Advancing biliary tract malignancy treatment: emerging frontiers in cell-based therapies

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 12, 2025

Biliary tract malignancies, including intrahepatic cholangiocarcinoma, extrahepatic and gallbladder cancer, represent a group of aggressive cancers with poor prognosis due to late-stage diagnosis, limited treatment options, resistance conventional therapies like chemotherapy radiotherapy. These challenges emphasize the urgent need for innovative therapeutic approaches. In recent years, cell-based have emerged as promising avenue, offering potential solutions through immune modulation, genetic engineering, targeted intervention in tumor microenvironment. This Mini-review provides an overview current advancements biliary encompassing strategies such CAR-T cells, NK dendritic cell vaccines, tumor-infiltrating lymphocytes. We also examine overcome immunosuppressive microenvironment discuss integration into multimodal regimens. By synthesizing preclinical clinical findings, this review highlights key insights future directions, aiming assist researchers clinicians translating these approaches effective treatments. The transformative discussed here makes valuable resource advancing malignancy research applications.

Language: Английский

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CDK4/6 inhibitors upregulate cIAP1/2, and Smac mimetic LCL161 enhances their antitumor effects in cholangiocarcinoma cells

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 25, 2025

Cholangiocarcinoma (CCA) is a highly aggressive bile duct cancer with poor prognosis and high mortality rates, primarily due to the lack of early diagnosis effective treatments. We have shown that cyclin D CDK4/6, key regulators cell cycle progression, are expressed in CCA patients. Moreover, levels D, CDK4, CDK6 associated shorter survival patients, suggesting CDK4/6 might be potential targets for therapy. However, we demonstrated inhibitor palbociclib monotherapy less cells. identified Cellular Inhibitor Apoptosis Proteins 1 2 (cIAP1/2), NF-κB target genes their expression as response. showed palbociclib, inhibitor, increases phosphorylated p65 its nuclear translocation, resulting cIAP1/2 upregulation Therefore, hypothesized combination antagonist enhance Interestingly, combined treatment Smac mimetic LCL161, antagonist, synergistically inhibits proliferation induces death both 2D monolayer 3D spheroid cultures. further this has effect on non-tumor cholangiocytes human peripheral blood mononuclear cells (PBMCs). Our findings demonstrate first time mimetics inhibitors promising novel targeted therapy

Language: Английский

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Frequent EPHA2 receptor mutations in cholangiocarcinoma disrupt receptor forward signaling supporting a tumor suppressor role

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

ABSTRACT EPHA2 is a receptor tyrosine kinase highly expressed in many cancers. By analyzing cancer patient databases for mutations the coding sequence, we found that cholangiocarcinoma (a hepatobiliary with dismal prognosis) exhibits uniquely high incidence of mutations. To deUine functional signiUicance these mutations, generated representative mutants and monitored major autophosphorylation sites as indicative activity-dependent signal transduction (known forward signaling). We missense ligand-binding domain abrogate ligand binding ligand-induced phosphorylation, while most activity. detected less pronounced effects other domains, which vary depending on phosphosite, suggesting might differentially affect (or bias) different downstream signaling pathways. Other introduce early stop codons encode truncated forms lacking all or part domain. also an secreted form, transmembrane full-length inactive mutant can inhibit phosphorylation co-expressed wild-type. Taken together, data suggest interfering facilitate development. indeed obtained evidence mutant, but not wild-type, induce proliferative masses consistent well differentiated validated mouse model cholangiocarcinogenesis. our Uindings driver gene its has tumor suppressor

Language: Английский

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Combined Therapy Targeting MET and Pro-HGF Activation Shows Significant Therapeutic Effect Against Liver Metastasis of CRPC

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2308 - 2308

Published: March 5, 2025

The liver is the most lethal metastatic site in castration-resistant prostate cancer (CRPC). Overexpression of MET protein has been reported CRPC, and an important driver gene androgen-independent CRPC cells. Mouse cell line CRTC2 was established by subcutaneous injection hormone-sensitive PC cells (TRAMP-C2) castrated nude mice. CRCT2/luc2 were injected into spleen mice, metastasis confirmed at 2 weeks post-injection. We administered inhibitor (MET-I) HGF activator (HGFA-I) to this model assessed therapeutic effect. After intrasplenic injection, showed a higher incidence whereas no observed TRAMP-C2. Microarray analysis revealed increased expression HGF, MET, HPN, HGFAC (encoding activating proteases) metastasis. Proliferation CRCT2 significantly inhibited co-administration MET-I HGFA-I vitro with HGF-enriched condition. In mouse model, combination-therapy group strongest reduction for Immunohistochemical staining also decrease phosphorylation group. Co-culture HGF-expressed fibroblasts attenuation inhibitory effect MET-I; however, additional overcame resistance. line, CRTC2, Significant combined treatment vivo analysis. results suggested importance both MET- HGF-targeting agents conditions including

Language: Английский

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Tumor-derived exosomal LINC01812 induces M2 macrophage polarization to promote perineural invasion in cholangiocarcinoma

Cancer Letters, Journal Year: 2025, Volume and Issue: 617, P. 217596 - 217596

Published: March 12, 2025

M2 macrophages play a critical role in the tumor microenvironment of invasive solid tumors. They are closely associated with perineural invasion (PNI) and often linked to poor prognosis. In this context, tumor-derived exosomes serve as important mediators intercellular communication. However, relationship between cell-induced PNI cholangiocarcinoma remains unexplored. study, we utilized multiplex immunofluorescence transcriptomic sequencing demonstrate upregulation LINC01812 tissues its positive correlation macrophage infiltration. Exosomal lncRNA sequencing, exosome uptake experiments, RNA pull-down assays, mass spectrometry analysis demonstrated that can internalize exosomal promote phenotype cells. Additionally, Transwell vitro cocultures dorsal root ganglia confirmed significantly enhances nerve infiltration cells via macrophages. The findings study indicate containing derived from induce polarization facilitate infiltration, thereby providing new potential therapeutic targets for managing cholangiocarcinoma.

Language: Английский

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