Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Des-gamma-carboxy prothrombin (DCP) is an aberrant prothrombin produced by hepatocellular carcinoma (HCC) cells. Serum and tissue DCP expressions are thought to reflect the biological malignant potential of HCC. However, the role of DCP in the development of angiogenesis is not well understood. Herein, we report the effects of DCP on growth and migration of human vascular endothelial cells. DCP significantly stimulated the proliferation of HUVEC (ECV304) cells in a dose and time dependent manner, as measured by the MTT assay. A continuous rapid migration of ECV304 cells was observed in the presence of DCP measured by the scratch wound assay. The continuous rapid invasive activity, measured by transwell chamber assay also showed that DCP increased endothelial cells migration through the reconstituted extracellular matrix (Matrigel). Further, the tube formation of vascular endothelial cells on 3-D Matrigel showed an increased number of branch points of ECV304 cells induced by DCP in a dose dependent manner. The levels of vascular endothelial cell growth-related angiogenic factors and matrix metalloproteinase were also examined. DCP significantly stimulated the expression levels of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP)-2 (latent and active). Together, these data suggest that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities in angiogenesis of HCC.
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PMID:Des-gamma-carboxy prothrombin stimulates human vascular endothelial cell growth and migration. 1926 29

Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Surgical intervention is the only curative option, with only a small fraction of patients being eligible. Conventional chemotherapy and radiotherapy have not been effective in treating this disease, thus leaving patients with an extremely poor prognosis. In viral, alcoholic, and other chronic hepatitis, it has been shown that there is an activation of the progenitor/stem cell population, which has been found to reside in the canals of Hering. In fact, the degree of inflammation and the disease stage have been correlated with the degree of activation. Dysregulation of key regulatory signaling pathways such as transforming growth factor-beta/transforming growth factor-beta receptor (TGF-beta/TBR), insulin-like growth factor/IGF-1 receptor (IGF/IGF-1R), hepatocyte growth factor (HGF/MET), Wnt/beta-catenin/FZD, and transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) in this progenitor/stem cell population could give rise to HCC. Further understanding of these key signaling pathways and the molecular and genetic alterations associated with HCC could provide major advances in new therapeutic and diagnostic modalities.
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PMID:Liver stem cells and molecular signaling pathways in hepatocellular carcinoma. 1936 Jan 42

Epidemiological studies have established that many tumours occur in association with persistent inflammation. One clear example of inflammation-related cancer is hepatocellular carcinoma (HCC). HCC slowly unfolds on a background of chronic inflammation triggered by exposure to infectious agents (hepatotropic viruses), toxic compounds (ethanol), or metabolic impairment. The molecular links that connect inflammation and cancer are not completely known, but evidence gathered over the past few years is beginning to define the precise mechanisms. A central role for cytokines such as interleukin-6 (IL-6) and IL-1 (alpha and beta) in liver cancer has been established in experimental models. Besides these inflammatory mediators, mounting evidence points to the dysregulation of specific growth and survival-related pathways in HCC development. Among them is the pathway governed by the epidermal growth factor receptor (EGFR), which can be bound and activated by a broad family of ligands. Of special relevance is the fact that the EGFR engages in extensive crosstalk with other signaling pathways, serving as a "signaling hub" for an increasing list of growth factors, cytokines, and inflammatory mediators. In this review, we summarize the most recent evidences supporting a role for the EGFR system in inflammation-related cell signaling, with special emphasis in liver inflammation and HCC. The molecular dissection of the pathways connecting the inflammatory reaction and neoplasia will facilitate the development of novel and more effective antitumor strategies.
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PMID:The epidermal growth factor receptor: a link between inflammation and liver cancer. 1942 59

Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, anti-proliferation and analgesic potential. However, the effects of pterostilbene in preventing invasion of cancer cells have not been studied. Here, we report our finding that pterostilbene significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma cells (HepG(2) cells). Increase in the enzyme activity, protein and messenger RNA levels of matrix metalloproteinase (MMP)-9 were observed in TPA-treated HepG(2) cells, and these were blocked by pterostilbene. In addition, pterostilbene can inhibit TPA-induced expression of vascular endothelial growth factor, epidermal growth factor and epidermal growth factor receptor. Transient transfection experiments also showed that pterostilbene strongly inhibited TPA-stimulated nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1)-dependent transcriptional activity in HepG(2) cells. Moreover, pterostilbene can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases 1/2 and phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 and 250 mg/kg intraperitoneally) after inoculation with HepG(2) cells into the tail vein. Presented data reveal that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.
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PMID:Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. 1944 59

Targeted agents are now an integral part of treatment regimens for some cancers. Trastuzumab is established in treatment of human epidermal receptor 2 (Her2) positive breast cancers, with improvements in both, the disease free and over all survival. Monoclonal antibody (MoAB) against vascular growth factor receptor (VEGF), bevacizumab and cetuximab a MoAB against epidermal growth factor receptor (EGFR) are establishing their role in a many cancers after making their mark in colorectal cancer. Sorafenib and sunitinib have success stories in renal carcinoma. The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial has established sorafenib role in advanced hepatocellular carcinoma, while in gastrointestinal tumors; imatinib and sunitinib have proven role. At this point in time side effect profile of all these agents appears relatively safe however cost for developing countries remains an issue.
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PMID:Old disease, new targets--part-I, solid malignancies. 1953 78

Sorafenib is a multikinase inhibitor newly approved for the treatment of renal cell carcinoma and hepatocellular carcinoma. Multiple cutaneous adverse effects of sorafenib have been described. We present a 68-year-old patient with renal cell carcinoma who developed multiple tender hyperkeratotic papules within weeks of starting sorafenib. The degree of symptoms and size of lesions corresponded directly with his sorafenib dosing. Four biopsy specimens of representative lesions were taken. Three lesions showed keratin-filled endophytic epithelial-lined invaginations, one with a coexistent actinic keratosis. The fourth biopsy specimen revealed an invasive squamous cell carcinoma with keratoacanthoma-like features. To our knowledge, diffuse eruptions of epidermal invaginations, ectatic follicular infundibula, and follicular infundibular cysts have not been reported previously with sorafenib, although they are well known to occur with epidermal growth factor receptor inhibitor therapy. Keratoacanthoma and squamous cell carcinoma as a result of sorafenib use are only beginning to be reported in the literature. At the time of acceptance of our manuscript, sorafenib-induced keratoacanthoma was noted only once in the literature, and deeply invasive squamous cell carcinoma has been reported once in the setting of sorafenib and tipifarnib combination therapy. We review the spectrum of dermatologic side effects of sorafenib to facilitate their recognition.
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PMID:The histologic spectrum of epithelial neoplasms induced by sorafenib. 1970 18

This study aims to determine the sensitivity, specificity and accuracy of epidermal growth factor receptor monoclonal antibody (EGFRmAb) modified poly(lactic acid-co-l-lysine) nanoparticles (PLA-PLL-EGFRmAb) NPs delivery system to EGFR positive cancer cells. In the study, a new PLA-PLL-EGFRmAb NPs was prepared. The cellular cytotoxicity, cellular uptake, and the targeted effect for hepatocellular carcinoma of PLA-PLL-EGFRmAb NPs were investigated. In vitro, the findings of Flow cytometry and Confocal Laser scanning Biological Microscopy showed that PLA-PLL-EGFRmAb NPs can bind to hepatocellular carcinoma cells and were uptaken effectively. In vivo in the SMMC-7721 xenograft mouse model, PLA-PLL-EGFRmAb NPs could target to the tumor effectively, which demonstrated a better targeting. These results showed that the PLA-PLL-EGFRmAb NPs have the potential to be used as a target delivery carrier for tumor therapies.
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PMID:Preparation of EGFR monoclonal antibody conjugated nanoparticles and targeting to hepatocellular carcinoma. 1992 4

Recently, we reported a novel transcriptional repressor, ZIP (for zinc finger and G-patch domain-containing), which recruits the Mi-2/NuRD (nucleosome remodeling and deacetylase) complex and represses the expression of epidermal growth factor receptor (EGFR). In doing so, ZIP inhibits cell proliferation and suppresses breast carcinogenesis. Here, we report the cloning and the characterization of an alternatively spliced isoform of ZIP, sZIP. sZIP is an N-terminal truncated form of ZIP, lacking the zinc finger but retaining part of the G-patch domain and C-terminal coiled-coil domain of ZIP. We showed that sZIP could interact with the NuRD complex but lost its DNA-binding capacity. We demonstrated that sZIP antagonizes the transcription repression by ZIP by competing for the binding of the NuRD complex and that sZIP alleviates the growth inhibitory effect of ZIP on hepatocarcinoma cells through attenuating the transcriptional repression of EGFR. Our data provide a finely tuned mechanism for EGFR regulation and add another player for transcription repression.
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PMID:sZIP, an alternative splice variant of ZIP, antagonizes transcription repression and growth inhibition by ZIP. 2023 18

Trastuzumab and lapatinib provide clinical benefit to women with human epidermal growth factor receptor 2 (HER)-positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. Consequently, there is an urgent need to identify new predictive factors for these agents. The aim of this study was to investigate the role of receptor tyrosine kinase signaling and phosphoinositide 3-kinase (PI3K)/AKT pathway activation in conferring resistance to trastuzumab and lapatinib. To address this question, we evaluated response to trastuzumab and lapatinib in a panel of 18 HER2-amplified cell lines, using both two- and three-dimensional culture. The SUM-225, HCC-1419, HCC-1954, UACC-893, HCC-1569, UACC-732, JIMT-1, and MDA-453 cell lines were found to be innately resistant to trastuzumab, whereas the MDA-361, MDA-453, HCC-1569, UACC-732, JIMT-1, HCC-202, and UACC-893 cells are innately lapatinib resistant. Lapatinib was active in de novo (SUM-225, HCC-1419, and HCC-1954) and in a BT-474 cell line with acquired resistance to trastuzumab. In these cells, trastuzumab had little effect on AKT phosphorylation, whereas lapatinib retained activity through the dephosphorylation of AKT. Increased phosphorylation of HER2, epidermal growth factor receptor, HER3, and insulin-like growth factor IR correlated with response to lapatinib but not trastuzumab. Loss of PTEN or the presence of activating mutations in PI3K marked resistance to trastuzumab, but lapatinib response was independent of these factors. Thus, increased activation of the PI3K/AKT pathway correlates with resistance to trastuzumab, which can be overcome by lapatinib. In conclusion, pharmacologic targeting of the PI3K/AKT pathway may provide benefit to HER2-positive breast cancer patients who are resistant to trastuzumab therapy.
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PMID:Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. 2070 Aug 98

In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar) was approved in Japan for "unresectable hepatocellular carcinoma (HCC)", and was the first molecular-targeted agent for use in liver cancer. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and it has now been approved worldwide. Phase III clinical trials are now underway to compare other molecular-targeted agents with sorafenib as first-line treatment agents, and to evaluate other multi-kinase inhibitors of the vascular endothelial growth factor and platelet-derived growth factor receptors, as well as drugs targeting the epidermal growth factor receptor, insulin-like growth factor receptor, and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways.
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PMID:Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice. 2050 38


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