Hepatocellular carcinoma represents the fifth most frequent cancer in the world; it commonly occurs on cirrhotic liver. Prognosis and survival are still poor, mainly because of diagnosis at a late ...stage and/or recurrence of the disease. For this reason, surveillance strategies are widely used to screen for early occurrence of cancer in populations at risk. Alpha-foetoprotein is so far the only serological marker available, but its diagnostic accuracy is unsatisfactory because of low sensitivity despite reliable specificity. For this reason, new biomarkers for the diagnosis of hepatocellular carcinoma are in strong demand by clinicians. In this review, we will focus on new biomarkers currently under investigation, but also on still newer, very promising biomarkers that seem to significantly improve diagnosis.
A better knowledge of the mechanisms underlying hepatocellular carcinoma (HCC) growth and spread is essential to improve the available treatment options. So far, the only therapies available for HCC ...are mainly based on tumor-destructive approaches, whereas no therapies are available to consolidate these invasive therapies or to cure the tumor. The fact that HCC develops on cirrhotic liver strongly limits the use of common anti-cancer drugs, but the need to find new therapies is strongly felt by clinicians. A large body of evidence suggests that the tissue microenvironment represents a potential target for therapies. Consistently, biological therapies such as inhibitors of the epithelial growth factor receptor (EGFR), are currently under investigation. Unfortunately, there is a discrepancy between the very promising experimental data and the results obtained in patients, although limited sample sizes and advanced stage of the disease could be important factors hampering a reliable judgment of the efficacy of such drugs. Nevertheless, a better identification of the molecular pathways involved in drug effectiveness as well as in HCC tumor progression indicates that the tissue microenvironment likely harbors the solution to the problem. In this review the role and the rationale of using biological drugs to target the microenvironment is discussed, taking into consideration new experimental advances in the field.
Prognosis and survival of patients with hepatocellular carcinoma (HCC) is still very poor, and no therapies are currently available to inhibit tumour growth and metastases. Recently, we reported that ...the expression of an extracellular matrix component (ECM), namely Laminin-5 (Ln-5), is directly related to poor prognosis in HCC patients. The aim of our study is to investigate the preclinical effect of gefitinib in an in vitro HCC model. We found that the IC(50) of gefitinib in HCC cells ranged from 0.7 to 10.0 muM, whereas Ln-5 inhibited the activity of gefitinib in a dose-dependent manner. Complete inhibition of phosphorylated (p)-EGFR (epidermal growth factor receptor) was obtained within 6 h exposure to gefitinib and complete restoration of the receptor status was obtained after 24 h. A downstream effect yields a decrease in p-Akt and p-Erk 1/2. The addition of exogenous Ln-5 has no effect on p-EGFR, whereas it restores p-Erk 1/2 and p-Akt. Consistently, Ln-5 induces recovery of HCC cells from Gefitinib-induced apoptosis. In conclusion, gefitinib inhibits HCC cell growth and we report for the first time that Ln-5, but not other ECM molecules, reduces the ability of gefitinib to inhibit cell growth via Akt. As patients with HCC have different Ln-5 expression levels, these results may help to better understand which patients might benefit from gefitinib treatment.
The increasing number of patients with hepatocellular carcinoma (HCC) and the highly unfavourable prognosis of the disease are two important reasons why more effort needs to be devoted to ...investigating other therapies able to block or reduce tumor progression and cancer metastasis. The underlying cirrhosis on which HCC develops limits the use of common chemotherapies, mainly because of their toxicity. Recently, great attention has been paid to a family of molecules that inhibits the tyrosine kinase (TK) receptors, because of their relevant role in activating intracellular pathways responsible for several biological activities of the HCC cells. In particular, proliferation, invasion, survival, apoptosis, are regulated by Erk1/2 and Akt pathways, that can be considered for this reason as potential therapeutic targets. Therefore, the idea is to fight HCC by blocking the molecular mechanisms exploited by the cancer to develop and to metastasize. The epithelial growth factor and the vascular endothelial growth factor receptors (EGFR and VEGFR, respectively) have been identified as the major targets for these new therapies. In this review the biological role of both growth factors in HCC will be discussed, together with the use of anti-EGFR and anti-VEGFR. The preliminary results obtained in vitro or in "in vivo" experimental models have been very promising, whereas the few studies conducted in patients have been not comparably satisfactory. This could be because of the limited number of patients and of their advanced stage of HCC, nevertheless the possibilities of using this family of drugs should be further explored, together with aspects contributing to a better understanding of the molecular mechanisms driving HCC progression.
The involvement of matrix metalloproteinase (MMPs)-2 and -9, also known as gelatinases, in cancer cell migration and invasion has been well documented, although it is not yet clear how they ...facilitate metastasis formation in the course of malignancies. The idea that gelatinases are responsible for degradation of extracellular matrix (ECM) components and breakdown of basement membrane (BM) tissue boundaries has turned out not to be entirely correct. An action by remodelling the ECM components of the BM exposing new cryptic sites, or releasing growth factors, cytokines, or active ECM proteolysed fragments seems to be nearer to the truth. On the other hand, tissue inhibitors of gelatinase activity (TIMP-2), are involved both in the MMP-2 activation process; in concert with membrane type 1-MMP (MT1-MMP), and in the inhibition of gelatinolytic activity. Therefore proteolysis, the central step for cancer metastasis, should occur as a result of an imbalance between MMP-2 and TIMP-2. Many studies have reported the importance of this balance in patients with different malignancies, and considerable effort is currently being spent on the study of molecules that can shift the balance in favour of inhibition of MMP proteolytic activity. In this review we focus on the role of gelatinase activity in cancer invasion, addressing the following issues: how and where proteolysis occurs in cancer tissues, how it can be regulated, what the clinical implications are of the studies reported in literature so far, and finally what the future developments in this field that could have an impact on the management of patients affected by malignancies may be.
Chimeric plant viruses are emerging as promising vectors for use in innovative vaccination strategies. In this context, cucumber mosaic virus (CMV) has proven to be a suitable carrier of the ...hepatitis C virus (HCV)-derived R9 mimotope. In the present work, a new chimeric CMV, expressing on its surface the HCV-derived R10 mimotope, was produced but lost the insert after the first passage on tobacco. A comparative analysis between R10- and R9-CMV properties indicated that R9-CMV stability was related to structural features typical of the foreign insert. Thus, in order to combine high virus viability with strong immuno-stimulating activity, we doubled R9 copies on each of the 180 coat protein (CP) subunits of CMV. One of the chimeras produced by this approach (2R9-CMV) was shown to systemically infect the host, stably maintaining both inserts. Notably, it was strongly recognized by sera of HCV-infected patients and, as compared with R9-CMV, displayed an enhanced ability to stimulate lymphocyte IFN-γ production. The high immunogen levels achievable in plants or fruits infected with 2R9-CMV suggest that this chimeric form of CMV may be useful in the development of oral vaccines against HCV.
Chronic C hepatitis represents a major health problem worldwide, mainly because progression of the tissue damage leads to the development of cirrhosis and hepatocellular carcinoma. In this review we ...discuss the molecular mechanisms underlying the development of liver fibrosis. In particular we consider some immunologic aspects that regulate the interaction between HCV and the host immune defense. Reflections are made about the roles played by the host capacity to respond to the viral infection during therapy and the consequences of the deposition of extracellular matrix (ECM) proteins leading to the development of fibrosis. The involvement of inflammatory cytokines in regulating the proteolytic remodeling of the liver and the ECM turn-over is essential for the activation of hepatic stellate cells (HSCs), that have an important role in the progression of liver fibrosis. Finally, we analyze one of the aspects involved in the activation of the HSCs, namely the proteolytic remodeling of the surrounding environment.
In patients with chronic hepatitis C, rapid virological response (RVR) at week 4 of treatment seems to be strongly associated with a high probability of achieving a sustained virological response ...(SVR). The aim of this study was to investigate the outcome of different pegylated interferon-alpha2b (Peg-IFN-alpha2b) dosages plus ribavirin (RBV) in patients with RVR. Forty-five naïve patients chronically infected with hepatitis C virus (HCV)-1b started Peg-IFN-alpha2b (1.5 microg/kg/week) in combination with weight-based RBV doses (800-1200 mg/day). Thirty-one patients (68.9%) attained RVR at week 4 of therapy, while four further patients showed negative HCV-RNA values for the first time at week 12 and were considered early virological responders (EVR). The 31 RVR patients were randomized to receive either RBV plus 1.5 microg/kg/week (17 pts) or 1.0 microg/kg/week (14 pts) of Peg-IFN-alpha2b for the remaining 44 weeks. The two groups were matched for age, sex, baseline alanine aminotransferase levels, viral load and fibrosis score. After 6 months of post-treatment follow-up, the prevalence of SVR was 94.1% (16/17) among RVR patients treated with 1.5 microg/kg/week and 92.8% (13/14) in RVR patients treated with 1.0 microg/kg/week (P = not significant). A high-baseline viral load (P = 0.01) and bridging fibrosis/cirrhosis (P = 0.02) negatively influenced the likelihood of achieving RVR. On the contrary, the ability of RVR patients to achieve SVR did not correlate with these baseline characteristics in either of the treatment group. Finally, the SVR rate among EVR patients who responded after more than 4 weeks of treatment was significantly lower than among RVR patients (1/4 = 25%vs 29/31 = 93.5%; P = 0.0058), because of a high prevalence of post-treatment relapse among patients with EVR.
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