Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC. Treatment options for HCC are strictly dependent on tumor staging and liver function, which are structured by the updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, and liver transplantation are valid and curative therapeutic options for early tumor stages. For multifocal and metastatic diseases, systemic therapy is recommended. While Sorafenib had been the standalone HCC first-line therapy for decades, recent developments had led to the approval of new treatment options as first-line as well as second-line treatment. Anti-PD-L1 directed combination therapies either with anti-VEGF directed agents or with anti-CTLA-4 active substances have been implemented as the new treatment standard in the first-line setting. However, data from clinical trials indicate different responses on specific therapeutic regimens depending on the underlying pathogenesis of hepatocellular cancer. Therefore, histopathological examinations have been re-emphasized by current international clinical guidelines in addition to the standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. In this review, we emphasize the current knowledge on molecular pathogenesis of hepatocellular carcinoma. On this occasion, the treatment sequences for early and advanced tumor stages according to the recently updated Barcelona Clinic Liver Cancer classification system and the current algorithm of systemic therapy (first-, second-, and third-line treatment) are summarized. Furthermore, we discuss novel precautional and pre-therapeutic approaches including therapeutic vaccination, adoptive cell transfer, locoregional therapy enhancement, and non-coding RNA-based therapy as promising treatment options. These novel treatments may prolong overall survival rates in regard with quality of life and liver function as mainstay of HCC therapy.

Since the initial identification of oncogenic Wnt in mice and Drosophila, the Wnt signaling pathway has been subjected to thorough and extensive investigation. Persistent activation of Wnt signaling exerts diverse cancer characteristics, encompassing tumor initiation, tumor growth, cell senescence, cell death, differentiation, and metastasis. Here we review the principal signaling mechanisms and the regulatory influence of pathway-intrinsic and extrinsic kinases on cancer progression. Additionally, we underscore the divergences and intricate interplays of the canonical and non-canonical Wnt signaling pathways and their critical influence in cancer pathophysiology, exhibiting both growth-promoting and growth-suppressing roles across diverse cancer types.

Background: p53 deletion and mutation as well as upregulation of alpha-fetoprotein (AFP) are hallmarks of hepatocarcinogenesis. p63 and p73 belong to the family of p53-related transcription factors expressing a variety of isoforms. The expression of dominant negative (ΔN) p73 is related to the reduced survival of patients with hepatocellular carcinoma (HCC). In this study, we characterized the interaction between p53 family-dependent signaling pathways and the regulation of AFP at the gene and protein levels as essential determinants of therapeutic response and prognosis in HCC. Methods: Putative p53-, p63- and p73-binding sites within the AFP gene were identified in silico. Hep3B cells were transfected with plasmids encoding for p53, p63 and p73 to analyze the interplay of the p53 family with AFP. AFP transcription was determined by RT-qPCR. Protein levels of AFP, p53, p63 and p73 were analyzed by Western blot. Results: Underlining the importance of the crosstalk between the p53 family-dependent pathways and AFP regulation we identified eight novel putative binding sites for the members of the p53 family within the introns 1, 2, 3, 4, 7, 8, 11, and 12 of the AFP gene. Accordingly, full-length isoforms of p53, p63 and p73 efficiently downregulated AFP both on mRNA and protein level. Thus, the p53 family members were identified to be major regulators of AFP repression. Of note, p63 was characterized as a novel and p73 as the most efficient repressor of AFP. Conclusion: p53 mutation and upregulation of AFP are essential oncogenic events in the development of HCC. Here we show that AFP gene regulation occurs via a combined action of the p53 family members p53, p63 and p73. All three tumor suppressors reduce AFP gene and protein expression. Thus, our findings reveal a novel interaction of p53 family-dependent signaling pathways and AFP regulation at the gene and protein levels in HCC.

Background: Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its pronounced molecular heterogeneity and frequent resistance to conventional therapies. A key driver of therapeutic failure is the overexpression of the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-XL), which collectively maintain mitochondrial integrity and promote tumor cell survival. Methods: In this study, we evaluated a rational combination strategy targeting these complementary survival pathways using the histone deacetylase inhibitor panobinostat and the DNA-damaging agent bleomycin in HepG2 cells, a p53-functional HCC cell model. Results: In HepG2 cells, each agent alone produced only limited cytotoxicity, whereas their combination resulted in a marked and synergistic induction of apoptosis. This was shown by increased Annexin V positivity, mitochondrial outer membrane permeabilization (MOMP), and activation of caspases-8, -9, and -3 as well as cleavage of poly(ADP-ribose) polymerase (PARP). Mechanistically, panobinostat reduced Bcl-XL expression and primed mitochondria for apoptosis but simultaneously triggered compensatory upregulation of Mcl-1, representing an adaptive resistance response within this experimental system. Bleomycin effectively counteracted this escape mechanism by suppressing Mcl-1 induction, thereby lowering the apoptotic threshold and enabling mitochondrial permeabilization. In parallel, combined treatment potentiated caspase-8 cleavage, suggesting an additional caspase-8-associated apoptotic signal that amplified caspase-3/PARP execution. Pharmacological inhibition with zVAD-FMK confirmed that the observed cell death was predominantly caspase-dependent, supporting a coordinated engagement of both intrinsic and extrinsic apoptotic pathways. In summary, the combination of panobinostat and bleomycin overcomes anti-apoptotic defenses in HepG2 cells through synergistic and coordinated disruption of mitochondrial survival checkpoints and dual apoptosis pathway activation. Conclusions: By blocking a compensatory Mcl-1 escape response while simultaneously engaging extrinsic apoptosis signaling, this strategy produces potent synergistic cell death in this defined p53-functional HCC model and represents a promising mechanistic proof of concept that warrants further validation in additional molecularly diverse HCC models before broader translational conclusions can be drawn.

Atezolizumab/bevacizumab (A/B) and durvalumab ± tremelimumab (DT/D) are preferred first-line regimens for the treatment of hepatocellular carcinoma (HCC). Although both therapies share an anti-PD-L1-backbone, only the A/B-combination is targeting vascular-endothelial-growth-factor (VEGF). This difference may have safety-implications, as the anti-VEGF component may elevate the risk of bleeding and thromboembolic events. This multicenter study analyzes bleeding or thromboembolic events in patients receiving therapy with DT/D, compared with A/B. Patients with HCC treated with A/B exclusively before the approval of DT/D, or treated with DT/D, were recruited from 11 tertiary centers and analyzed retrospectively. Information on baseline characteristics was collected. Kaplan-Meier analyses and multivariate Cox regression modeling was used to compare event rates. This study included 490 patients (n = 165 DT/D; n = 325 A/B). The DT/D group showed a higher prevalence of gastroesophageal varices and increased spleen size. Median follow-up time was similar in both groups. A total of 74 patients (22.8%) treated with A/B showed a bleeding event of any grade vs. 22 patients (13.3%) treated with DT/D (p = 0.016). High-grade ≥3 bleeding episodes were more frequent in the A/B group with 47 patients (14.5%) vs. 12 patients (7.3%) in the DT/D group (p = 0.027). Kaplan-Meier analysis showed significantly shorter time to first bleeding (p = 0.037) with A/B as compared with DT/D. Multivariate regression confirmed that treatment with A/B was independently associated with an increased bleeding risk (p = 0.010). Variceal bleeding and thromboembolic events did not differ significantly between both groups. Overall and high-grade bleeding events were more frequent and occurred earlier in patients treated with A/B vs. DT/D, whereas variceal bleeding, grade 4-5 bleeding, and thromboembolic events did not differ significantly between groups. These findings should be confirmed in randomized trials or, if not feasible, through meta-analyses to provide more robust evidence for treatment decisions in advanced HCC. This multicenter retrospective study was scientifically justified by the need to clarify whether the addition of VEGF inhibition to PD-L1-based immunotherapy confers differential bleeding or thromboembolic risks in patients with advanced HCC. The results are particularly relevant for clinicians and trialists, as they demonstrate a higher incidence and earlier onset of overall and high-grade bleeding events with atezolizumab/bevacizumab compared with durvalumab ± tremelimumab, despite similar rates of variceal bleeding and thromboembolic events. These findings may inform treatment selection, risk stratification, and surveillance strategies in routine practice, especially in patients with portal hypertension or other bleeding risk factors. Given the retrospective design and baseline-imbalances between treatment groups, the results should be interpreted cautiously and warrant confirmation in prospective randomized studies or, if not feasible, through meta-analyses.

Cutaneous T cell lymphoma (CTCL) comprises a heterogeneous group of skin-homing T cell malignancies, with mycosis fungoides (MF) and Sézary Syndrome representing the most frequent and clinically relevant entities. Their clinical behavior differs substantially: MF often follows an indolent course over years, whereas Sézary Syndrome is a distinct clinicopathological entity that is typically characterized by erythroderma, a high burden of circulating malignant T cells and frequent lymph node involvement. Early-stage MF can often be controlled with skin-directed therapies, but advanced, relapsed or refractory CTCL remains therapeutically challenging. Established treatments are selected primarily according to disease stage, disease compartment and surface-target expression, whereas most pathway-directed, redox-modulating and apoptosis-sensitizing approaches remain investigational. Increasing evidence indicates that malignant T cells are maintained by an interconnected survival network rather than by a single dominant oncogenic pathway. This network includes constitutive inflammatory signaling, nuclear factor kappa B (NF-κB) activation, apoptosis resistance, altered redox homeostasis, mitochondrial and metabolic adaptation, rat sarcoma viral oncogene homolog (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK) signaling and epigenetic regulation. These mechanisms cooperate to promote malignant T cell survival, therapy resistance, and disease progression, but they also create opportunities for targeted therapeutic intervention. Particular emphasis is placed on redox-regulated cell death, nuclear factor kappa B (NF-κB)-dependent survival, B-cell lymphoma 2 (BCL-2) family proteins, RAS pathway alterations, epigenetic sensitization and mechanism-informed treatment strategies. Integrating clinicopathological staging with molecular profiling and functional vulnerability screens may support more rational combination therapies and improve patient stratification in CTCL.