Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets

Abstract

Hepatocellular carcinoma (HCC) is a type of primary liver cancer with poor prognosis, and its incidence and mortality rate are increasing worldwide. It is refractory to conventional chemotherapy and radiotherapy owing to its high tumor heterogeneity. Accumulated genetic alterations and aberrant cell signaling pathway have been characterized in HCC. The fibroblast growth factor (FGF) family and their receptors (FGFRs) are involved in diverse biological activities, including embryonic development, proliferation, differentiation, survival, angiogenesis, and migration, etc. Data mining results of The Cancer Genome Atlas demonstrate high levels of FGF and/or FGFR expression in HCC tumors compared with normal tissues. Moreover, substantial evidence indicates that the FGF/FGFR signaling axis plays an important role in various mechanisms that contribute to HCC development. At present, several inhibitors targeting FGF/FGFR, such as multikinase inhibitors, specific FGFR4 inhibitors, and FGF ligand traps, exhibit antitumor activity in preclinical or early development phases in HCC. In this review, we summarize the research progress regarding the molecular implications of FGF/FGFR-mediated signaling and the development of FGFR-targeted therapeutics in hepatocarcinogenesis.

Immunotherapies for hepatocellular carcinoma

“…), Wnt/ß‐catenin, MAPK/ERK, PI3K/AKT/mTOR, and the JAK/STAT signalling pathways. 68 , 69 , 70 , 71 , 72 They are associated with decreased intratumoural infiltration and effector function of T‐cells and dendritic cells (DCs), and increased T‐cell exhaustion. 64 , 65 , 66 , 67 Furthermore, cytokines such as interleukin (IL)‐10 and TGF‐ß promote tumour cell proliferation and immune evasion through a reduction in the recruitment of APCs and antigen presentation, along with overexpression of alternative co‐inhibitory cell‐surface ligands such as T‐cell immunoglobulin domain and mucin domain 3 and lymphocyte‐activation gene 3.…”

“…Oncogenic cell signalling pathways that are upregulated in HCC include receptor tyrosine kinases (EGFR, FGFR, c‐MET, VEGFR, etc. ), Wnt/ß‐catenin, MAPK/ERK, PI3K/AKT/mTOR, and the JAK/STAT signalling pathways 68–72 . They are associated with decreased intratumoural infiltration and effector function of T‐cells and dendritic cells (DCs), and increased T‐cell exhaustion 64–67 .…”

Natural Products: A Promising Therapeutics for Targeting Tumor Angiogenesis

“…Moreover, latent forms of VEGF ligands are separated in the extracellular matrix, that are regulated by the release and activation of extracellular matrix-degrading proteases (e.g., MMP-9) (20). The up-regulation of other pro-angiogenic signals, such as FGF family, is involved in sustaining tumor angiogenesis (3,21). Besides the VEGF signaling pathway, other signaling pathways and associated factors are involved in tumor angiogenesis.…”

“…VEGF is the key regulator of the proper development of tumor blood vessels. Members of the angiopoietins, platelet-derived growth factor (PDGF-B), transforming growth factor (TGF-b) families and basic fibroblast growth factor (bFGF) are also significant factors in the formation of an immature vascular network in tumors (3). Moreover, recent literature has demonstrated that a variety of pro-angiogenic factors (VEGF, angiopoietin-1, bFGF) have the ability of inhibiting EC apoptosis (4) in tumor angiogenesis.…”

Papel de IRS2 en la regulación de la comunicación a través de FGFs en el nicho de células progenitoras hepáticas

“…Aunque todavía existe controversia sobre el origen del HCC, diversos estudios señalan a que podría originarse a partir de la transformación maligna de las CPH [322][323] [324]. La comunicación entre CPH y CEH activadas promueve la progresión del HCC siendo para ello determinante el microambiente generado por la población de CEH activadas de la zona peritumoral [325][326] de manera que existen numerosas evidencias de que la señalización FGF/FGFR contribuye al desarrollo del HCC [327]. Por otra parte, la activación de NRF2 en fibroblastos de piel no solo induce re-epitelización sino también tumorigénesis [244] y previene la finalización de la EMT estabilizando un fenotipo "híbrido epitelial-mesenquimal" que presenta un elevado potencial iniciador de tumores y que facilita la metástasis derivando en una mayor agresividad del tumor y peor prognosis [328].…”