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  • 1
    Online Resource
    Online Resource
    Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer—from Tumor Development to Therapeutic Implications
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 8 ( 2019-07-25), p. 1053-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 8 ( 2019-07-25), p. 1053-
    Abstract: Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). Considerable research efforts have focused on the identification of predisposing factors that promote induction of an oncogenic field effect within the inflammatory liver microenvironment. Among the most prominent factors involved in this so-called inflammation-fibrosis-cancer axis is the NF-κB pathway. The dominant role of this pathway for malignant transformation and progression in HCC is well documented. Pathway activation is significantly linked to poor prognostic traits as well as stemness characteristics, which places modulation of NF-κB signaling in the focus of therapeutic interventions. However, it is well recognized that the mechanistic importance of the pathway for HCC is highly context and cell type dependent. While constitutive pathway activation in an inflammatory etiological background can significantly promote HCC development and progression, absence of NF-κB signaling in differentiated liver cells also significantly enhances liver cancer development. Thus, therapeutic targeting of NF-κB as well as associated family members may not only exert beneficial effects but also negatively impact viability of healthy hepatocytes and/or cholangiocytes, respectively. The review presented here aims to decipher the complexity and paradoxical functions of NF-κB signaling in primary liver and non-parenchymal cells, as well as the induced molecular alterations that drive HCC development and progression with a particular focus on (immune-) therapeutic interventions.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11081053
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    Tailored Systemic Therapy for Colorectal Cancer Liver Metastases
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 21 ( 2021-10-29), p. 11780-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 21 ( 2021-10-29), p. 11780-
    Abstract: Liver metastases are the most common site of metastatic spread in colorectal cancer. Current treatment approaches involve effective systemic therapies in combination with surgical and/or interventional strategies. Multimodal strategies greatly improved clinical outcomes of patients with metastatic colorectal cancer over the last decades. Identification of predictive and prognostic biomarkers helped to comprehensively refine individual targeted treatment approaches and resulted in median overall survival rates of 30 months or longer. Current guidelines, thus, recommend treatment selection according to patients’ performance status, tumor localization and stage as well as the tumor’s molecular and genetic status. Here, we outline the latest developments in molecular decision-making for patients with upfront resectable, potentially or initially unresectable and non/never-resectable colorectal cancer liver metastases.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms222111780
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 13 ( 2021-06-25), p. 2803-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 13 ( 2021-06-25), p. 2803-
    Abstract: Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10132803
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662592-1
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  • 4
    Online Resource
    Online Resource
    The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma
    MDPI AG ; 2021
    In:  Journal of Clinical Medicine Vol. 10, No. 12 ( 2021-06-21), p. 2732-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 10, No. 12 ( 2021-06-21), p. 2732-
    Abstract: Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months in the pCTX + TACE group versus 13.1 months in the pCTX group (p = 0.008). Controlling for albumin, bilirubin, ECOG (Eastern Cooperative Oncology Group) performance status, and UICC (Union for International Cancer Control) stage, the addition of TACE still conferred an OS benefit of 12.95 months (p = 0.014). A propensity score matching analysis yielded an OS benefit of 14 months from the time of unresectability for the pCTX + TACE group (p = 0.020). The addition of TACE to pCTX may provide an OS benefit for patients with unresectable iCCA. Thus, patients with liver-dominant iCCA undergoing standard-of-care pCTX should be considered for additional treatment with TACE.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm10122732
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662592-1
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  • 5
    Online Resource
    Online Resource
    BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 6 ( 2020-05-31), p. 1437-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 6 ( 2020-05-31), p. 1437-
    Abstract: Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative BAX/BAK localization was analyzed in tumor and corresponding non-tumor samples from 34 hepatocellular carcinoma (HCC) patients. Key transcriptome changes and gene expression profiles related to the status of BAX regulation were applied to two independent cohorts including over 500 HCC patients. The prediction of apoptotic response was tested using cell lines and polyclonal tumor isolates. Cellular protection from BAX was confirmed by challenging cells with mitochondrial BAX. We discovered a subgroup of HCC with selective protection from BAX-dependent apoptosis. BAX-protected tumors showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. Gene expression profiles characteristic to BAX-specific protection are enriched in poorly differentiated HCCs and show significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of BAX-protected cancer cells caused selective sensitivity to PARP inhibition. Molecular characteristics of BAX-protected HCC were enriched in cells challenged with mitochondrial BAX. Our results demonstrate that predisposition to BAX activation impairs tumor biology in HCC. Selective BAX inhibition or lack thereof delineates distinct subgroups of HCC patients with molecular features and differential response pattern to apoptotic stimuli and inhibition of DNA repair mechanisms.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12061437
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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