immunogenic cell death of tumor cells is triggered, subsequently leading to the maturation of dendritic cells for further immune cascade. Moreover, by accommodating BD@LM in a dissolvable microneedle patch, the skin barrier is directly broken for efficacious delivery of BD@LM into solid tumors, which boosts the effectiveness of aPD-L1-based checkpoint blockade therapy. Consequently, the growth of both orthotopic and post-surgical breast tumor and melanoma is significantly inhibited. Specifically, an effective T cell activation accompanied with dramatic inhibition of immunosuppressive cells is observed. Meanwhile, the proportion of memory T cells remarkably grows after proposed treatment, indicating the establishment of a long-term immune memory effect for prevention of second tumor attack. Altogether, this work offers a meaningful strategy by combining photo-immune-inspired nanoparticles with microneedle patches for boosting aPD-L1-based tumor immunotherapy.

En bloc resection of large bladder tumor: is it feasible and reasonable?

Transurethral resection of bladder tumor (TURBT) remains the basis of bladder tumor diagnosis and an effective means of treating nonmuscle invasive bladder cancer (NMIBC). There are several limitations to this procedure: TURBT may cause free floating of malignant cells in the bladder and as a result re-implantation and early recurrence. Also, it does not allow the pathologist to define the correct spatial orientation of the specimen. The development of en bloc resection of bladder tumor (ERBT) has helped overcome the abovementioned key disadvantages of TURBT. However, many urologists doubt whether this approach is feasible for treating larger tumors. In this review, it is shown that ERBT of large bladder tumor (>3 cm) is in fact a feasible and well tolerated method. Although there is a lack of comparative data proving its advantages over TURBT, en bloc in large tumor seems to result in better local cancer control (due to higher prevalence of detrusor specimen, lower need for re-TURBT), lower rate of relapse outside the resection area (due to lower risk of tumor cells circulation), and higher quality of pathology specimen. Despite the skepticism of some surgeons, potential difficulties caused by larger tumor size may be overcome easily, and most agree that tumor size should not limit the implementation of the method in their daily practice.

Bone-Induced Her2 Promotes Secondary Metastasis in HR+/Her2- Breast Cancer.

Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2-expressing (Her2E) circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2- status and employ preclinical models of bone metastasis (BM) to validate the role of Her2E CTCs in multi-organ metastases. While Her2 expression was higher in patients with bone metastasis, experimental analyses revealed that Her2E CTCs derived from bone lesions were more dependent on Her2 activity and more susceptible to anti-Her2 therapy. Targeting the bone-mediated Her2 induction reduces CTC detection and abrogates secondary metastasis from bone. Overall, we elucidate that Her2E CTCs can serve as a non-invasive biomarker for BM formation with high therapeutic benefit for HR+ MBC patients.

Informatics strategies for early detection and risk mitigation in pancreatic cancer patients.

This review provides a comprehensive overview of the current landscape in pancreatic cancer (PC) screening, diagnosis, and early detection. This emphasizes the need for targeted screening in high-risk groups, particularly those with familial predispositions and genetic mutations, such as BRCA1, BRCA2, and PALB2. This review highlights the sporadic nature of most PC cases and significant risk factors, including smoking, alcohol consumption, obesity, and diabetes. Advanced imaging techniques, such as Endoscopic Ultrasound (EUS) and Contrast-Enhanced Harmonic Imaging (CEH-EUS), have been discussed for their superior sensitivity in early detection. This review also explores the potential of novel biomarkers, including those found in body fluids, such as serum, plasma, urine, and bile, as well as the emerging role of liquid biopsy technologies in analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes. AI-driven approaches, such as those employed in Project Felix and CancerSEEK, have been highlighted for their potential to enhance early detection through deep learning and biomarker discovery. This review underscores the importance of universal genetic testing and the integration of AI with traditional diagnostic methods to improve outcomes in high-risk individuals. Additionally, this review points to future directions in PC diagnostics, including next-generation imaging, molecular biomarkers, and personalized medicine, aiming to overcome current diagnostic challenges and improve survival rates. Ultimately, the review advocates the adoption of informatics and AI-driven strategies to enhance early detection, reduce morbidity, and save lives in the fight against pancreatic cancer.

TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors

This study suggests a modified model of TNFR1-induced complex I-mediated NFκB signaling. Evaluation of a panel of five tumor cell lines (HCT116-PIK3CAmut, SK-MEL-23, HeLa-RIPK3, HT29, D10) with TRAF2 knockout revealed in two cell lines (HT29, HeLa-RIPK3) a sensitizing effect for death receptor-induced necroptosis and in one cell line (D10) a mild sensitization for TNFR1-induced apoptosis. TRAF2 deficiency inhibited death receptor-induced classical NFκB-mediated production of IL-8 only in a subset of cell lines and only partly. TRAF5, furthermore, failed to improve DR-induced NFκB signaling in HCT116-PIK3CAmut and HCT116-PIK3CAmut-TRAF2KO cells. These findings argue for a non-obligatory role of TRAF2 in death receptor-induced classical NFκB signaling. Similar as in TRAF2-deficient cells, TNF- and CD95L-induced NFκB signaling was found to be only poorly affected in RIPK1KO cells and in cells treated with the RIPK1-specific PROTAC LD4172. Intriguingly, however, death receptor-induced NFκB signaling was completely inhibited in HCT116-PIK3CAmut cells double deficient for TRAF2 and RIPK1 and in TRAF2-deficient cells treated with LD4172. Moreover, with exception of recruitment of TRADD, acting upstream to TRAF2 and parallel to RIPK1, TNFR1 signaling complex formation was abrogated in TRAF2-RIPK1 DKO cells. Based on our findings, two distinguishable types of TNFR1-interacting complexes promote TNF-induced NFκB signaling: First, a TRADD-TRAF2/cIAP utilizing complex Ia which becomes evident in RIPK1-deficient cells. Second, a non-modified RIPK1 utilizing complex Ib which acts in TRADD- or TRAF2-deficient cells. Complex Ia and Ib may furthermore interact and cooperate to ubiquitinate RIPK1 resulting in a modified complex Ia/b preventing complex Ia and Ib to convert to the established TNFR1-induced cytotoxic complexes IIa and IIb.

MARVELD1 Promotes the Invasiveness in Pancreatic Adenocarcinoma through the Activation of Epithelial-to-Mesenchymal Transition.

MARVEL domain-containing 1 (MARVELD1) has been implicated in the progression of several cancers, but its role in pancreatic adenocarcinoma (PAAD) remains poorly understood. RNA-seq data from the TCGA-PAAD and GTEx-Pancreas cohorts were analyzed to assess MARVELD1 expression. Stable MARVELD1 knockdown and overexpression were conducted in BxPC3 and PANC-1 cells. Cell viability, proliferation, migration, and invasion were evaluated using functional assays, and western blotting was employed to examine EMT-associated protein levels, including Vimentin, MMP2, MMP9, and E-cadherin. Differentially expressed genes (DEGs) between MARVELD1-high and MARVELD1-low groups were identified, and pathway enrichment analyses were performed. We observed a significant increase of MARVELD1 in PAAD patient samples, with elevated MARVELD1 levels correlating with poor clinical survival. Knockdown of MARVELD1 in PAAD cells remarkably decreased cell proliferation and colony formation, while overexpression of MARVELD1 enhanced these properties. Moreover, simulated cell invasion and migration assay further suggested that MARVELD1 might contribute to PAAD cell aggressiveness. Mechanistically, MARVELD1 promoted tumor cell migration and invasion through the activation of Vimentin, MMP2, and MMP9 protein while suppressing E-cadherin. Bioinformatics analysis revealed that MARVELD1-high samples were enriched in EMT-related pathways, including TGF-β receptor signaling, actin cytoskeleton regulation, and cell adhesion. Taken together, our study highlights the roles of MARVELD1 in promoting tumor cell proliferation and invasion, suggesting its potential application as a prognostic and diagnostic biomarker for PAAD in the clinical context.

Combination of adenosine blockade and ferroptosis for photo-immunotherapy of triple negative breast cancer with aptamer-modified copper sulfide.

Combination of immunotherapy and photothermal therapy (PTT) provides a promising therapeutic performance for tumors. However, it still faces negative feedback from suppressive factors such as adenosine. Herein, we developed a new nanodrug that can combine adenosine blockade and ferroptosis to promote the photoimmunotherapy of triple negative breast cancer (TNBC). The nanodrug, named CuS-PEG@Apt, was constructed via the modification of copper sulfide (CuS) nanoparticles with adenosine aptamer and PEG. CuS-PEG@Apt could be effectively enriched in the tumor site and locally generate a strong photothermal effect, directly ablating tumors and inducing immunogenic death (ICD). On the other hand, the aptamers could block the adenosine pathway to inhibit the immune suppression by adenosine, which further promoted the anti-tumor immunity. Moreover, the CuS nanoparticles could consume GSH and inhibit GPX4 to cause the ferroptosis of tumor cells. Collectively, CuS-PEG@Apt achieved potent efficacy of tumor suppression via the combination of PTT, immune activation and ferroptosis, representing an appealing platform for TNBC treatment.

Inhibition of PDT-induced PGE2 surge for enhanced photo-immunotherapy.

Nowadays, photodynamic therapy (PDT) offers a non-invasive tumor treatment with high safety profiles and minimal side effects, implying a promising clinical application for patients with malignant tumors. However, the lack of efficacy in metastasis and recurrence still notably limits its application. To solve this problem, one promising strategy is to improve the immune response activated by PDT. Unfortunately, tumor cells derived PGE2 could create immunosuppressive microenvironments and impair the function of multiple immune cells, leading to a failure of immune system activation. Moreover, our research revealed the up-regulation of Ptgs2 in tumor cells after the PDT process, which is associated with a series of pro-tumor effects, including proliferation, invasion, metastasis, apoptotic resistance, and immune evasion. Consequently, controlling the PGE2 surge induced by PDT is crucial for optimizing the efficacy of photo-immunotherapy. Therefore, we combined the regulation of the COX2-PGE2 axis with PDT. The addition of COX inhibitors (COX-Is) could improve the efficiency of PDT, reduce the immunosuppressive effect of PGE2, and help dying tumor cells activate the immune system. Herein, a tumor-targeted nano-delivery platform (FI@T-Lipo) was developed using advanced microfluidic technology. FI@T-Lipo based PDT showed a systemic therapeutic effect in triple negative breast cancer through reclaiming the anti-tumor effect of the immune system under COX2-PGE2 blockage. In a word, we developed an in-situ tumor vaccination strategy based on COX-Is enhanced PDT, which could alleviate intra-tumoral immune suppression and boost immune system activation. Our study offers a promising modality for advancing clinical treatment strategies for metastatic malignant tumors.

The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells.

Chimeric antigen receptor (CAR) T cells have encouraging results in the treatment of hematological malignancies. However, CAR-T therapy still faces numerous challenges against solid tumors, such as hepatocellular carcinoma (HCC), owing to heterogeneous antigen expression in tumor cells, limited persistence of CAR-T cells, etc. Therefore, to treat HCC more effectively, we connected the molecular receptor NKBB to a second-generation glypican-3 (GPC3) CAR to construct GC3328z-NKBB CAR-T cells, which have double specific targets of GPC3 and NKG2DLs (natural killer group 2, member D ligands), dual co-stimulation of CD28 and 41BB, and a single CD3ζ chain. Our study showed that the molecular receptor NKBB conferred GPC3 CAR-T cells with enhanced migration and infiltration abilities towards HCC, higher central memory T (TCM) cell proportion and proliferation capacity, and reduced exhaustion level. GC3328z-NKBB CAR-T cells exhibited improved cytotoxicity against HCC cells and prolonged persistence. The cathepsin L/interleukin-17 (CTSL/IL-17) axis contributed to the superior anti-HCC activity of GC3328z-NKBB CAR-T cells. Overall, the molecular receptor NKBB significantly increased the persistence of GPC3 CAR-T cells, and GC3328z-NKBB CAR-T cells possessed potent anti-HCC activity in mice, providing a new strategy for the potential improvement of adoptive T cell therapy in the treatment of HCC.

Effect of perioperative analgesia on immunity in lung cancer.

COX inhibitors are frequently used for pain management during the perioperative period and may influence tumor progression and the tumor microenvironment by modulating inflammation and immune responses. This study investigates the effects of COX inhibitors on tumor growth and the immune microenvironment. In vivo experiments demonstrate that COX inhibitors can reduce tumor cell growth, elevate PD-L1 expression on tumor cells, and enhance the proportion of myeloid cells within the tumor immune microenvironment. Furthermore, COX inhibitors are found to improve the efficacy of the immune checkpoint inhibitor anti-PD-L1. These results underscore the influence of perioperative COX inhibitors on tumor immunity and suggest potential new strategies for optimizing tumor immunotherapy.

CRISPR knock-in of a chimeric antigen receptor into GAPDH 3'UTR locus generates potent B7H3-specific NK-92MI cells.

CAR-NK therapy is becoming a promising approach to treat solid tumors. However, the random insertion of the CAR gene and inflexible CAR expression caused by common preparation methods significantly impact its efficacy and safety. Here we successfully established a novel type of CAR-NK cells by integrating CAR sequences into the GAPDH 3'UTR locus of NK-92MI cells (CRISPR-CAR-NK), achieving site-specific integration of the CAR gene and allowing endogenous regulatory components to govern CAR expression. CRISPR-CAR-NK cells had comparable growth capacity but displayed superior anti-tumor activity compared with their lentiviral counterparts. They activated and degranulated more effectively when co-cultured with tumor cells, due to increased expression of activating receptors and decreased expression of inhibitory molecules. They also enhanced the production of Granzyme B and IFN-γ, and more effectively triggered the IFN-γ pathway. Moreover, CRISPR-CAR-NK cells demonstrated distinct properties from conventional CAR-NK concerning metabolic features and signal dependence. Notably, CRISPR-CAR-NK cells exhibited lower metabolic levels without compromising antitumor activity, and their function was less reliant on the PI3K-AKT pathway, implying that the CRISPR-CAR-NK cells have significant potential for enhanced synergy with AKT inhibitors and adaptation to nutrient stress within the tumor microenvironment. These findings provide a novel potential strategy for cancer immunotherapy and an experimental foundation and paradigm for optimizing CAR-NK cells utilizing CRISPR technology, highlighting the potential of CRISPR to advance immunotherapies.

Impact of Hyaluronic Acid on the Cutaneous T-Cell Lymphoma Microenvironment: A Novel Anti-Tumor Mechanism of Bexarotene.

Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin's lymphoma that primarily affects the skin, rich in hyaluronic acid (HA). HA is a component of the extracellular matrix in the dermis and likely affects the development of CTCL, but the mechanism is poorly understood. Here we show that low-molecular-weight HA (LMWHA) possibly exacerbates CTCL, and bexarotene, already used in CTCL treatment, decreases HA production. We conducted immunohistochemistry, qRT-PCR, immunoblotting, and HA quantification using both mouse and human specimens to evaluate the impact of HA on CTCL. Additionally, we assessed the effect of bexarotene, which is already used for CTCL treatment, on HA metabolism. HA expression was higher in patients' serum and skin sections than in healthy controls. HA extracted from the skin of mice inoculated with tumors showed an increase in LMWHA. LMWHA increased lymphoma cell proliferation in vitro and accelerated tumor formation in mice in vivo. LMWHA also created a favorable environment for tumor cells by affecting fibroblasts, vascular endothelial cells, and tumor-associated macrophages. Thus, increased levels of HA, mainly LMWHA, exacerbate CTCL progression by affecting tumor cells and their microenvironment. Bexarotene treatment reduced the amount of total HA in murine tumor-inoculated skin, as well as the supernatant of cultured normal human dermal fibroblasts (NHDFs) and HuT78 cells. Detailed in vitro analyses showed that bexarotene treatment decreased HA synthase (HAS)1 and HAS2 expression in NHDFs and HAS1 and HAS3, and CEMIP expression in HuT78 cells. Chromatin immunoprecipitation assays revealed that bexarotene reduced retinoid X receptor-α binding to the HAS1 and HAS2 promoters in NHDFs. Bexarotene potentially exerts its anti-tumor effect by reducing HA levels through decreased expression of HAS. These findings provide new insights into the process of CTCL development and additional insights regarding bexarotene treatment.

AXL promotes malignant phenotypes in tumor cells and might be a potential antitumor target of natural products

AXL promotes malignant phenotypes in tumor cells and might be a potential antitumor target of natural products

Hyaluronic acid-conjugated lipid nanocarriers in advancing cancer therapy: A review.

Lipid nanoparticles are obtaining significant attention in cancer treatment because of their efficacy at delivering drugs and reducing side effects. These things are like a flexible platform for getting anticancer drugs to the tumor site, especially upon HA modification, a polymer that is known to target tumors overexpressing CD44. HA is promising in cancer therapy because it taregtes tumor cells by binding onto CD44 receptors, which are often upregulated in cancer cells. Lipid nanoparticles are not only beneficial in improving solubility and stability of drugs; they also use the EPR effect, meaning they accumulate more in tumor tissue than in healthy tissue. Adding HA to these nanoparticles expands their biocompatibility and makes them more accurate and specific towards tumor cells. Studies show that HA-modified nanoparticles carrying drugs such as paclitaxel or doxorubicin improve how well cells absorb the drugs, reduce drug resistance, and make tumor shrinking. These nanoparticles can respond to tumor microenvironment stimuli in targeted delivery. This targeted delivery diminishes side effects and improves anti-cancer activity of drugs. Thus, lipid-based nanoparticles conjugated with HA are a promising way to treat cancer by delivering drugs effectively, minimizing side effects, and giving us better therapeutic results.