Matrix Gla Protein drives stemness and tumor initiation in ovarian cancer.

Ovarian cancer (OC) displays the highest mortality among gynecological tumors, mainly due to early peritoneal dissemination, the high frequency of tumor relapse following primary debulking, and the development of chemoresistance. All these events are thought to be initiated and sustained by a subpopulation of neoplastic cells, termed ovarian cancer stem cells (OCSC), that are endowed with self-renewing and tumor-initiating properties. This implies that interfering with OCSC function should offer novel therapeutic perspectives to defeat OC progression. To this aim, a better understanding of the molecular and functional makeup of OCSC in clinically relevant model systems is essential. We have profiled the transcriptome of OCSC vs. their bulk cell counterpart from a panel of patient-derived OC cell cultures. This revealed that Matrix Gla Protein (MGP), classically known as a calcification-preventing factor in cartilage and blood vessels, is markedly enriched in OCSC. Functional assays showed that MGP confers several stemness-associated traits to OC cells, including a transcriptional reprogramming. Patient-derived organotypic cultures pointed to the peritoneal microenvironment as a major inducer of MGP expression in OC cells. Furthermore, MGP was found to be necessary and sufficient for tumor initiation in OC mouse models, by shortening tumor latency and increasing dramatically the frequency of tumor-initiating cells. Mechanistically, MGP-driven OC stemness was mediated by the stimulation of Hedgehog signaling, in particular through the induction of the Hedgehog effector GLI1, thus highlighting a novel MGP/Hedgehog pathway axis in OCSC. Finally, MGP expression was found to correlate with poor prognosis in OC patients, and was increased in tumor tissue after chemotherapy, supporting the clinical relevance of our findings. Thus, MGP is a novel driver in OCSC pathophysiology, with a major role in stemness and in tumor initiation.

Detection of a numeric value predictive of increased dose to left anterior descending coronary artery (LAD) in radiotherapy of breast cancer.

PURPOSE: We have evaluated thoracic conformation of patients in order to derive a numeric value predictive of an increased dose to left anterior descending coronary artery (LAD), critical structure for the development of late radio induced cardiac morbidity. METHODS: We have evaluated 91 patients (36-88 years) affected by breast cancer stage I-II (Tis-T1-2 N0-1), undergoing adjuvant radiotherapy with conventional fractionation. For each patient on CT images was measured the distance between the back face of the sternum (manubrium) and the anterior face of body of the corresponding vertebra (a), and the distance measured on the line at 45° between the vertebral body of the same vertebra and the back face of the rib corresponding (b). The a/b ratio showed values between 0.626 and 1.123. We used the median value (0.821) as cut-off to divide the patients in two groups. We calculated in both groups: Volume (Vol) heart, Vol LAD with an expansion of 0.6 mm; Dmean LAD (Gy); Dmax LAD (Gy); V10-V20-V30 (%) LAD and we correlated these values with parametric and non-parametric tests. RESULTS: The Pearson test has showed a statistically significant correlation between Vol breast and V10, V20, V30 with borderline significance (p = 0.006; p = 0.02; p = 0.05). The data were confirmed by testing non-parametric Kendall (tau = 0.004; tau = 0.015; tau = 0.016) and Spearman (rho = 0.003; rho = 0.016; rho = 0.015). We conducted categorizing into quartiles of breast volume and evaluated the correlation with a/b. We have found a significative correlation (p = 0.01) between small Vol breast (≤660.23 cc) and a/b < 0.0821 and greater Vol breast (>660.23 cc) with a/b > 0.0821. From the evaluation of the distribution of V10 in the two groups taking account of the Dmean ≤5 or >5 significance was found with a/b; Chi square 0.009 (0.01). Values ≤5 were observed in women with a/b < 0.0821. Values >5 in women with a/b > 0.0821. CONCLUSIONS: The geometric conformity of chest thorax considering a/b and the value of 0.0821 can reveals an important parameter in the selection of patients suitable for radiation therapy on left breast in order to evaluate the risk of late cardiac events. This consideration during treatment planning can change the technique or the set-up allowing the development of a customized plan.

[Study on mortality by specific cause among workers at a lead and zinc foundry in Sardinia]. / Studio di mortalità per cause specifiche in lavoratori di una fonderia di piombo e zinco della Sardegna.

The mortality of 918 Sardinian lead-smelter workers followed between 1972 and 2001 is reported. The assessment of individual exposure to inorganic lead was based on several environmental and blood lead measurements available, for each department and task, between 1985 and 2001. The mortality for all cancers was within the expected numbers (SMR 1.01, n 108). Even if not statistically significant, the mortality for gastric cancer (SMR 1.22, n 4), for lung cancer (SMR 1.21, n 18) and for lymphomas and leukaemias (SMR 1.82, n 6) was higher than that expected from the regional rates during the follow-up. Only for the lung cancer mortality a statistically significant upward trend with increasing categories of lead exposure was observed (SMR 1.96, 95% CI 1.02-3.68 for the highest exposure group). Our study, even if of small size, suggests an association between occupational exposure to inorganic lead and lung cancer risk.

[Mortality from lung cancer among workers of a Sardinian lead smelter [Follow-up: 1972-2001]]. / Mortalità per cancro polmonare in lavoratori di una fonderia di piombo della Sardegna [Follow-up: 1972-2001].

The mortality of 918 Sardinian lead-smelter workers followed between 1972 and 2001 is reported. The assessment of individual exposure to inorganic lead was based on several environmental and blood lead measurements available, for each department and task, between 1985 and 2001. The mortality for all cancers was within the expected numbers (SMR 1.01, n 108). Even if not statistically significant, the mortality for gastric cancer (SMR 1.22, n 4), for lung cancer (SMR 1.21, n 18) and for lymphomas and leukaemias (SMR 1.82, n 6) was higher than that expected from the regional rates during the follow-up. Only for the lung cancer mortality a statistically significant upward trend with increasing categories of lead exposure was observed (SMR 1.96, 95% CI 1.02-3.68 for the highest exposure group). Our study, even if of small size, suggests an association between occupational exposure to inorganic lead and lung cancer risk.