International Journal of Cancer (Int J Canc)

Publications in this journal

• Article: Induction of CaSR expression circumvents the molecular features of malignant CaSR null colon cancer cells.

  Navneet Singh, Subhas Chakrabarty
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  ABSTRACT: We recently reported on the isolation and characterization of CaSR null human colon cancer cells (Int. J Cancer, 132, 1996, 2013). CaSR null cells possess a myriad of molecular features that are linked to a highly malignant and drug resistant phenotype of colon cancer. The CaSR null phenotype can be maintained in defined human embryonic stem cell culture medium. We now show that the CaSR null cells can be induced to differentiate in conventional culture medium, regained the expression of CaSR with a concurrent reversal of the cellular and molecular features associated with the null phenotype. These features include cellular morphology, expression of colon cancer stem cell markers, expression of survivin and thymidylate synthase and sensitivity to fluorouracil. Other features include the expression of epithelial mesenchymal transition linked molecules and transcription factors, oncogenic miRNAs and tumor suppressive molecule and miRNA. With the exception of cancer stem cell markers, the reversal of molecular features, upon the induction of CaSR expression, is directly linked to the expression and function of CaSR because blocking CaSR induction by shRNA circumvented such reversal. We further report that methylation and demethylation of the CaSR gene promoter underlie CaSR expression. Due to the malignant nature of the CaSR null cells, inclusion of the CaSR null phenotype in disease management may improve on the mortality of this disease. Because CaSR is a robust promoter of differentiation and mediates its action through diverse mechanisms and pathways, inactivation of CaSR may serve as a new paradigm in colon carcinogenesis. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: A prospective analysis of telomere length and pancreatic cancer in the Alpha-Tocopherol Beta-Carotene cancer prevention (ATBC) study.

  Shannon M Lynch, Jacqueline M Major, Richard Cawthon, Stephanie J Weinstein, Jarmo Virtamo, Qing Lan, Nathaniel Rothman, Demetrius Albanes, Rachael Z Stolzenberg-Solomon
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  ABSTRACT: Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR=1.26 95% CI=1.09-1.46; highest quartile compared to lowest, OR=1.57, 95% CI=1.01-2.43, p-trend=0.007). This association remained for subjects diagnosed within the first five years of blood draw(continuous OR=1.46, 95% CI=1.19-1.79 highest quartile OR=2.92, 95%CI=1.47-5.77, p-trend=0.002), but not those diagnosed greater than five years after blood draw (continuous OR=1.03, 95%CI=0.85-1.22; highest quartile OR=1.04, 95%CI=0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors, and increase nanoparticle delivery.

  Xinping Fu, Armando Rivera, Lihua Tao, Xiaoliu Zhang
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  ABSTRACT: Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a chimeric antigen receptor containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to αvβ3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express αvβ3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was co-delivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Familial risk of childhood cancer and tumors in the Li-Fraumeni spectrum in the Utah population database: Implications for genetic evaluation in pediatric practice.

  Karen Curtin, Ken R Smith, Alison Fraser, Richard Pimentel, Wendy Kohlmann, Joshua D Schiffman
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  ABSTRACT: We used the Utah Population Database to examine risk of cancer in relatives of 4482 pediatric cancer cases (≤18 years old) diagnosed from 1966-2009 compared to matched population controls. We quantified cancer risk in relatives of children with cancer to determine evidence of familial aggregation and to inform risk assessment and counseling for families. Odds ratios that reflect risk were obtained using conditional logistic regression models adjusting for number of biological relatives, their degree of genetic relatedness, and their person-years at risk. First-degree relatives (primarily siblings) of pediatric cases faced a 2-fold increased risk of a cancer diagnosis before age 19, which extended to their second-degree relatives (P<10(-4) , respectively). Furthermore, first-degree relatives of children diagnosed before age 5 had a 3.6-fold increased risk of developing pediatric cancer (P<10(-7) ), second-degree relatives of very young (under age 5) cases were at 2.5-fold risk (P<10(-4) ), and third-degree relatives were at 2-fold risk (P<10(-3) ) of childhood cancer. While first-degree relatives of pediatric cases have a slight increased risk of adult tumors, when they do develop cancer they have a 1.7-fold risk of developing a tumor in the Li-Fraumeni spectrum. Our findings support the hypothesis of familial aggregation in pediatric cancer and suggest a higher percent of childhood cancers may be related to hereditary syndromes than are adult cancers. We encourage the collection of a family medical history that is routinely updated for all pediatric cancer patients, and that families with early onset adult cancers or clusters of several cancers are referred for genetic counseling. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Frequent detection of human cytomegalovirus in neuroblastoma: A novel therapeutic target?

  Nina Wolmer-Solberg, Ninib Baryawno, Afsar Rahbar, Dieter Fuchs, Jenny Odeberg, Chato Taher, Vanessa Wilhelmi, Jelena Milosevic, Abdul-Aleem Mohammad, Tommy Martinsson, Baldur Sveinbjörnsson, John Inge Johnsen, Per Kogner, Cecilia Söderberg-Nauclér
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  ABSTRACT: Neuroblastoma is the most common and deadly tumor of childhood, where new therapy options for patients with high-risk disease are highly warranted. Human cytomegalovirus (HCMV) is prevalent in the human population and has recently been implicated in different cancer forms where it may provide mechanisms for oncogenic transformation, oncomodulation and tumour cell immune evasion. Here we show that the majority of primary neuroblastomas and neuroblastoma cell lines are infected with HCMV. Our analysis show that HCMV immediate-early protein was expressed in 100% of 36 primary neuroblastoma samples, and HCMV late protein was expressed in 92%, However, no infectious virus was detected in primary neuroblastoma tissue extracts. Remarkably, all six human neuroblastoma cell lines investigated contained CMV DNA and expressed HCMV proteins. HCMV proteins were expressed in neuroblastoma cells expressing the proposed stem cell markers CD133 and CD44. When engrafted into NMRI nu/nu mice, human neuroblastoma cells expressed HCMV DNA, RNA and proteins but did not produce infectious virus. The HCMV-specific antiviral drug valganciclovir significantly reduced viral protein expression and tumor cell growth both in vitro and in vivo. These findings indicate that HCMV is important for the pathogenesis of neuroblastoma and that anti-viral therapy may be a novel adjuvant treatment option for children with neuroblastoma. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: CD133 expression in circulating tumor cells from breast cancer patients: Potential role in resistance to chemotherapy.

  Rosa Nadal, F Gabriel Ortega, Marta Salido, Jose A Lorente, Maria Rodríguez-Rivera, Miguel Delgado-Rodríguez, Marta Macià, Ana Fernández, Josep M Corominas, J Luis García-Puche, Pedro Sánchez-Rovira, Francesc Solé, M Jose Serrano
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  ABSTRACT: CD133 has been associated with cell properties such as self renewal, migration and vasculogenic mimicry, potentially involved in generation of circulating tumor cells (CTCs). We characterized CD133 expression in CTCs of 98 no-metastatic breast cancer patients. CTCs were isolated by immunomagnetic techniques using magnetic beads labelled with a multi-cytokeratin(CK)-specific antibody (CK3-11D5) and CTCs and CD133 detection through immunocytochemical methods. CK(+) /CD133(+) CTCs were identified in 65% of patients at baseline and 47,8% after systemic therapy (p=0.53). Correlation of CD133 status in CTCs with classical clinicopathological characteristics and response to therapy was performed. Her2 not amplified and low Ki-67 index were positively correlated with presence of CK(+) /CD133(+) CTCs. Before any treatment, CK(+) /CD133(+) CTCs were more frequently isolated in patients with luminal breast cancer subtype. No statistically significant differences were found between proportion of CK(+) /CD133(+) CTCs and BC subtypes after systemic therapy, implying a relative enrichment of CK(+) /CD133(+) CTCs in triple negative and HER2-amplified tumors. While we CK(+) /CTCs decreases after chemotherapy when analyzing the whole population, CK(+) /CD133(+) CTCs were enriched in post-treatment samples in non-luminal BC subtypes suggesting the potential role of CD133 as a promising marker of chemoresistance in these patient. Further prospective studies and extensive pre-clinical modeling will be needed to confirm whether CD133 is a marker of resistance to chemotherapy, and its role as a target for novel anticancer therapies targeting cancer stem cells and tumor vasculature. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: αv-Integrin isoform expression in primary human tumors and brain metastases.

  Alexander Vogetseder, Svenja Thies, Barbara Ingold, Patrick Roth, Michael Weller, Peter Schraml, Simon L Goodman, Holger Moch
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  ABSTRACT: PURPOSE: To determine whether metastasis to brain is associated with altered expression patterns of integrins, we investigated the expression of αvβ3, αvβ5, αvβ6 and αvβ8 integrins in primary malignancies and metastases to brain of breast, lung and renal carcinomas and in malignant melanoma. Inhibitors of αv integrins are currently in clinical trials for glioblastoma. The role of integrins in the process of brain metastasis from other human tumors is unknown. EXPERIMENTAL DESIGN: Immunohistochemistry with novel integrin subtype specific rabbit monoclonal antibodies was performed on tissue microarrays of archival material of surgical biopsies taken from primary tumors and brain metastases. RESULTS: Integrin αvβ3 expression was increased in brain metastases compared to primary tumors of breast adenocarcinoma, non-small cell lung cancer, renal clear cell cancer and malignant cutaneous melanoma (all p<0.01). Similarly integrin αvβ8 expression was increased in brain metastases compared to primary tumors of breast cancer (p<0.0001), lung cancer (p<0.01) and renal cancer (p<0.0001), with a similar trend in metastatic melanoma. Integrin αvβ5 was expressed in most primary tumors (98% breast cancer; 67% lung cancer; 90% renal cancer; 89% melanoma) and showed a stronger expression in brain metastases compared to primary tumors from lung cancer and melanoma (p<0.05). Also integrin αvβ6 expression was increased in brain metastases compared to primary breast cancer (p<0.001). CONCLUSIONS: The stronger αv integrin expression in brain metastases, especially of αvβ3 and αvβ8 integrins, suggests that certain αv integrin are involved in the process of brain metastasis. αv integrins may be therapeutic targets for patients with metastatic cancer in brain. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Endothelial plasticity governs the site-specific leukocyte recruitment in hepatocellular cancer.

  Olga Salnikova, Kai Breuhahn, Natalie Hartmann, Jan Schmidt, Eduard Ryschich
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  ABSTRACT: The correct programming of the endothelial cell phenotype is crucial for efficient leukocyte recruitment to tumor tissue. It has been previously described that T cells infiltrated hepatocellular cancer (HCC) tissue mainly in peritumoral, stromal and tumor border areas. In the current study, phenotype features of tumor endothelial cells and their potential impact on leukocyte recruitment were analyzed in murine tissue of hepatocellular cancer. In the murine model, pro-inflammatory stimulation with IL-1β induced leukocyte recruitment in the blood vessels of peripheral tumor areas and in non-malignant liver tissue, but not in deeper tumor blood vessels. Furthermore, peripheral tumor endothelium, but not deeper tumor blood vessels exhibited a "normalized" hepatic sinusoidal endothelial cell (HSEC)-like phenotype with regard to the expression of adhesion molecules and liver sinusoidal endothelial markers. When tumor endothelial cells were isolated and incubated in vitro, their phenotype rapidly changed and became almost identical to normal hepatic endothelial cells. Interestingly, cytokine production in HCC was strongly dysregulated compared to normal liver, with IL-1RN exhibiting the most prominent elevation. Experiments with isolated hepatic endothelial cells showed that IL-1RN effectively antagonized the activating action of IL-1β on the expression of adhesion molecules and T cell attachment. These novel insights indicate that tumor endothelium of HCC represents a plastic system that is susceptible to microenvironmental changes. The peritumoral and tumor border areas have distinct endothelial cell phenotype which promotes leukocyte recruitment to HCC tissue. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Tumor necrosis factor alpha induced warburg-like metabolism and is reversed by anti-inflammatory curcumin in breast epithelial cells.

  Roger A Vaughan, Randi Garcia-Smith, Jonathan Dorsey, Jeffrey K Griffith, Marco Bisoffi, Kristina A Trujillo
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  ABSTRACT: The re-programming of cellular metabolism in cancer cells is a well-documented effect. It has previously been shown that common oncogene expression can induce aerobic glycolysis in cancer cells. However, the direct effect of an inflammatory microenvironment on cancer cell metabolism is not known. Here, we illustrate that treatment of non-malignant (MCF-10a) and malignant (MCF-7) breast epithelial cells with low-level (10 ng/ml) Tumor Necrosis Factor alpha (TNF-α) significantly increased glycolytic reliance, lactate export, and expression of the glucose transporter, GLUT1. TNF-α decreased total mitochondrial content, however oxygen consumption rate was not significantly altered, meaning that overall mitochondrial function was increased. Upon glucose starvation, MCF7 cells treated with TNF-α, demonstrated significantly lower viability than non-treated cells. Interestingly, these properties can be partially reversed by co-incubation with the anti-inflammatory agent curcumin in a dose-dependent manner. This work demonstrates that aerobic glycolysis can be directly induced by an inflammatory microenvironment independent of additional genetic mutations and signals from adjacent cells. Furthermore, we have identified that a natural dietary compound can reverse this effect. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Estrogen and insulin-like growth factor synergistically promote the development of lung adenocarcinoma in mice.

  Hexiao Tang, Yongde Liao, Liqiang Xu, Chao Zhang, Zhaoguo Liu, Yu Deng, Zhixiao Jiang, Shengling Fu, Zhenguang Chen, Sheng Zhou
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  ABSTRACT: Objective: Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on our previous findings, we sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. Methods: LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17β-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024, and control groups. After 14 weeks, the mice were sacrificed and tumor growth was determined. The expression of ERα/ERβ, IGF-1, IGF-1R, and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ERβ, p-IGF-1R, p-MAPK, and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative PCR was used to detect the mRNA expression of ERβ, ERβ2, and IGF-1R. Results: Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (P <0.05), the IGF-1 group (P <0.05), and control group (P <0.05). Similarly, the expression of ERβ, p-ERβ, ERβ2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT, and Ki67 at the protein and/or mRNA levels were markedly higher in the ligand group than in the ligand + inhibitor groups (all P <0.05). Conclusion: The present study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERβ1, ERβ2, and IGF-1R play important roles. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Long term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats.

  Angelo Pietro Femia, Laura Raimondi, Giulia Maglieri, Maura Lodovici, Edoardo Mannucci, Giovanna Caderni
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  ABSTRACT: Type 2 Diabetes Mellitus (T2DM) and insulin resistance (IR) increase colon cancer risk. Anti-diabetic drugs stabilizing incretin hormones, such as inhibitors of dipeptidyl peptidase-4 activity (DPP4i) may affect colon carcinogenesis but the data are controversial. Therefore, we studied whether long-term administration of the DPP4i Sitagliptin (SITA) affects 1,2-dimethylhdrazine (DMH)-induced colon carcinogenesis. Male F344 rats fed a high-fat (HF) diet promoting colon carcinogenesis and IR, were induced with DMH (100 mg/kg x 2 times). One week later, animals were allocated to two groups: one continuing with HF diet (Controls; n=8) or receiving SITA (n=8) mixed in the diet (260 ppm). Body weight, food consumption and glycemia were not affected by SITA. Fifteen weeks after DMH the number of the precancerous lesions Mucin Depleted Foci (MDF) was significantly lower in rats treated with SITA (MDF/colon: 9.5±0.9 and 6.4±0.9, in Controls(n=8) and SITA groups(n=8), respectively; means±SE, P<0.05). Reactive oxygen species (ROS) in the blood were also significantly lower in the SITA group (6.75±0.69 and 5.63±0.75 (H2 O2 mM) in Controls (n=5) and SITA (n=6)respectively, means±SE P<0.05). Rats treated with SITA had a lower DPP4 activity in the intestine but not in the plasma. Intestine growth morphometric parameters and colon proliferation, as Proliferating Cell Nuclear Antigen expression, were not affected by SITA. In conclusion, the results suggest a protective effect of DPP4i against colon carcinogenesis, that could be exploited in chemoprevention trials. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Molecular targeted agents (MTA) combination therapy for cancer: Developments and potentials.

  Feifei Li, Changqi Zhao, Lili Wang
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  ABSTRACT: Although chemotherapy has advanced into the era of targeted drugs, the antitumor efficacies of current therapies are limited, most likely because of the high degree of cancer clonal heterogeneity, intratumor genetic heterogeneity, and cell signal complexity. Since shutdown of a single target does not necessarily eradicate the cancer, the use of combinations of molecular targeted agents has been proposed, and some pioneering research has been conducted to examine the efficacy of this strategy. Here, we summarize the clinical and preclinical studies that are underway in an attempt to improve the anticancer efficacy of chemotherapies through combination strategies. Studies of combining cytotoxic agents with molecular targeted agents, co-inhibiting two or more targets in a single pathway, or co-inhibiting parallel or compensatory pathways as well as specific combinations will be introduced respectively, and the antitumor potentials of each combination strategy will be evaluated. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells.

  M Vives, M M Ginestà, K Gracova, M Graupera, O Casanovas, G Capellà, T Serrano, B Laquente, F Viñals
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  ABSTRACT: In this article we report the effectiveness of a multi-targeted chemo-switch schedule (C-S) that combines metronomic chemotherapy (MET) after treatment with the maximum tolerated dose (MTD). We tested this schedule with gemcitabine in two distinct human pancreatic adenocarcinoma orthotopic models and with cyclophosphamide in an orthotopic ovarian cancer model. In both models the C-S schedule had the most favourable effect, achieving at least 80% tumour growth inhibition without increased toxicity. Moreover, in the pancreatic cancer model, while peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C-S groups. C-S treatment caused a decrease in angiogenesis and its effect on tumour growth was similar to that produced by the MTD followed by antiangiogenic DC101 treatment. C-S treatment combined an increase in thrombospondin-1 expression with a decrease in the number of CD133+ cancer cells and triple-positive CD133+/CD44+/CD24+ cancer stem cells. These findings confirm that the chemo-switch schedule is a challenging clinical strategy with demonstrable inhibitory effects on tumour dissemination, angiogenesis and cancer stem cells. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Modelling the benefits of early diagnosis of pancreatic cancer using a biomarker signature.

  Ola Ghatnekar, Roland Andersson, Marianne Svensson, Ulf Persson, Ulrika Ringdahl, Paula Zeilon, Carl A K Borrebaeck
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  ABSTRACT: Pancreatic cancer (PC) has a poor prognosis, with a 5-year survival of 3-4%. This is mainly due to late diagnosis because of diffuse symptoms, where 80-85% of the patients are inoperable. Consequently, early diagnosis would be of significant benefit, resulting in a potential 5-year survival of 30-40%. However, new technologies must be carefully evaluated concerning effectiveness and healthcare costs. We have developed a framework for modelling cost and health effects from early detection of PC, which for the first time allowed us to analyse its cost-effectiveness. A probabilistic cohort model for estimating costs and quality adjusted life-years (QALY) arising from screening for PC, compared to a "wait-and-see"-approach, was designed. The test accuracy, Swedish survival and costs by tumour stage, expected life gain from early detection and pre-test probabilities in risk-groups, were retrieved from previous investigations. In a cohort of newly diagnosed diabetic patient (incidence 0.71%) the incremental cost per QALY gained (ICER) was €13,500, which is considered cost-effective in Europe. Results were mainly sensitive to the incidence with the ICER ranging from €315 to €204,000 (familial PC 35% and general population 0.046%, respectively). This is the first study focusing on clinical implementation of advanced testing and what is required for novel technologies in cancer care to be cost-effective. The model clearly demonstrated the potential of multiplexed proteomic-testing of PC and also identified the requirements for test accuracy. Consequently, it can serve as a model for assessing the possibilities to introduce advanced test platforms also for other cancer indications. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: The metastatic microenvironment: Lung-derived factors control the viability of neuroblastoma lung metastasis.

  Shelly Maman, Liat Edry-Botzer, Orit Sagi-Assif, Tsipi Meshel, Weirong Yuan, Wuyuan Lu, Isaac P Witz
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  ABSTRACT: Recent data suggest that the mechanisms determining whether a tumor cell reaching a secondary organ will enter a dormant state, progress toward metastasis or go through apoptosis are regulated by the microenvironment of the distant organ. In neuroblastoma, 60 -70% of children with high-risk disease will ultimately experience relapse due to the presence of micrometastases. The main goal of this study is to evaluate the role of the lung microenvironment in determining the fate of neuroblastoma lung metastases and micrometastases. Utilizing an orthotopic mouse model for human neuroblastoma metastasis, we were able to generate two neuroblastoma cell populations - lung micrometastatic (MicroNB) cells and lung macrometastatic (MacroNB) cells. These two types of cells share the same genetic background, invade the same distant organ, but differ in their ability to create metastasis in the lungs. We hypothesize that factors present in the lung microenvironment inhibit the propagation of MicroNB cells preventing them from forming overt lung metastasis. This study indeed shows that lung-derived factors significantly reduce the viability of MicroNB cells by up regulating the expression of pro-apoptotic genes, inducing cell cycle arrest and decreasing ERK and FAK phosphorylation. Lung-derived factors affected various additional progression-linked cellular characteristics of neuroblastoma cells, such as the expression of stem cell markers, morphology and migratory capacity. An insight into the microenvironmental effects governing neuroblastoma recurrence and progression would be of pivotal importance as they could have a therapeutic potential for the treatment of neuroblastoma residual disease. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Dietary flavonoid, lignan and antioxidant capacity and risk of hepatocellular carcinoma in the european prospective investigation into cancer and nutrition (EPIC) study.

  Raul Zamora-Ros, Veronika Fedirko, Antonia Trichopoulou, Carlos A González, Christina Bamia, Elisabeth Trepo, Ute Nöthlings, Talita Duarte-Salles, Mauro Serafini, Lea Bredsdorff, [......], Eva Ardanaz, Ulrika Ericson, Emily Sonestedt, Malin Sund, Rikard Landberg, Kay-Tee Khaw, Nicholas J Wareham, Francesca L Crowe, Elio Riboli, Mazda Jenab
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  ABSTRACT: Limited epidemiological evidence suggests a protective role for plant foods rich in flavonoids and antioxidants in hepatocellular cancer (HCC) aetiology. Our aim was to prospectively investigate the association between dietary intake of flavonoids, lignans and non enzymatic antioxidant capacity (NEAC) and HCC risk. Data analysed were from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 477,206 subjects (29.8% male) recruited from ten Western European countries, was analyzed. Flavonoid, lignan and NEAC intakes were calculated using a compilation of existing food composition databases linked to dietary information from validated dietary questionnaires. Dietary NEAC was based on ferric reducing antioxidant capacity (FRAP) and total radical-trapping antioxidant parameter (TRAP). Hepatitis B/C status was measured in a nested case-control subset. During a mean follow-up of 11-years, 191 incident HCC cases (66.5% men) were identified. Using Cox Regression, multivariable adjusted models showed a borderline non-significant association of HCC with total flavonoid intake (highest versus lowest tertile, HR=0.65, 95% CI: 0.40-1.04; Ptrend =0.065), but not with lignans. Among flavonoid subclasses, flavanols were inversely associated with HCC risk (HR=0.62, 95% CI: 0.39-0.99; Ptrend =0.06). Dietary NEAC was inversely associated with HCC (FRAP: HR 0.50, 95% CI: 0.31-0.81; Ptrend =0.001; TRAP: HR 0.49, 95% CI: 0.31-0.79; Ptrend =0.002), but statistical significance was lost after exclusion of the first two years of follow-up. This study suggests that higher intake of dietary flavanols and antioxidants may be associated with a reduced HCC risk. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Mortality risk in former smokers with breast cancer: Pack-years vs. smoking status.

  Nazmus Saquib, Marcia L Stefanick, Loki Natarajan, John P Pierce
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  ABSTRACT: It is unclear why successful quitting at time of breast cancer diagnosis should remove risk from a significant lifetime of smoking. Studies concluding this may be biased by how smoking is measured in many epidemiological cohorts. In the late 1990s, a randomized trial of diet and breast cancer outcomes enrolled early-stage female breast cancer survivors diagnosed within the previous 4 years. Smoking history and key covariate measures were available at study entry for 2953 participants. Participants were followed for an average of 7.3 years (96% response rate). There were 10.1% deaths (83% from breast cancer). At enrollment, 55.2% were never smokers, 41.2% former smokers, and 4.6% current smokers. Using current smoking status in a Cox regression, there was no increased risk for former smokers for either all-cause mortality (HR=1.11; 95% CI=0.87, 1.41; p-value = 0.42) or breast cancer mortality. However, when we categorized on extensive lifetime exposure, former smokers with 20+ pack-years of smoking (25.8%) had a significantly higher risk of both all-cause (HR=1.77; 95% CI =1.17, 2.48; p-value = 0.0007) and breast cancer specific mortality (HR=1.62; 95% CI =1.11, 2.37; p-value = 0.01). Lifetime smoking exposure, not current status should be used to assess mortality risk among former smokers. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: Response to comments.

  Ragnhild Sørum Falk, Solveig Hofvind, Per Skaane, Tor Haldorsen
  International Journal of Cancer 05/2013;
• Article: A population-based prospective study of energy-providing nutrients in relation to cancer mortality and cancers of digestive organs mortality.

  Maria Argos, Stephanie Melkonian, Faruque Parvez, Muhammad Rakibuz-Zaman, Alauddin Ahmed, Yu Chen, Habibul Ahsan
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  ABSTRACT: The effect of dietary composition on mortality in low income countries is largely unknown. We evaluated whether percentages of dietary energy derived from protein, fat, and carbohydrates were associated with all-cause and cancer mortalities in a Bangladeshi population. Data from a prospective population-based cohort study of 17,244 men and women were used. Percentages of dietary energy derived from protein, fat, and carbohydrates, assessed using a validated food-frequency questionnaire at baseline, were analyzed in relation to mortality over an average of 9 years (155,126 person-years) of follow-up. Cox proportional hazards regression models were used to estimate hazard ratios for all cause, all cancer, and cancers of the digestive organs mortalities. Percentage of dietary energy from protein appeared to be significantly associated with cancer mortality. Fully adjusted hazard ratios for cancer mortality in increasing tertiles of percentage of dietary energy from protein were 1.0 (reference), 1.21 (0.73, 2.00), and 1.84 (1.08, 3.15) (P for trend = 0.023). These associations were much stronger for deaths from cancers of the digestive organs with fully adjusted hazard ratios in increasing tertiles of percentage of dietary energy from protein being 1.0 (reference), 2.25 (0.91, 5.59), and 4.85 (1.88, 12.51) (P for trend = 0.001). No significant associations in relation to cancer-related mortality were observed for percentage of dietary energy from fat. Novel findings from this prospective study show protein is an important risk factor or proxy to an important risk factor for cancer mortality especially from digestive organ cancers in Bangladesh. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;
• Article: MicroRNA profiling in locally advanced esophageal cancer indicates a high potential of miR-192 in prediction of multimodality therapy response.

  M Odenthal, E Bollschweiler, P P Grimminger, W Schröder, J Brabender, U Drebber, A H Hölscher, R Metzger, D Vallböhmer
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  ABSTRACT: In order to identify possible predictive markers, this study aimed to characterize miRNA profiles of responder and non-responder in the multimodality therapy of locally advanced esophageal cancer. Initially a microarray-based approach was performed including eight patients with esophageal cancer. Patients received neoadjuvant chemoradiation followed by surgical resection. Major histopathological response was defined if resected specimens contained less than 10% vital tumor cells (major/minor response: 4/4 patients). Intratumoral RNA was isolated from both, pre-therapeutic tissue biopsies in addition to corresponding surgical specimens. The profile of 768 miRNAs was analyzed in 16 specimens (pre- and post-neoadjuvant therapy). Selected miRNAs were than analyzed on pre- and posttherapeutic biopsies of 80 patients with esophageal cancer, who underwent multimodality therapy (major/minor response: 30/50 patients). Comprehensive miRNA profiling identified miRNAs in pre-therapeutic biopsies that were significantly different between major/minor responders. Based on the microarray results, miR-192, miR-194, and miR-622 were selected and the dysregulated miRNAs were studied on an extended series of esophageal cancer patients. The expression of miR-192, miR-194, and miR-622 was significantly reduced after neoadjuvant therapy confirming the array profiling data. Importantly, the pre-therapeutic intratumoral expression of miR-192 and miR-194 was significantly associated with the histopathologic response of esophageal squamous cell carcinoma to multimodal therapeutic treatment. Therefore, in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation followed by esophagectomy, miR-192 and miR-194 in pre-therapeutic biopsies are considered as indicators of major histopathologic regression. © 2013 Wiley Periodicals, Inc.
  International Journal of Cancer 05/2013;