Kinase activation profile associated with TGF-β-dependent migration of HCC cells: a preclinical study

Fransvea, Emilia; Mazzocca, Antonio; Santamato, Angela; Azzariti, Amalia; Antonaci, Salvatore; Giannelli, Gianluigi

doi:10.1007/s00280-010-1459-x

Cited by 43 publications

(41 citation statements)

References 18 publications

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“…This inhibition is associated with the decreased phosphorylation of Smad2, FAK and ␤1-integrin (intracytoplasmic tail), and with increased levels of Ecadherin. Finally, in a xenograft model of HCC, LY2109761 strongly inhibited tumor growth, intravasation and metastasis [276]. These studies support the use of LY2157299 in clinical trials.…”

Section: Targeting Tgf-ˇ In Cancer Using Small Molecule Inhibitorsmentioning

confidence: 82%

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

Jiang

Sanders

Katoh³

et al. 2015

Seminars in Cancer Biology

427

295

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Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

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Section: Targeting Tgf-ˇ In Cancer Using Small Molecule Inhibitorsmentioning

confidence: 82%

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

Jiang

Sanders

Katoh³

et al. 2015

Seminars in Cancer Biology

427

295

View full text Add to dashboard Cite

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“…Blocking TGF-b by using small molecule inhibitors of TGF-b or anti-TGF antibodies appears to inhibit HCC cell migration and to attenuate tumor cell-mediated NK-cytotoxicity inhibition. [108][109][110] Interestingly, in human lung cancer or colorectal cancer patients, elevated TGF-b1 secretion is inversely correlated with the expression of NKG2D and cytotoxicity of NK cells. TGF-b1 neutralization by anti-TGF-b1 monoclonal antibodies in vitro can restore NKG2D expression.…”

Section: Nkr Expression By Inhibitory Cytokinesmentioning

confidence: 99%

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono-and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC. Keywords: activating receptor; hepatocellular carcinoma; inhibitory receptor; natural killer cell; natural killer receptor INTRODUCTION Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. 1 Common clinical risk factors for HCC include hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, heavy alcohol intake, steatohepatitis and diabetes. 2 Approximately 50% of HCC cases worldwide can be attributed to chronic HBV infection (CHB) and almost 75% of HCC cases occur in developing countries where HBV is endemic. 3,4 According to statistics, older male patients who are infected with HBV genotype C or co-infected with HCV, have high levels of viral load and have been exposed to the aflatoxin, or older male patients who have a family history of HCC tend to have a high risk of developing HCC. [5][6][7] Accumulating clinical and epidemiological evidence shows a significant correlation between chronic HBV infection and hepatocarcinogenesis. However, the underlying mechanisms

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“…TGF-b signaling is associated with loss of cell polarity, acquisition of cellular motility, and increased tumor invasion (5,(16)(17)(18)(19)(20)(21)(22). A main change in tumor cells is related to EMT as measured by E-cadherin expression, a marker of EMT.…”

Section: Tgf-b Signaling In Hepatocellular Carcinomamentioning

confidence: 99%

Transforming Growth Factor-β as a Therapeutic Target in Hepatocellular Carcinoma

2014

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Hepatocellular carcinoma arises in patients as a consequence of long-standing preexisting liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. In such preexisting liver diseases, TGF-b plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial-mesenchymal transition (EMT). TGF-b signaling promotes hepatocellular carcinoma progression by two mechanisms: first, via an intrinsic activity as an autocrine or paracrine growth factor and, second, via an extrinsic activity by inducing microenvironment changes, including cancer-associated fibroblasts, T regulatory cells, and inflammatory mediators. Although there is an increasing understanding on how TGF-b signaling is associated with tumor progression in hepatocellular carcinoma, it is not clear whether TGF-b signaling is limited to a certain subgroup of patients with hepatocellular carcinoma or is a key driver of hepatocellular carcinoma during the entire tumorigenesis of hepatocellular carcinoma. Inhibitors of the TGFb signaling have been shown to block hepatocellular carcinoma growth and progression by modulating EMT in different experimental models, leading to the clinical investigation of the TGF-b inhibitor LY2157299 monohydrate in hepatocellular carcinoma. Preliminary results from a phase II clinical trial have shown improved clinical outcome and also changes consistent with a reduction of EMT. Cancer Res; 74(7);

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Kinase activation profile associated with TGF-β-dependent migration of HCC cells: a preclinical study

Cited by 43 publications

References 18 publications

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

Transforming Growth Factor-β as a Therapeutic Target in Hepatocellular Carcinoma

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