Medicine, Italy
Medicine, Italy

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Martin-Padura I.,Italian National Cancer Institute | Marighetti P.,Italian National Cancer Institute | Foglieni B.,Hospital A Manzoni | Spreafico M.,Hospital A Manzoni | And 10 more authors.
PLoS ONE | Year: 2011

Background and Aims: Increasing evidence that a number of malignancies are characterised by tumour cell heterogeneity has recently been published, but there is still a lack of data concerning liver cancers. The aim of this study was to investigate and characterise tumour-propagating cell (TPC) compartments within human hepatocellular carcinoma (HCC). Methods: After long-term culture, we identified three morphologically different tumour cell populations in a single HCC specimen, and extensively characterised them by means of flow cytometry, fluorescence microscopy, karyotyping and microarray analyses, single cell cloning, and xenotransplantation in NOD/SCID/IL2Rγ-/- mice. Results: The primary cell populations (hcc-1, -2 and -3) and two clones generated by means of limiting dilutions from hcc-1 (clone-1/7 and -1/8) differently expressed a number of tumour-associated stem cell markers, including EpCAM, CD49f, CD44, CD133, CD56, Thy-1, ALDH and CK19, and also showed different doubling times, drug resistance and tumorigenic potential. Moreover, we found that ALDH expression, in combination with CD44 or Thy-1 negativity or CD56 positivity identified subpopulations with a higher clonogenic potential within hcc-1, hcc-2 and hcc-3 primary cell populations, respectively. Karyotyping revealed the clonal evolution of the cell populations and clones within the primary tumour. Importantly, the primary tumour cell population with the greatest tumorigenic potential and drug resistance showed more chromosomal alterations than the others and contained clones with epithelial and mesenchymal features. Conclusions: Individual HCCs can harbor different self-renewing tumorigenic cell types expressing a variety of morphological and phenotypical markers, karyotypic evolution and different gene expression profiles. This suggests that the models of hepatic carcinogenesis should take into account TPC heterogeneity due to intratumour clonal evolution. © 2011 Colombo et al.


Pezzilli R.,University of Bologna | Barassi A.,Surgery and Dentistry | Corsi M.M.,University of Milan | Morselli-Labate A.M.,University of Bologna | And 5 more authors.
Scandinavian Journal of Gastroenterology | Year: 2010

Objective. Serum leptin and adiponectin determinations have been proposed as markers for distinguishing pancreatic cancer and chronic pancreatitis from autoimmune pancreatitis; however, no studies exist in patients with autoimmune pancreatitis and in those with intraductal papillary mucinous tumors of the pancreas. The aim of this paper was to evaluate the circulating concentrations of receptor for advanced glycation end products (RAGE), leptin and adiponectin in patients with chronic pancreatic diseases. Material and methods. Seventy-five consecutive patients with chronic pancreatic diseases (47 males, 28 females; mean age 67.0 ± 13.2 years; range 37-97 years) were studied: six (8.0%) had autoimmune pancreatitis, 23 (30.7%) had chronic pancreatitis, 34 (45.3%) had pancreatic cancer and the remaining 12 (16.0%) had intraductal papillary mutinous tumors of the pancreas. Leptin, adiponectin and RAGE were determined in serum using commercially available kits. The leptin concentrations were normalized to the lower and upper reference limits because of the different gender reference ranges. Results. Normalized leptin concentrations were significantly lower in chronic pancreatitis patients (0.53 ± 1.28; p 0.008) and in those with pancreatic cancer (0.12 ± 0.33; p < 0.001) compared to the overall population (0.58 ± 1.23), whereas autoimmune pancreatitis patients had significantly higher concentrations of this protein (2.18 ± 2.56; p 0.004) compared to the overall population. RAGE and adiponectin concentrations were similar among the four groups of patients studied. Among the clinical variables considered, only pain was significantly related to leptin concentrations (patients with pain 0.18 ± 0.54, patients without pain 1.07 ± 1.64; p 0.001). Conclusion. Serum leptin seems to be a good serum marker for differentiating autoimmune pancreatitis patients from those with chronic pancreatitis and pancreatic cancer. © 2010 Informa UK Ltd.


Tabano S.,Surgery and Dentistry | Colapietro P.,Surgery and Dentistry | Cetin I.,Unit of Obstetrics and Gynecology | Cetin I.,University of Milan | And 12 more authors.
Epigenetics | Year: 2010

Genomic imprinting, resulting in parent-of-origin-dependent gene expression, is mainly achieved by DNAmethylation. IGF2 and H19, belonging to the same cluster of imprinted genes and regulated by ICR1, DMR2 and H19 promoter elements, play a major role in fetal/placental growth. Using quantitative approaches, we explored the epigenetic modulation of IGF2/H19 during human development in 60 normal and 66 idiopathic IUGR (Intrauterine Growth Restriction) pregnancies, studying embryonic (cord blood) and extraembryonic (placenta and umbilical cord) tissues. We found ICR1 normal methylation levels (∼50%) and H19 promoter/DMR2 hypomethylation in extra-embryonic tissues. In contrast, in embryonic samples the three loci displayed normal methylation values comparable to those in postnatal blood. This feature is stably maintained throughout gestation and does not vary in IUGR cases. We reported asymmetric allelic expression of H19 and IGF2 as a common feature in pre- and post-natal tissues, independent of H19 promoter and DMR2 methylation levels. In addition, we excluded in IUGR post-transcriptional IGF2 interference possibly related to miRNA483-3p (IGF2, intron 2) expression defects. Through LINE1 methylation analysis, we observed a methylation gradient with increasing methylation from pre- to post-natal life. The involvement of UPD (Uniparental Disomy) in IUGR aetiology was excluded. Our data indicate that: (1) ICR1 methylation status is a necessary and sufficient condition to drive the imprinting of IGF2 and H19 present in embryonic as well as in extra-embryonic tissues; (2) hypomethylation of H19 promoter and DMR2 does not influence the expression pattern of IGF2 and H19; (3) there is a gradient of global methylation, increasing from extra-embryonic to embryonic and adult tissues. Finally, because of placental hypomethylation, cautions should be exercised in diagnosis of imprinting diseases using chorionic villi. © 2010 Landes Bioscience.


Villa A.,Surgery and Dentistry | Mariani U.,Ospedali Riuniti di Bergamo
Oral and Maxillofacial Surgery | Year: 2012

Background: Bone metastases are a major cause of morbidity in cancer patients. Jawbone metastasis from lung cancer is a rare condition that may occur in the late state of the disease. Case report: We report the case of a 74-year-old male presenting with an oral asymptomatic swelling that had grown substantially over the last 2 months. Biopsy and histological examination revealed the presence of a metastatic lung cell adenocarcinoma. Discussion: Although metastases to the oral cavity are uncommon, clinicians may play a crucial role also in the diagnosis of primary tumors. © 2011 Springer-Verlag.

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