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Western populations are becoming increasingly sedentary and the incidence of nonalcoholic fatty liver disease (NAFLD) is increasing and becoming one of the most common causes of liver disease worldwide. Also, NAFLD is considered one the new emerging risk factors for development of tumors of the gastro-intestinal tract, particularly hepatocellular carcinoma (HCC). Visceral obesity is an important risk factor for the onset of NAFLD. An accumulation of ectopic fat, including visceral obesity and fatty liver leads to a dysfunction of the adipose tissue with impaired production of adipocytokines which, in turn, favor an increase in pro-inflammatory cytokines. In this review, we discuss how the obesity-related chronic state of low-grade inflammation and the presence of NAFLD lead to the emergence of a microenvironment favorable to the development of cancer.

Objectives Hepatocellular carcinoma (HCC) is one of the most frequent tumours worldwide and available drugs are inadequate for therapeutic results and tolerability. Hence, novel effective therapeutic tools with fewer side effects are of paramount importance. We have previously shown that Crithmum maritimum ethyl acetate extract exerts a cytostatic effect in HCC cells. Here, we tested whether C. maritimum ethyl acetate extract in combination with half sorafenib IC50 dose ameliorated efficacy and toxicity of sorafenib in inhibiting liver cancer cell growth. Moreover, we investigated the mechanisms involved. Methods Two HCC cell lines (Huh7 and HepG2) were treated with C. maritimum ethyl acetate extract and half IC50 sorafenib dose usually employed in vitro. Then, cell proliferation, growth kinetics and cell toxicity were analysed together with an investigation of the cellular mechanisms involved, focusing on cell cycle regulation and apoptosis. Key findings Results show that combined treatment with C. maritimum ethyl acetate extract and half IC50 sorafenib dose decreased cell proliferation comparably to full-dose sorafenib without increasing cell toxicity as confirmed by the effect on cell cycle regulation and apoptosis. Conclusions These results provide scientific support for the possibility of an effective integrative therapeutic approach for HCC with fewer side effects on patients.

Non-alcoholic fatty liver disease (NAFLD) is an emerging and threatening pathological condition, ranging from fatty liver (FL) to chronic steatohepatitis (NASH), liver cirrhosis, and eventually to hepatocellular carcinoma (HCC). Recent findings suggest that patients with NAFLD have a higher risk of cardiovascular events and thromboembolism and that this risk is independent of metabolic diseases that are frequently associated with NAFLD, such as diabetes, hyperlipidaemia, and obesity. The vascular involvement of NAFLD might be considered its systemic burden, conditioning higher mortality in patients affected by the disease. These clinical findings suggested the existence of a prothrombotic state in NAFLD, which is partially unexplored and whose underlying mechanisms are to date not completely understood. Here, we review the mechanisms involved in the pathogenesis of the prothrombotic state in NAFLD across the progression from the healthy liver through the different stages of the disease. We focused on the possible role of several metabolic features of NAFLD possibly leading to hypercoagulation other than endothelial and platelet activation, such as insulin-resistance, nitric oxide production regulation, and gut microbiota homeostasis. Also, we analysed the involvement of plasminogen activator inhibitor-1 (PAI-1) and thromboinflammation taking place in NAFLD. Finally, we described factors striking a prothrombotic imbalance in NASH cirrhosis, with a particular focus on the pathogenesis of portal vein thrombosis.

Genetic heterogeneity is a well-recognized feature of hepatocellular carcinoma (HCC). The coexistence of multiple genetic alterations in the same HCC nodule contributes to explain why gene-targeted therapy has largely failed. Targeting of early genetic alterations could theoretically be a more effective therapeutic strategy preventing HCC. However, the failure of most targeted therapies has raised much perplexity regarding the role of genetic alterations in driving cancer as the main paradigm. Here, we discuss the methodological and conceptual limitations of targeting genetic alterations and their products that may explain the limited success of the novel mechanism-based drugs in the treatment of HCC. In light of these limitations and despite the era of the so-called “precision medicine,” prevention and early diagnosis of conditions predisposing to HCC remain the gold standard approach to prevent the development of this type of cancer. Finally, a paradigm shift to a more systemic approach to cancer is required to find optimal therapeutic solutions to treat this disease.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the commonest liver cancer. It is expected to become the third leading cause of cancer-related deaths in Western countries by 2030. Effective pharmacological approaches for HCC are still unavailable, and the currently approved systemic treatments are unsatisfactory in terms of therapeutic results, showing many side effects. Thus, searching for new effective and nontoxic molecules for HCC treatment is of paramount importance. We previously demonstrated that lysophosphatidic acid (LPA) is an important contributor to the pathogenesis of HCC and that lysophosphatidic acid receptor 6 (LPAR6) actively supports HCC tumorigenicity. Here, we screened for novel LPAR6 antagonists and found that two compounds, 4-methylene-2-octyl-5-oxotetra-hydrofuran-3-carboxylic acid (C75) and 9-xanthenylacetic acid (XAA), efficiently inhibit HCC growth, both in vitro and in vitro, without displaying toxic effects at the effective doses. We further investigated the mechanisms of action of C75 and XAA and found that these compounds determine a G1-phase cell cycle arrest, without inducing apoptosis at the effective doses. Moreover, we discovered that both molecules act on mitochondrial homeostasis, by increasing mitochondrial biogenesis and reducing mitochondrial membrane potential. Overall, our results show two newly identified LPAR6 antagonists with a concrete potential to be translated into effective and side effect-free molecules for HCC therapy.

Usually, meningiomas are benign neoplasms and their malignant behavior is limited to local recurrence and brain invasion. The rate of local recurrence increases according to histological grade as reported by WHO criteria while extracranial metastases are rare. Anaplastic meningiomas (AM) represent the most rare and aggressive subtype of all meningiomas. This tumor may progress from lower grade I or II meningiomas (secondary AM) or develops as de novo disease (primary AM). We report a case of extracranial metastatic progression of a heavily treated intracranial secondary anaplastic meningioma. The metastatic progression was detected as unexpected and unsuspected diagnosis because it occurred in absence of local intracranial recurrence. There are no criteria to evaluate the risk for the metastatic spread. In hindsight, a malignant progression in tumor histological grade and a significant increase of ki-67 index represent useful predictors of the aggressive behavior.

Over the last decades, a better knowledge of the molecular machinery supervising the regulation of circadian clocks has been achieved, and numerous findings have helped in unravelling the outstanding significance of the molecular clock for the proper regulation of our physiologic and metabolic homeostasis. Non-alcoholic fatty liver disease (NAFLD) is currently considered as one of the emerging liver pathologies in the Western countries due to the modification of eating habits and lifestyle. Although NAFLD is considered a pretty benign condition, it can progress towards non-alcoholic steatohepatitis (NASH) and eventually hepatocellular carcinoma (HCC). The pathogenic mechanisms involved in NAFLD development are complex, since this disease is a multifactorial condition. Major metabolic deregulations along with a genetic background are believed to take part in this process. In this light, the aim of this review is to give a comprehensive description of how our circadian machinery is regulated and to describe to what extent our internal clock is involved in the regulation of hormonal and metabolic homeostasis, and by extension in the development and progression of NAFLD/NASH and eventually in the onset of HCC.

Endometrial cancer is the most common cancer of the female genital tract in Western Countries, with an incidence of 150.000 new cases/year. Despite high incidence, little is known about the molecular pathogenesis of this tumor. Phospholipids including lysophosphatidic acid (LPA) are involved in proliferation and dissemination of cancer. LPA is a potent bioactive phospholipid synthesized by autotaxin (ATX) through its lysophospholipase D activity. Recent evidence suggests that the ATX/LPA signaling axis plays a role in endometrial cancer. We carried out a prospective study involving two groups of patients classified in accordance to hysteroscopic-guided biopsy. Patients with histological diagnosis of endometrial cancer were enrolled into group one, whereas control patients with pelvic organ prolapse were assigned group two. Both groups underwent hysterectomy, with either open or laparoscopic surgery. After uterine extraction, a second endometrial biopsy was performed to collect tissues. Real-Time PCR was performed to evaluate ATX gene expression in collected tissues. Statistical analysis including unpaired two-way or one-way Student’s t test and ANOVA was performed. We found ATX gene expression significantly higher in neoplastic endometrium compared with normal tissue (P value = 0.0002). In particular, the expression of ATX was significantly elevated in type I endometrial cancer (i.e., endometrioid histotype) compared to type II, in premenopausal women and in patients affected either by obesity (BMI > 30) or diabetes. We propose ATX as a novel potential biomarker particularly implicated in the pathobiology of type I endometrial cancer. Also, we propose ATX as a useful theranostic target in endometrial cancer.

Although several molecular markers have been proposed as prognostic of disease progression in Hepatocellular carcinoma (HCC), predictive markers of response to treatment are still unsatisfactory. Here, we propose a genetic polymorphism as a potential predictive factor of poor prognosis in HCC patients treated with transcatheter arterial chemoembolization (TACE). In particular, we show that the guanosine insertion/deletion polymorphism in the promoter region of SERPINE1 gene at the −675 bp position, named 4G/4G, predicts poor prognosis in a cohort of 75 patients with HCC undergoing TACE. By a combination of ELISA and SERPINE1 promoter study, we found that the presence of elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) in patients with 4G/4G genotype is significantly associated with reduced overall survival compared to patients with 5G/5G or 4G/5G genotype in HCC patients after TACE. Our analysis provided evidence that variation in SERPINE1 gene plays a role in defining the outcome in patients treated with TACE. In addition to a poor disease outcome, the 4G/4G variant represents an unfavorable predictive factor for response to chemotherapy as well.

ABSTRACT Sorafenib is an oral multikinase inhibitor with anticancer activity against a wide spectrum of cancers. It is currently approved for the treatment of patients with hepatocellular carcinoma, advanced renal cell carcinoma or progressive, locally advanced or metastatic differentiated thyroid carcinoma. In this review, we present a number of studies that investigated the efficacy and safety of sorafenib in these settings. We also discuss the perspectives on the use of this molecule, including the role of sorafenib as comparator for the development of new drugs, the combination of sorafenib with additional therapies (such as transarterial chemoembolization for hepatocellular carcinoma) and the use of this treatment in several other advanced refractory solid tumors.

Despite the reducing incidence of chronic hepatitis infections, an unexpected increasing incidence of hepatocellular carcinoma (HCC) has being occurred. This may be explained by the increasing number of HCCs developing on steatosis (NAFLD) and steatohepatitis (NASH), related to metabolic risk factors (i.e. diabetes mellitus type II, obesity, metabolic syndrome), which are becoming emerging risk factors for HCC. This led to a growing scientific interest on the oncogenic mechanisms underlying the transition from NAFLD to HCC. However, patients with NASH receive significantly less HCC surveillance than patients with chronic hepatitis, and no specific preventive pharmacological treatments have recommended for NASH-related HCC. This review focuses on the pathogenic role of the emerging factors involved in the transition from NAFLD/NASH to HCC, including microbiota, insulin resistance, inflammation, lipid and bile acids metabolism. It will be emphasize their impact on the liver microenvironment, the implications in clinical practice and the future directions of research.

Hepatocellular carcinoma, the most frequent solid tumor of the liver, has a very poor prognosis, being the second most common cause of death from cancer worldwide. The incidence and mortality of this liver tumor are increasing in most areas of the world as a consequence of aging and the emerging of new risk factors such as the metabolic syndrome, beside the recognized role of hepatitis B and C viral infections and alcohol abuse. Despite the increasing knowledge on the molecular mechanisms underlying hepatic carcinogenesis, effective therapeutic strategies are still an unmet clinical need. Efforts have been made to develop selective drugs as well as effective targeted drug delivery systems. The development of novel drug carriers for therapeutic molecules can indeed offer a valuable strategy to ameliorate the efficacy of HCC treatment. In this review, we discuss recent drug delivery strategies for HCC treatment based on the exploitation of targeted nanoparticles (NPs). Indeed, a few of these platforms have achieved an advanced stage of preclinical development. Here, we review the most promising drug nanovehicles based on both synthetic and natural polymers, including polysaccharides that have emerged for their biocompatibility and biodegradability. To maximize site-selectivity and therapeutic efficacy, drug delivery systems should be functionalized with ligands which can specifically recognize and bind targets expressed by HCC, namely cell membrane associated antigens, receptors or biotransporters. Cell surface and intracellular molecular targets are exploited either to selectively deliver drug-loaded nanovehicles or to design novel selective therapeutics. In conclusion, the combination of novel and safe drug delivery strategies based on site-specific targeted drug nanovehicles with therapeutic molecular targets may significantly improve the pharmacological efficacy for the treatment of HCC.

Angiotensin II receptor blockers (ARBs) are drugs generally well tolerated. There are few reports about cutaneous side effects of ARBs. The present authors describe herein four cases of purpuric eruption mainly involving sites of friction in patients taking ARBs. These eruptions completely cleared after stopping the drug and implementing preservative measures to reduce friction.

Background: Cancer Antigen 15-3 (CA 15-3) is a tumor-associated antigen used as serum marker for breast cancer surveillance in patients and for monitoring the response to treatment. Aim of this study was to retrospectively evaluate CA 15-3 as a prognostic factor in early detection of breast cancer relapse as well as to analyze the statistical correlation between CA 15-3 levels and clinical-pathological parameters including staging, grading, estrogen and progesterone receptors. Methods: Sera of 726 women with breast carcinoma obtained preoperatively and postoperatively were assayed for CA 15- 3 by chemoluminescent immunometric assay. Results: We found that the mean serum CA 15-3 levels in patients before surgery were significantly higher (36.59 U/ml) compared with those of CA 15-3 after surgery (27.11 U/ml). We also found that elevated preoperative serum levels of CA 15-3 were significantly correlated with the presence of metastatic disease. In particular, among 305/700 patients (43,6%) that displayed over cut-off (>40U/ml) preoperative levels of CA 15-3, 94 patients (30,8%) developed advanced disease (metastases to distant sites). By contrast, in a subgroup of 395/700 patients (56.4%) with CA 15.3 serum levels < 40U/ml, only 32/305 patients (8%) showed signs of advanced disease during follow-up. Cox regression analysis revealed that only the presence of metastasis and the increased serum levels of CA 15-3 after surgery are significant risk factors for relapse of disease. Conclusion: Elevated preoperative concentrations of CA 15-3 may be a useful predictive factor for cancer progression in postoperative patients.

Background: ADIPOQ gene, which encode for Adiponectin (APN), is sited on chromosome 3q27 and linked to a susceptibility locus for metabolic syndrome (MetS). The ADIPOQ rs266729 G/C gene polymorphism is significantly associated with low APN levels and linked to susceptibility to develop cancer. In addition, decreased APN serum levels are linked with tumor development and progression and inversely associated with markers of inflammation. Here, we investigate the influence of APN rs266729 G/C polymorphism on adipocytokine circulating levels and their association with MetS in colorectal cancer patients (CRC). Methods: Blood samples from 105 CRC patients (50 women and 55 men) with and without MetS were genotyped for APN rs266729 G/C polymorphism by TETRA ARMS PCR. ELISA assay was used to measure plasma levels of APN and inflammatory TNF-α cytokine. Biochemical and anthropometric parameters of MetS were also analyzed. Results: We found that CRC patients (N=75) with genotype rs266729G/C or carriers of G allele were associated with a significantly increased risk of MetS development (OR =2.9) compared to those with CC genotype (N=30). Also, CG/GG genotypes were associated with significantly lower plasma APN levels and higher TNF-α levels in comparison to CC genotype (P=0.034) and APN levels were decreased in relation to BMI increases (P=0.001). Conclusions: Our findings show that APN rs266729 G/C polymorphism is associated with lower APN levels in CRC patients, indicating that decreased circulating levels of APN may be a determinant risk factor for CRC in MetS patients.

Hepatocellular carcinoma (HCC) is a cancer that usually develops on a liver already compromised by cirrhosis. Study of the underlying molecular mechanisms is essential so as to improve therapeutic strategies and to develop new pharmacological agents that may prevent or improve the course of this malignancy. Transforming growth factor-beta (TGF-β) intervenes in the process of hepatic fibrogenesis and cirrhosis, two pathogenic preconditions for the formation and progression of HCC [1] [2]. In addition, TGF-β plays a crucial role in the molecular pathogenesis of HCC and may, therefore, prove to be a promising drug target. We and other authors have recently demonstrated that inhibition of the TGF-β signaling pathway results in a synergistic downstream action with an inhibitory effect on the progression of HCC. Several TGF-β inhibitors have recently been developed, most of which are still in a preclinical phase, but they may soon be available for testing in patients with HCC. However, well-designed clinical trials will be needed to evaluate the effectiveness of these new agents prior to routine use in the clinic. Aim of this article is to make a brief review of the benefits and limitations of targeting the TGF-β signaling pathway in HCC.

The combination of pegylated interferon (Peg-IFN) and ribavirin is currently the gold standard therapy in patients with HCV chronic infection. The duration of therapy, as well as the therapeutic dosage, depend on the genotype. Identification of the genotype and rapid virological response (RVR) are widely accepted as the most important predictors of clinical outcome during antiviral therapy but to optimize cost-benefits and to reduce possible side effects, further prognostic factors are needed. Squamous cell carcinoma antigens immunocomplex (SCCA-IC) has been reported to be increased in the serum of patients with liver cancer. In this multicentric prospective study, we investigated the serum levels of SCCA-IC in 103 patients with HCV chronic infection. Serum HCV-RNA was detected before the beginning of treatment, after 4, 12, 24 or 48 weeks, and at week 24 during follow-up. RVR, early virological response and sustained virological response (SVR) were assessed following the international guidelines. SCCA-IC levels were higher in responders (238 AU, interquartile difference 130-556 AU) and decreased significantly to 125 AU (70-290 AU). The mean baseline value in nonresponders was 149 AU (86.5-306.5 AU), but after 4 weeks of treatment the serum levels decreased to 115 AU (80-280 AU): the profile of reduction was different between patients with or without a positive SVR. Logistic regression with SVR as dependent variable identified as significant independent variables: the reduction in SCCA-IC after 1 month (OR = 4.82; 95% CI 1.39-16.67; P = 0.131) and a genotype other than 1 (OR = 0.094; 95% CI 0.21-0.42; P = 0.002); sex and age were also significant factors influencing SVR. SCCA-IC seems to be a reliable independent prognostic marker of therapeutic effectiveness in anti-HCV positive patients undergoing antiviral therapy.

One of the main complications in patients with liver fibrosis is the development of hepatocellular carcinoma (HCC). An understanding of the molecular mechanisms leading to HCC is important in order to be able to design new pharmacological agents serving either to prevent or mitigate the outcome of this malignancy. The transforming growth factor-beta (TGF-β) cytokine and its isoforms initiate a signaling cascade which is closely linked to liver fibrosis, cirrhosis and subsequent progression to HCC. Because of its role in these stages of disease progression, TGF-β appears to play a unique role in the molecular pathogenesis of HCC. Thus, it is a promising target for pharmacological treatment strategies. Recent studies have shown that inhibition of TGF-β signaling results in multiple synergistic down-stream effects which will likely improve the clinical outcome in HCC. We also review a number of TGF-β inhibitors, most of which are still in a preclinical stage of development, but may soon be available for trial in HCC patients. Hence, it is anticipated that there will soon be new agents available for clinical investigations to evaluate the role of the TGF-β-associated signaling in this deadly cancer.

“It is likely that the development of new drugs acting on the RAS/RAF/MEK/ERK signaling pathway and the receptor crosstalk mechanisms may lead to a further improvement in the overall survival of patients with advanced hepatocellular carcinoma.”

Background A close relationship between Metabolic Syndrome (MetS) and Chronic Obstructive Pulmonary Disease (COPD) has been described, but the exact nature of this link remains unclear. Current epidemiological data refer exclusively to the MetS prevalence among patients with COPD and data about the prevalence of COPD in MetS patients are still unavailable. Aim of the study To analyse and compare risk factors, clinical and metabolic characteristics, as well as the main respiratory function parameters, among patients affected by MetS, COPD or both diseases. Patients We recruited 59 outpatients with MetS and 76 outpatients with COPD. After medical history collection, physical examination, blood sampling for routine analysis, spirometric evaluation, they were subdivided into MetS (n = 46), MetS+COPD (n = 60), COPD (n = 29). Results A MetS diagnosis was assigned to 62% of COPD patients recruited in the COPD Outpatients Clinic of the Pneumology Department, while the COPD prevalence in MetS patients enrolled in the Internal Medicine Metabolic Disorders Outpatients Clinic was 22%. More than 60% of subjects enrolled in each Department were unaware that they suffered from an additional disease. MetS+COPD patients exhibited significantly higher C-peptide levels. We also found a positive relation between C-peptide and pack-years in all subjects and a negative correlation between C-peptide and vitamin D only in current smokers. Finally, a negative association emerged between smoking and vitamin D. Conclusions We have estimated, for the first time, the COPD prevalence in MetS and suggest a potential role of smoking in inducing insulin resistance. Moreover, a direct effect of smoking on vitamin D levels is proposed as a novel mechanism, which may account for both insulin resistance and COPD development.

Colon carcinoma is a malignant tumor showing a marked preference to metastasize to distant organs. The presence of circulating tumor cells (CTCs) in the peripheral blood is a prerequisite for the formation of distant metastases. However, whether circulating cytokines are linked to the circulation of tumor cells, as individual cells or clusters, remain unclear. In this study, we investigated the circulating levels of TGF-beta, CXCL1, VEGF and PAI-1 as potential bioindicators of the presence of CTCs in patients with metastatic colon cancer.Circulating tumor cells (CTCs) were isolated from peripheral blood by immunomagnetic separation and phenotypically characterized in a cohort of 103 patients with metastatic colon cancer. TGF-beta, CXCL1, VEGF and PAI-1 concentrations were determined by immunoassay in plasma samples from the same patients.We detected two different populations of CTCs, single cells or clusters in patients with metastatic colon cancer. Importantly, we found that the presence of clustered CTCs is significantly associated with elevated circulating levels of TGF-beta and CXCL1 and with reduced overall survival. Finally, we observed that circulating levels of cytokines are differently associated with the two populations of CTCs.Taken together, these findings show that detection of clustered CTCs represents a negative prognostic factor in patients with metastatic colon cancer. The presence of clustered CTCs is associated with elevated circulating levels of cytokines such as TGF-beta and CXCL1. This suggests an additional role for circulating cytokines as predictive tool for cancer prognosis and diagnosis of minimal residual disease as well as assessment of tumor sensitivity to anticancer therapy.

We investigated blocking the TGF-β signaling pathway in HCC using two small molecule inhibitors (LY2157299, LY2109761) and a neutralizing humanized antibody (D10) against TGF-βRII. LY2157299 and LY2109761 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-βRII. In contrast to LY2157299, D10 showed a reduction in pSMAD2 only after a short exposure. This study supports the use of LY2157299 in clinical trials, and presents new insights into TGF-β receptor cycling in cancer cells.

e23280Background: Adiponectin (APN), the product of the ADIPOQ gene, is sited on chromosome 3q27, which is linked to a susceptibility locus for metabolic syndrome (MetS). MetS is associated with an...

Purpose Colon carcinoma is a malignant tumor showing a marked preference to metastasize to distant organs. The presence of circulating tumor cells (CTCs) in the peripheral blood is a prerequisite for the formation of distant metastases. However, whether circulating cytokines are linked to the circulation of tumor cells, as individual cells or clusters, remain unclear. In this study, we investigated the circulating levels of TGF-beta, CXCL1, VEGF and PAI-1 as potential bioindicators of the presence of CTCs in patients with metastatic colon cancer.

Tumor–stroma interactions in hepatocellular carcinoma (HCC) are of key importance to tumor progression. In this study, we show that HCC invasive cells produce high levels of connective tissue growth factor (CTGF) and generate tumors with a high stromal component in a xenograft model. A transforming growth factor β (TGF-β) receptor inhibitor, LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the tumors. In addition, the TGF-β–dependent down-regulation of CTGF diminished tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon TGF-β1 stimulation, noninvasive HCC cells form tumors with a high stromal content and CTGF expression, which is inhibited by treatment with LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after TGF-β1 stimulation was blocked by LY2109761. LY2109761 interrupts the cross-talk between cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing TGF-β–dependent CTGF expression may offer clinical benefits. Conclusion: Taken together, our preclinical results indicate that LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials. (HEPATOLOGY 2009.)

Curative therapies for patients with hepatocellular carcinoma (HCC) are mainly invasive, and with the exception of sorafenib, no medical treatments are available for advanced or metastatic stages of HCC. We investigated the antitumoral effect of blocking the transforming growth factor β (TGF-β) signaling pathway in HCC with LY2109761, a kinase inhibitor of TGF-β receptor I kinase. The antitumor activity of LY2109761 was associated with inhibition of molecular pathways involved in neo-angiogenesis and tumor growth of HCC. This anti-angiogenic effect is more effective than that of bevacizumab, which specifically targets vascular endothelial growth factor (VEGF). We found that the paracrine cross-talk between HCC and endothelial cells is blocked by LY210976, inhibiting blood vessel formation. This effect was mediated by SMAD2/3 and affected the secretion of VEGF. Finally, LY2109761 does not show significant effects on phsyiological angiogenetic development. Conclusion: These data support the rationale for targeting TGF-β signaling in patients with HCC. (HEPATOLOGY 2009.)

ejd.2012.1853 Auteur(s) : Caterina Foti1 c.foti@dermatologia.uniba.it, Annarita Antelmi1, Antonio Mazzocca2, Francesco Saverio Vella2, Paolo Romita1, Stefania Pugliese3, Daniela Lomazzo3, Piero Portincasa3, Giuseppe Palasciano3 1 Section of Dermatology, Department of Biomedical Sciences and Human Oncology, 2 Department of Emergency and Organ Transplantation, 3 Clinica Medica Augusto Murri, Department of Biomedical Sciences and Human Oncology University of Bari Medical School, 70124 Bari, Italy Drug [...]

1044 LYSOPHOSPHATIDIC ACID RECEPTOR 6 (LPA6) PROMOTES HEPATOCELLULAR CARCINOMA GROWTH AND PROGRESSION THROUGH ACTIVATION OF PIM-3 PROTO-ONCOGENE KINASE A. Mazzocca, F. Dituri, F. De Santis, L. Lupo, A. Azzariti, C. Sabba, G. Giannelli. Internal Medicine Unit C. ‘Frugoni’ University of Bari A. Moro, Section of General Surgery and Organ Transplantation, University of Bari Medical School, Department of Experimental Oncology, National Cancer Institute, Bari, Italy E-mail: gianluigi.giannelli@uniba.it

276 LYSOPHOSPHATIDIC ACID RECEPTOR 6 (LPA6) IS A MASTER REGULATOR ORCHESTRATING AND PROMOTING TUMOR GROWTH DURING HCC PROGRESSION A. Mazzocca, F. Dituri, F. De Santis, S. Antonaci, G. Giannelli. Department of Emergency and Organ Transplantation, Section of Internal Medicine Allergology and Immunology, Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari, Bari, Italy E-mail: g.giannelli@intmed.uniba.it

276 LYSOPHOSPHATIDIC ACID RECEPTOR 6 (LPA6) IS A MASTER REGULATOR ORCHESTRATING AND PROMOTING TUMOR GROWTH DURING HCC PROGRESSION A. Mazzocca, F. Dituri, F. De Santis, S. Antonaci, G. Giannelli. Department of Emergency and Organ Transplantation, Section of Internal Medicine Allergology and Immunology, Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari, Bari, Italy E-mail: g.giannelli@intmed.uniba.it

Background: A sentinel lymph node is the first lymph node to receive lymphatic drainage from a tumour. In patients with breast cancer, several studies suggest that sentinel lymph node biopsy can accurately predict the status of axillary lymph nodes and so avoid them removal. Invasion and metastasis are the most important problems in the management of breast cancer. These events require diverse proteolytic enzymes among which MMP-2 and MMP-9 play a significant role in degradation of type IV collagen, the major component of the Basement Membrane (BM). The main objective of this study is to evaluate the expression of MMP-2 and MMP-9 in sentinel lymph node and serum of breast cancer patients at the aim to evaluate their clinical usefulness as diagnostic tumour markers in breast cancer. Material and Methods: Expression of MMP-2 and MMP-9 was performed on sentinel lymph node by immunohistochemistry while gelatine zymography was used to determinate the serum expression of both Metalloproteinases. The association of MMP-2 and MMP-9 with clinicopathological features, including histological type, estrogen (ER) and progesterone (PgR), cancer familiarity and CA 15.3 levels were also analysed. In all 50 metastatic e non metastatic breast cancer patients and 34 healthy women were involved. Results: MMP-2 and MMP-9 expression were statistically significant higher in metastatic breast cancer patients respect to non metastatic cancer patients and control group both in the sentinel lymph node and serum (p< 0.01). Besides our results show a statistically significant correlation between higher of MMP-2 and MMP-9 and cancer familiarity (p Conclusion: Our date suggest a possible significant clinical utility of these proteolytic markers in malignant tumour, growth, invasion and metastasis in breast cancer and the role of sentinel lymph node to predict a possible involvement of axillary lymph nodes. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B48

Background/aim The aim of this study was to evaluate whether the altered profile of adipocytokine and genetic fingerprint in NAFLD-associated metabolic syndrome "cluster" represents synergistic risk factors predicting onset of liver colorectal cancer metastases. Materials and methods A total of 165 colorectal cancer patients were enrolled, 56,3% were with metabolic syndrome/NAFLD. Serum samples were assayed for ADIPOQ, leptin and TNF-a levels by ELISA. ADIPOQ rs266729 C/G and TNF-308 A/G genotypes were analyzed in DNA isolated from whole blood. Results Reduction in adiponectin levels and increase in leptin and TNF-α was shown in patients with liver metastases. This trend was influenced by BMI, MetS/NAFLD, and insulin resistance. ADIPOQ G rs266729 and TNF- 308 A allele are associated with obesity, MetS/NAFLD and insulin resistance. ADIPOQ CG/GG and GA/AA TNF-alpha genotypes confer susceptibility to liver metastases. Conclusion Obesity and hepatic steatosis significantly favor the development of colorectal cancer liver metastases and the individual adipocytokines genetic profile may play an important predictive role.