Simona Aloe

Overexpression of transforming growth factor β-type II receptor reduces tumorigenicity and metastastic potential of K-ras-transformed thyroid cells

Expression of type II receptor of transforming growth factor beta (TbetaRII) is necessary for this factor to inhibit the growth of thyroid epithelial cells. In rat thyroid transformed cells, the resistance to transforming growth factor beta (TGFbeta) is associated with a decreased expression of TbetaRII mRNA and protein. Reduced TbetaRII expression has also been found in human thyroid differentiated and undifferentiated carcinomas. To investigate the role of TbetaRII in modulating the tumorigenic potential of k-ras-transformed thyroid cells, we transfected these cells with an expression vector carrying the human TbetaRII gene, regulated by an inducible promoter. Isolated clones, overexpressing TbetaRII, showed a reduction in the anchorage-dependent and -independent cell growth, compared with control k-ras-transformed cells. When transplanted in athymic nude mice, the transfected clones presented a decrease in tumorigenicity with respect to the highly malignant parental cells. Moreover, the diminished tumorigenic ability of the clones studied was accompanied by a statistically significant reduction in spontaneous and lung artificial metastases. Taken together, our data demonstrate that TbetaRII acts as a potent tumor suppressor gene when overexpressed in malignant thyroid cells.

Prognostic value of soluble P‐selectin levels in colorectal cancer

Measurement of soluble (s) P‐selectin levels has been proposed as a diagnostic tool for monitoring the clinical course of human neoplasms. Thus, our study was aimed at analyzing the role of sP‐selectin in association with clinicopathological variables in 181 patients with primary (n=149) or metastatic (n=32) colorectal cancer (CRC), 34 patients with benign diseases and 181 control subjects. The results obtained showed that sP‐selectin levels were higher in patients with CRC compared either to patients with benign disease (p= 0.006) or controls (p= 0.003). No differences were observed between the latter and patients with benign diseases. Increased median sP‐selectin levels were significantly associated with the presence of distant metastasis (68.2 ng/ml vs. 48.6 ng/ml, p= 0.002). Of interest, carcinoembryonic antigen (CEA) levels were independently associated to sP‐selectin (regression coefficient= 0.28, p< 0.002). Coxs proportional hazards survival analysis of primary CRC patients demonstrated that beside the stage of disease sP‐selectin levels had an independent prognostic role in predicting recurrent disease (HR= 2.22, p= 0.019) and mortality from CRC (HR= 3.44, p= 0.017). These results suggest that measurement of plasma sP‐selectin might represent a prognostic indicator in the management of patients with CRC.

Serum tissue polypeptide specific antigen (TPS): a complementary tumor marker to CA 15-3 in the management of breast cancer

The efficacy of CEA and CA15-3 tumor markers in monitoring breast cancer was evaluated in 1365 patients with either benign (n=534) or malignant (n=831) breast diseases. Thirty-nine breast cancer patients were monitored before and after neoadjuvant chemotherapy. Three hundred forty-nine patients were monitored during post-surgical follow-up for either a minimum of 5 years or until time of recurrence. Twenty-one patients with metastases were also monitored during chemotherapy. Elevated CA 15-3 and TPS levels were found in 28.6% and 30.0% of patients. CA 15-3 and TPS sensitivities rose to 71.9% and 66.3% in metastatic patients, respectively. The addition of TPS to CA 15-3 increased the sensitivity up to 44.4% in the overall population, and to 87.6% in patients with metastases. During post-surgical follow-up CA 15-3 was elevated in 65.7% and TPS in 61.3% of patients with recurrence. The combination of TPS and CA 15-3 increased the overall sensitivity by 12.7%. Longitudinal monitoring of metastatic patients undergoing chemotherapy demonstrated that, when positive, both CA 15-3 and TPS paralleled response to treatment. TPS monitoring may provide additional value when used in combination with CA15-3 during post-surgical follow-up of breast cancer patients.

Prognostic value of serum and tumor tissue CA 72-4 content in gastric cancer.

To date no general agreement has been reached regarding the prognostic significance of CEA, CA 19-9 and CA 72-4 as serum markers in gastric cancer, and only scattered information is available on the predictive value of marker expression in tumor tissue. Therefore, a longitudinal study was designed to analyze the presurgical serum and tumor tissue content of CA 72-4, CEA and CA 19-9 in 166 patients at different stages of gastric cancer, and to evaluate the possible correlation with clinicopathological features in respect to prognostic information on relapse-free survival. The results obtained showed that 48.4% of patients with tumor recurrence had positive presurgical CA 72-4 levels compared to approximately 24% of patients who remained free of disease. Furthermore, the median presurgical serum CA 72-4 levels were significantly elevated in relapsing patients. Serosa and lymph node involvement as well as positive presurgical serum CA 72-4 levels had independent prognostic value in predicting recurrence. A significant association between disease-free survival and lymph node involvement, depth of invasion and tumor tissue content of CA 72-4 was also demonstrated. We may therefore conclude that CA 72-4 antigen can be considered the marker of choice in the follow-up of gastric cancer patients and may be used as a prognostic indicator of relapse.

Association between serum carcinoembryonic antigen and endothelial cell adhesion molecules in colorectal cancer

Objectives: To analyse the behaviour of pre-surgical serum levels of soluble (s)E-selectin and vascular cell adhesion molecule (sVCAM) in patients with colorectal cancer, and to evaluate their possible correlation with carcinoembryonic antigen (CEA), pro-inflammatory cytokines and clinicopathological features with respect to their prognostic value in predicting metastatic disease. Methods: Pre-surgical serum levels of sE-selectin, sVCAM, interleukin-6 (IL-6), IL-1β, tumour necrosis factor-α (TNF-α) and CEA were measured in 194 patients with colorectal adenocarcinoma, 40 patients with benign colorectal diseases and 59 healthy subjects. Results: sE-selectin, sVCAM, TNF-α and IL-6 levels were significantly higher in patients with colorectal cancer compared to either healthy subjects or patients with benign disease. Positive rates of sE-selectin, sVCAM and TNF-α levels were significantly associated with Dukes’ stage D colorectal cancer, and all three variables were independently associated to the presence of distant metastases. Positive sE-selectin, sVCAM and TNF-α levels were significantly associated to CEA. TNF-α and CEA levels were independently related to the presence of positive levels of sE-selectin and/or sVCAM. Conclusions: Our findings suggest that the host inflammatory response to cancer cells, and/or their released products (i.e. CEA), might be responsible (via cytokine release) for the elevation in circulating adhesion molecules in patients with colorectal cancer.

Effects of Isolated Limb Perfusion With Tumor Necrosis Factor-α on Circulating Levels of Proinflammatory Cytokines

Hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor-&agr; (TNF&agr;) and cytotoxic drugs is currently used for treatment of melanoma and sarcoma of the limbs. Tumor necrosis factor-&agr; is involved in the systemic inflammatory response syndrome as a result of activation of inflammatory cells and production of bioactive substances. The goal of this study was to determine the circulating levels of proinflammatory cytokines and soluble adhesion molecules in 19 patients with limb melanoma or sarcoma undergoing ILP with (n = 9) or without TNF&agr; (n = 10). The results obtained demonstrated that ILP with TNF&agr; was responsible for a leakage of TNF&agr; in the systemic circulation, followed by a rise in interleukin (IL)-6 and IL-8 levels within 1 h. Elevated soluble (s)P-selectin levels were found 1–3 h after ILP. Plasma sE-selectin peaked 6–9 h after ILP, and soluble vascular cell adhesion molecule (sVCAM) levels reached a maximum after 24 h. Significant correlations were observed among these variables, confirming the interdependence of all changes observed. On the other hand, ILP with cytotoxic drugs alone induced only a modest release of TNF&agr;, which was not followed by an immediate rise in IL-6 and IL-8. Four of the 9 patients undergoing ILP with TNF had severe systemic toxicity. No association was found between systemic TNF levels and the clinical outcome, whereas elevated TNF perfusion levels as well as systemic IL-6 and IL-8 levels were constantly elevated in patients with severe toxicity. These results are suggestive of an important role of TNF&agr; levels in the perfusion system (more than leakage of perfusate) in causing postoperative toxicity, although other ILP-related factors should not be excluded.