Antonella Daniele

Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation

Adipose tissue in addition to its ability to keep lipids is now recognized as a real organ with both metabolic and endocrine functions. Recent studies demonstrated that in obese animals is established a status of adipocyte hypoxia and in this hypoxic state interaction between adipocytes and stromal vascular cells contribute to tumor development and progression. In several tumors such as breast, colon, liver and prostate, obesity represents a poor predictor of clinical outcomes. Dysfunctional adipose tissue in obesity releases a disturbed profile of adipokines with elevated levels of pro-inflammatory factors and a consequent alteration of key signaling mediators which may be an active local player in establishing the peritumoral environment promoting tumor growth and progression. Therefore, adipose tissue hypoxia might contribute to cancer risk in the obese population. To date the precise mechanisms behind this obesity-cancer link is not yet fully understood. In the light of information provided in this review that aims to identify the key mechanisms underlying the link between obesity and cancer we support that inflammatory state specific of obesity may be important in obesity-cancer link.

Epidermal growth factor receptor serum levels and prognostic value in malignant gliomas.

Aims and background The epidermal growth factor receptor (EGFR) is a member of a family of cell membrane receptors that use tyrosine kinase activity as the signal transduction mechanism. It is commonly expressed or overexpressed by many solid tumors and correlates with disease progression and a poor clinical prognosis. Increased EGFR expression might therefore be a strong prognostic feature in multiple tumor types, and inhibition of its cellular actions may have substantial therapeutic benefit. The aim of this study was to estimate the EGFR serum concentration for potential use as a biological marker of brain cancer to predict prognosis and follow-up after treatment. Methods and study design Serum samples obtained from 50 healthy individuals and 65 brain cancer patients (35 glioblastoma multiforme and 30 anaplastic astrocytomas) were collected before and after treatment and assayed for EGFR extracellular domain serum concentrations by a sandwich ELISA. Results EGFR was elevated in 47 of 65 brain cancer patients, with mean serum values of 84 ± 18 ng/ml, compared with that of healthy controls (43.6 ± 11 ng/ml, P = 0.001). There was a significant difference in the mean serum levels of EGFR between glioblastoma multiforme patients (96.2 ± 12 ng/ml) and anaplastic astrocytoma patients (71.6 ± 18 ng/ml, P = 0.04). Sixty brain cancer patients underwent surgery; EGFR serum levels did not show significant differences from those observed before surgery. For all patients, median overall survival was 13 months (anaplastic astrocytoma, 18 months; glioblastoma multiforme, 12.5 months). In 47 patients with high EGFR serum levels, overall survival was reduced (P = 0. 01), with a median survival time corresponding to 11.5 months (anaplastic astrocytoma, 14.5 months; glioblastoma multiforme, 10.5 months). Conclusions Although a prospective study with large sample size is warranted, serum EGFR extracellular domain may be potentially useful as a biological marker of gliomas for prediction of prognosis and follow-up after treatment.

Proteolytic imbalance is reversed after therapeutic surgery in breast cancer patients.

The occurrence of metastasis severely affects prognosis and survival of breast cancer patients. In order to metastasize, breast cancer cells need to cross the basement membrane (BM) tissue boundaries. Matrix metalloproteases (MMPs) are enzymes with proteolytic activity towards extracellular matrix components (ECM) of the BM, that are blocked by physiological tissue inhibitors (TIMPs). Cancer metastasis occurs as a result of an imbalance between MMPs, in particular MMP‐2 and MMP‐9, and TIMPs, in particular TIMP‐2 and TIMP‐1. This is the first study to report that pro‐MMP‐9 and TIMP‐1 serum concentrations are inversely correlated in breast cancer patients. In the same patients, we determined the pro‐MMP‐9, the TIMP‐1, the pro‐MMP‐2 and TIMP‐2 before and after surgical eradication of the breast cancer. Our results show that after surgery, when the breast cancer tissue was removed, pro‐MMP‐9 concentrations dramatically decreased and TIMP‐1 concentrations strongly increased, with statistically significant differences, so that a new balance was established. No statistically significant differences were observed regarding pro‐MMP‐2 and TIMP‐2. Also, no correlation was found between pro‐MMP‐2, pro‐MMP‐9, TIMP‐1 and TIMP‐2 and a number of clinical and pathological parameters. In conclusion, our study suggests that pro‐MMP‐9 and TIMP‐1 could be used as markers of disease during the follow‐up of breast cancer patients and possibly as prognostic markers, although more studies are needed to address this issue.

c-erbB-2 PROTEIN LEVEL IN TISSUE AND SERA OF BREAST CANCER PATIENTS: A POSSIBLY USEFUL CLINICAL CORRELATION

Aims and background The aims of this study were to assess the clinical utility of circulating preoperative HER-2 extracellular domain p105 detected by enzyme immunoassay (ELISA), to compare the tissue expression of HER-2/neu determined by immunohistochemistry (IHC), to correlate prognostic factors including tumor size, nodal involvement, and hormone receptor status, and to analyze the prognostic significance of the marker in relation to clinical outcome as measured by disease-free and overall survival. Methods In this study, we enrolled 108 consecutive patients with breast carcinoma, and obtained serum samples and frozen tumor tissues. We compared them with 57 women with fibroadenoma and 63 healthy women as controls. Results Univariate ANOVA analysis showed no relationship between HER-2/neu in tissue and serum. Preoperative serum levels of p105 were significantly higher in breast cancer patients than in women with benign disease or healthy women. Concerning the correlation between p105, HER-2/neu tissue expression, and the other prognostic factors, a statistically significant correlation between high serum p105 levels and ER-negative status in breast cancer patients was found. Kaplan-Meier analysis confirmed that patients with positive HER-2/neu tissue expression had a significantly shorter survival than those with negative expression. Analysis with the Cox model demonstrated that tumor size was the only significant independent prognostic factor. Conclusions This research failed to demonstrate a relationship between preoperative tissue overexpression and circulating HER-2/neu, suggesting that p105 does not represent a valid alternative to predict a worsened prognosis in breast cancer, but it could be a diagnostic marker to discriminate healthy subjects from breast cancer patients.

Sorafenib and locoregional deep electro‑hyperthermia in advanced hepatocellular carcinoma: A phase II study

The standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib, a multikinase inhibitor of tumor cell proliferation and angiogenesis. Hyperthermia inhibits angiogenesis and promotes apoptosis. Potential synergic antiangiogenic and proapoptotic effects represent the rationale for combining sorafenib with electro-hyperthermia (EHY) in HCC. A total of 21 patients (median age, 64 years; range, 55–73 years) with advanced HCC were enrolled in the current study between February 2009 and September 2010. EHY was achieved by arranging capacitive electrodes with a deep hypothermia radiofrequency field of 13.56 Mhz at 80 W for 60 min, three times per week for six weeks, followed by two weeks without treatment, in combination with sorafenib at a dose of 800 mg every other day. According to the modified Response Evaluation Criteria in Solid Tumors criteria, 50% achieved stable disease, 5% achieved partial response and 45% achieved progressive disease. No complete response was observed. The progression-free survival (PFS) rate at six months was 38%, while the median PFS and overall survival times were 5.2 [95% confidence interval (CI), 4.2–6.2) and 10.4 (95% CI, 10–11) months, respectively. The overall incidence of treatment-related adverse events was 80%, predominantly of grade 1 or 2. Grade 3 toxicity included fatigue, diarrhea, hand-foot skin reaction and hypertension. In the present study, the sorafenib plus EHY combination was feasible and well tolerated, and no major complications were observed. The initial findings indicated that this combination offers a promising option for advanced HCC.

Clinical and prognostic role of matrix metalloproteinase-2, -9 and their inhibitors in breast cancer and liver diseases: A review.

Matrix metalloproteinases are a family of zinc endopeptidases with proteolytic activity against the extracellular matrix components. In particular, two members of this family named Gelatinase A and B, as amply documented in the literature, play a key role in the process of tumor growth/metastasis in breast and hepatocellular carcinoma. Their activity is regulated by Tissue Inhibitor of metalloproteinases-1 and -2, which are the physiological inhibitor of Gelatinases A and B respectively. The aim of this review is to determine the current understanding of the clinical and prognostic role of Metalloproteinases-2 and -9 and their inhibitors in the course of breast cancer and liver diseases. Forty-one articles were selected from PubMed by entering the following keywords: liver diseases, breast cancer, MMP-2, TIMP-2; all articles were read and notes were made regarding the number of enrolled patients, pathology, measures, results and these data were used to write this review. Over-expression of both gelatinases is associated with the relapse of disease, metastasis, shorter overall survival in breast cancer and hepatocellular carcinoma and invasion and progression to tumors in chronic liver diseases, and MMPs/TIMPs ratio could be useful in the follow-up of these patients.

Clinical and prognostic role of circulating MMP-2 and its inhibitor TIMP-2 in HCC patients prior to and after trans-hepatic arterial chemo-embolization

BACKGROUND AND AIMS Trans-hepatic arterial chemo-embolization is the most commonly used treatment for unresectable hepatocellular carcinoma. The prognostic impact of tumor biomarkers has not therefore been evaluated in this treatment. Imbalance between matrix metalloproteinase-2 and tissue inhibitor metalloproteinase-2 is considered to play an important role in extracellular matrix remodeling and degradation. Higher serum levels of MMP-2 have been shown to predict a poor prognosis and shorter overall survival in HCC after TACE. The objective of this study was to evaluate the serum levels of MMP-2 and TIMP-2 in HCC patients before and after TACE to evaluate their clinical significance and usefulness as prognostic biomarkers. METHODS MMP-2 and TIMP-2 levels were measured by ELISA in 75 HCC patients and 30 healthy controls. Sera MMP-2 and TIMP-2 were correlated with clinico-pathological features. RESULTS The mean serum MMP-2 and TIMP-2 levels of HCC patients before TACE were 1700±71ng/mL and 89±45ng/mL respectively, significantly higher than that of the control group: 771±60ng/mL (p<0.0001, t-test) and 25.7±20ng/mL respectively (p<0.0001, t-test). A significant decrease of MMP-2 levels after 1 and 3months compared to baseline time was observed (p<0.0001), while with TIMP-2 a gradual increase in serum before and after TACE (p<0.01) was detected. No significant correlation between serum MMP-2 levels and other clinico-pathological features was observed. Patients with serum MMP-2 >1500ng/mL (median value) had worse overall and recurrence-free survival compared with those with serum MMP-2 levels <1500ng/mL before treatment. CONCLUSION Higher serum MMP-2 levels and MMP-2/TIMP-2 ratio could predict poor prognosis after TACE, suggesting prognostic role of these biomarkers in HCC.

The presence of clustered circulating tumor cells (CTCs) and circulating cytokines define an aggressive phenotype in metastatic colorectal cancer

AbstractPurpose 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.MethodsCirculating 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.ResultsWe 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.ConclusionsTaken 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.

Circulating Levels of PAI-1 and SERPINE1 4G/4G Polymorphism Are Predictive of Poor Prognosis in HCC Patients Undergoing TACE

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.

Sorafenib: The gold standard therapy in advanced hepatocellular carcinoma and beyond

“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.”