More than one million new cases of prostate cancer (PCa) were reported worldwide in 2020, and a significant increase of PCa incidence up to 2040 is estimated. Despite potential treatability in early ...stages, PCa diagnosis is challenging because of late symptoms' onset and limits of current screening procedures. It has been now accepted that cell transformation leads to release of volatile organic compounds in biologic fluids, including urine. Thus, several studies proposed the possibility to develop new diagnostic tools based on urine analysis. Among these, electronic noses (eNoses) represent one of the most promising devices, because of their potential to provide a non-invasive diagnosis. Here we describe the approach aimed at defining the experimental protocol for eNose application for PCa diagnosis. Our research investigates effects of sample preparation and analysis on eNose responses and repeatability. The dependence of eNose diagnostic performance on urine portion analysed, techniques involved for extracting urine volatiles and conditioning temperature were analysed. 192 subjects (132 PCa patients and 60 controls) were involved. The developed experimental protocol has resulted in accuracy, sensitivity and specificity of 83% (CI
77-89), 82% (CI
73-88) and 87% (CI
75-94), respectively. Our findings define eNoses as valuable diagnostic tool allowing rapid and non-invasive PCa diagnosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cancer Immunoediting and beyond in 2021 Borroni, Elena Monica; Grizzi, Fabio
International journal of molecular sciences,
12/2021, Volume:
22, Issue:
24
Journal Article
Peer reviewed
Open access
Human cancer has been depicted as a non-linear dynamic system that is discontinuous in space and time, but progresses through different sequential states (Figure 1) ....
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Iron Metabolism in Cancer Progression Forciniti, Stefania; Greco, Luana; Grizzi, Fabio ...
International journal of molecular sciences,
03/2020, Volume:
21, Issue:
6
Journal Article
Peer reviewed
Open access
Iron is indispensable for cell metabolism of both normal and cancer cells. In the latter, several disruptions of its metabolism occur at the steps of tumor initiation, progression and metastasis. ...Noticeably, cancer cells require a large amount of iron, and exhibit a strong dependence on it for their proliferation. Numerous iron metabolism-related proteins and signaling pathways are altered by iron in malignancies, displaying the pivotal role of iron in cancer. Iron homeostasis is regulated at several levels, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Mutations in
gene alter iron homeostasis leading to hereditary hemochromatosis and to an increased cancer risk because the accumulation of iron induces oxidative DNA damage and free radical activity. Additionally, the iron capability to modulate immune responses is pivotal in cancer progression. Macrophages show an iron release phenotype and potentially deliver iron to cancer cells, resulting in tumor promotion. Overall, alterations in iron metabolism are among the metabolic and immunological hallmarks of cancer, and further studies are required to dissect how perturbations of this element relate to tumor development and progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Colorectal cancer (CRC) remains one of the major public health problems throughout the world. Originally depicted as a multi-step dynamical disease, CRC develops slowly over several years and ...progresses through cytologically distinct benign and malignant states, from single crypt lesions through adenoma, to malignant carcinoma with the potential for invasion and metastasis. Moving from histological observations since a long time, it has been recognized that inflammation and immunity actively participate in the pathogenesis, surveillance and progression of CRC. The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC. It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment. Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival. Several lines of evidence support the concept that tumor stromal cells, are not merely a scaffold, but rather they influence growth, survival, and invasiveness of cancer cells, dynamically contributing to the tumor microenvironment, together with immune cells. Different types of immune cells infiltrate CRC, comprising cells of both the innate and adaptive immune system. A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation, invasion, and dissemination induced by some types of inflammatory cells. Here, we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC, and the prognostic information that we can currently understand and exploit.
Summary Background The density of tumour-infiltrating lymphocytes (TIL) has been proposed as an independent predictor of outcome in patients with colorectal cancer. However, the relative roles of TIL ...density, nodal status, and microsatellite instability (MSI) in predicting tumour progression to metachronous metastasis remain to be elucidated. The aim of this study was to assess the relationship between the density of CD3+ TIL and the postsurgical occurrence of distant-organ metastases in a large series of patients with deeply invading and MSI-typed colorectal cancer. Methods Per cent areas of immunoreactivity due to CD3+ TIL at the invasive margin of the tumour (CD3+ TILIM ) were measured by computer-assisted image analysis in 286 tissue specimens from pT3 or pT4 MSI-tested colorectal cancer. Tissue samples were taken from consecutive patients who underwent resection at the IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy, from January, 1997, to November, 2004, for colorectal cancer with no evidence of metastasis at diagnosis. Occurrence of metachronous metastasis, disease-specific survival (DSS), and disease-free survival (DFS), were assessed retrospectively in relation to per cent immunoreactivity. Findings CD3+ TILIM density was higher in MSI colorectal cancer than in mismatch repair-system-proficient tumours (6·53% vs 2·19%; p<0·0001). At Cox analysis, higher CD3+ TILIM densities, colonic site, and absence of nodal involvement were significantly associated with a lower risk of metachronous metastasis, but only the interaction between CD3+ TILIM density and N-stage was significant on multivariate analysis (p=0·002). On separate analysis of node-negative colorectal cancer, increasing percentage of CD3+ immunoreactive area progressively reduced the risk of metachronous metastasis (<1%, reference; 1–5%, HR 0·28, 95% CI 0·10–0·81, p=0·02; >5%, 0·06, 0·01–0·48, p=0·008). Conversely, no significant association was seen between CD3+ immunoreactive area and risk of metachronous metastasis in node-positive colorectal cancer. Accordingly, CD3+ TILIM density was associated with a better DSS (p=0·01) and DFS (p=0·006) only in patients with node-negative colorectal cancer. In primary tumours that had progressed to metachronous metastasis, stage III tumours had higher CD3+ TILIM densities than stage II tumours (p=0·0004). Interpretation Metachronous metastases are unlikely to arise from node-negative colorectal cancers with a high-density CD3+ TILIM , whereas high densities of CD3+ TILIM are not associated with the absence of postsurgical metastasis in patients with node-positive colorectal cancer. Our data suggest that densities of CD3+ TILIM cannot be used as an independent predictor of clinical outcome in patients with stage III colorectal cancer and, at least for now, the tumour-node-metastasis classification should remain the preferred prognostic system. Our findings are consistent with a relationship between nodal involvement and tumour immunoevasion. Funding MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca), Target Project Oncologia 2006, and Alleanza Contro il Cancro.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Inflammatory cells are involved in tumour initiation and progression. In parallel, the adaptive immune response plays a key role in fighting tumour growth and dissemination. The double‐edged role of ...the immune system in solid tumours is well represented in colorectal cancer (CRC). The development and progression of CRC are affected by the interactions between the tumour and the host's response, occurring in a milieu named tumour microenvironment. The role of immune cells in human CRC is being unravelled and there is a strong interest in understanding their dynamics as to tumour promotion, immunosurveillance and immunoevasion. A better definition of immune infiltration would be important not only with respect to the ‘natural history’ of CRC, but in a clinically relevant perspective in the 21st century, with respect to its post‐surgical management, including chemotherapy responsiveness. While it is becoming established that the amount of tumour‐infiltrating lymphocytes influences the post‐surgical progression of early‐stage CRC, the relevance of this immune parameter as to chemotherapy responsiveness remains to be clarified. Despite recent experimental work supporting the notion that infiltrating immune cells may influence chemotherapy‐mediated tumour cell death, tumour‐infiltrating cells are not employed to identify patients who are more likely to benefit from adjuvant treatment. This review focuses on studies addressing the role of innate and adaptive immune cells along the occurrence and the progression of potentially curable CRC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Despite the accepted dogma that TRAIL kills only tumor cells and spares normal ones, we show in this study that mononuclear phagocytes are susceptible to recombinant TRAIL via caspase-dependent ...apoptosis. Human resting monocytes and in vitro-differentiated macrophages expressed substantial levels of the functional TRAIL receptors (TRAIL-R1 and TRAIL-R2), while neutrophils and lymphocytes mostly expressed the non-signaling decoy receptor (TRAIL-R3). Accordingly, exclusively monocytes and macrophages activated caspase-8 and underwent apoptosis upon recombinant TRAIL treatment. TRAIL-Rs were up-regulated by anti-inflammatory agents (IL-10, glucocorticoids) and by natural compounds (Apigenin, Quercetin, Palmitate) and their treatment resulted in increased TRAIL-induced apoptosis. In mice, the only signaling TRAIL-R (DR5) was preferentially expressed by blood monocytes rather than neutrophils or lymphocytes. In both mice and humans, Tumor-Associated Macrophages (TAM) expressed functional TRAIL-R, while resident macrophages in normal tissues did not. As a proof of principle, we treated mice bearing a murine TRAIL-resistant fibrosarcoma with recombinant TRAIL. We observed significant decrease of circulating monocytes and infiltrating TAM, as well as reduced tumor growth and lower metastasis formation. Overall, these findings demonstrate that human and murine monocytes/macrophages are, among leukocytes, uniquely susceptible to TRAIL-mediated killing. This differential susceptibility to TRAIL could be exploited to selectively target macrophages in tumors.
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