Cancers

3516 KiB

Open AccessArticle

Stat5 Exerts Distinct, Vital Functions in the Cytoplasm and Nucleus of Bcr-Abl⁺ K562 and Jak2(V617F)⁺ HEL Leukemia Cells

by Axel Weber, Corina Borghouts, Christian Brendel, Richard Moriggl, Natalia Delis, Boris Brill, Vida Vafaizadeh and Bernd Groner

Cancers 2015, 7(1), 503-537; https://doi.org/10.3390/cancers7010503 - 19 Mar 2015

Cited by 18 | Viewed by 10011

Abstract

Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and [...] Read more.

Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl⁺ K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5 is predominantly present in the cytoplasm and the survival of the Jak2(V617F)⁺ HEL cells is impeded through the inhibition of the cytoplasmic functions of Stat5. Full article

(This article belongs to the Special Issue STAT3 Signalling in Cancer: Friend or Foe)

► Show Figures

Figure 1

4263 KiB

Open AccessArticle

Effects of Alpha Particle and Proton Beam Irradiation as Putative Cross-Talk between A549 Cancer Cells and the Endothelial Cells in a Co-Culture System

by Hélène Riquier, Denis Abel, Anne-Catherine Wera, Anne-Catherine Heuskin, Géraldine Genard, Stéphane Lucas and Carine Michiels

Cancers 2015, 7(1), 481-502; https://doi.org/10.3390/cancers7010481 - 18 Mar 2015

Cited by 7 | Viewed by 6100

Abstract

Background: High-LET ion irradiation is being more and more often used to control tumors in patients. Given that tumors are now considered as complex organs composed of multiple cell types that can influence radiosensitivity, we investigated the effects of proton and alpha [...] Read more.

Background: High-LET ion irradiation is being more and more often used to control tumors in patients. Given that tumors are now considered as complex organs composed of multiple cell types that can influence radiosensitivity, we investigated the effects of proton and alpha particle irradiation on the possible radioprotective cross-talk between cancer and endothelial cells. Materials and Methods: We designed new irradiation chambers that allow co-culture study of cells irradiated with a particle beam. A549 lung carcinoma cells and endothelial cells (EC) were exposed to 1.5 Gy of proton beam or 1 and 2 Gy of alpha particles. Cell responses were studied by clonogenic assays and cell cycle was analyzed by flow cytometry. Gene expression studies were performed using Taqman low density array and by RT-qPCR. Results: A549 cells and EC displayed similar survival fraction and they had similar cell cycle distribution when irradiated alone or in co-culture. Both types of irradiation induced the overexpression of genes involved in cell growth, inflammation and angiogenesis. Conclusions: We set up new irradiation chamber in which two cell types were irradiated together with a particle beam. We could not show that tumor cells and endothelial cells were able to protect each other from particle irradiation. Gene expression changes were observed after particle irradiation that could suggest a possible radioprotective inter-cellular communication between the two cell types but further investigations are needed to confirm these results. Full article

(This article belongs to the Special Issue Proton Therapy for Cancer)

► Show Figures

Figure 1

3241 KiB

Open AccessArticle

Towards Achieving the Full Clinical Potential of Proton Therapy by Inclusion of LET and RBE Models

by Bleddyn Jones

Cancers 2015, 7(1), 460-480; https://doi.org/10.3390/cancers7010460 - 17 Mar 2015

Cited by 54 | Viewed by 8807

Abstract

Despite increasing use of proton therapy (PBT), several systematic literature reviews show limited gains in clinical outcomes, with publications mostly devoted to recent technical developments. The lack of randomised control studies has also hampered progress in the acceptance of PBT by many [...] Read more.

Despite increasing use of proton therapy (PBT), several systematic literature reviews show limited gains in clinical outcomes, with publications mostly devoted to recent technical developments. The lack of randomised control studies has also hampered progress in the acceptance of PBT by many oncologists and policy makers. There remain two important uncertainties associated with PBT, namely: (1) accuracy and reproducibility of Bragg peak position (BPP); and (2) imprecise knowledge of the relative biological effect (RBE) for different tissues and tumours, and at different doses. Incorrect BPP will change dose, linear energy transfer (LET) and RBE, with risks of reduced tumour control and enhanced toxicity. These interrelationships are discussed qualitatively with respect to the ICRU target volume definitions. The internationally accepted proton RBE of 1.1 was based on assays and dose ranges unlikely to reveal the complete range of RBE in the human body. RBE values are not known for human (or animal) brain, spine, kidney, liver, intestine, etc. A simple efficiency model for estimating proton RBE values is described, based on data of Belli et al. and other authors, which allows linear increases in α and β with LET, with a gradient estimated using a saturation model from the low LET α and β radiosensitivity parameter input values, and decreasing RBE with increasing dose. To improve outcomes, 3-D dose-LET-RBE and bio-effectiveness maps are required. Validation experiments are indicated in relevant tissues. Randomised clinical studies that test the invariant 1.1 RBE allocation against higher values in late reacting tissues, and lower tumour RBE values in the case of radiosensitive tumours, are also indicated. Full article

(This article belongs to the Special Issue Proton Therapy for Cancer)

► Show Figures

Figure 1

126 KiB

Open AccessArticle

Cancer in Women over 50 Years of Age: A Focus on Smoking

by Luiz Francisco Baccaro, Délio Marques Conde, Lúcia Costa-Paiva, Vanessa De Souza Santos Machado and Aarão Mendes Pinto-Neto

Cancers 2015, 7(1), 450-459; https://doi.org/10.3390/cancers7010450 - 17 Mar 2015

Cited by 7 | Viewed by 6339

Abstract

The increase in life expectancy worldwide has resulted in a greater prevalence of chronic non-communicable diseases. This study aims to evaluate the prevalence and factors associated with the occurrence of cancer among Brazilian women over the age of 50. A cross-sectional study with [...] Read more.

The increase in life expectancy worldwide has resulted in a greater prevalence of chronic non-communicable diseases. This study aims to evaluate the prevalence and factors associated with the occurrence of cancer among Brazilian women over the age of 50. A cross-sectional study with 622 women over the age of 50 was performed using a population survey. The outcome variable was the occurrence of a malignant tumor in any location. The independent variables were sociodemographic characteristics, self-perception of health, health-related habits and morbidities. Statistical analysis was carried out using the chi-square test and Poisson regression. The mean age of the women was 64.1 years. The prevalence of cancer was 6.8%. The main sites of occurrence of malignant tumors were the breast (31.9%), colorectal (12.7%) and skin (12.7%). In the final statistical model, the only factor associated with cancer was smoking > 15 cigarettes/day either currently or in the past: PR 2.03 (95% CI 1.06–3.89). The results have improved understanding of the prevalence and factors associated with cancer in Brazilian women aged 50 years or more. They should be encouraged to maintain a healthy lifestyle and pay particular attention to modifiable risk factors such as smoking. Full article

(This article belongs to the Special Issue Cancers and Aging)

402 KiB

Open AccessReview

The Place of Targeted Agents in the Treatment of Elderly Patients with Metastatic Colorectal Cancer

by Alexios Matikas, Natalia Asimakopoulou, Vassilis Georgoulias and John Souglakos

Cancers 2015, 7(1), 439-449; https://doi.org/10.3390/cancers7010439 - 13 Mar 2015

Cited by 2 | Viewed by 6061

Abstract

Despite the high prevalence of colorectal cancer in a continuously aging population and the substantial advances in the treatment of metastatic disease during the past decade, the treatment of elderly patients with advanced, unresectable or metastatic colorectal cancer is a clearly unmet need. [...] Read more.

Despite the high prevalence of colorectal cancer in a continuously aging population and the substantial advances in the treatment of metastatic disease during the past decade, the treatment of elderly patients with advanced, unresectable or metastatic colorectal cancer is a clearly unmet need. Since older patients are under-represented or even excluded from randomized trials, the evidence that oncologists use as guidance is weak. However, small prospective studies, pooled analyses and observational studies show that combination approaches are safe, efficacious and feasible in the geriatric population with metastatic colorectal cancer. The use of biologic agents targeting angiogenesis and the epidermal growth factor receptor, which have been shown to clearly improve outcomes in multiple prospective trials in patients with advanced colorectal cancer, is a vital component of the aforementioned combination approaches. Herein, we review all available data concerning the management of elderly patients with these agents and underscore the differences between this age subgroup and younger patients. Full article

(This article belongs to the Special Issue Cancers and Aging)

1333 KiB

Open AccessArticle

Implementation of an Analytical Model for Leakage Neutron Equivalent Dose in a Proton Radiotherapy Planning System

by John Eley, Wayne Newhauser, Kenneth Homann, Rebecca Howell, Christopher Schneider, Marco Durante and Christoph Bert

Cancers 2015, 7(1), 427-438; https://doi.org/10.3390/cancers7010427 - 11 Mar 2015

Cited by 14 | Viewed by 6797

Abstract

Equivalent dose from neutrons produced during proton radiotherapy increases the predicted risk of radiogenic late effects. However, out-of-field neutron dose is not taken into account by commercial proton radiotherapy treatment planning systems. The purpose of this study was to demonstrate the feasibility of [...] Read more.

Equivalent dose from neutrons produced during proton radiotherapy increases the predicted risk of radiogenic late effects. However, out-of-field neutron dose is not taken into account by commercial proton radiotherapy treatment planning systems. The purpose of this study was to demonstrate the feasibility of implementing an analytical model to calculate leakage neutron equivalent dose in a treatment planning system. Passive scattering proton treatment plans were created for a water phantom and for a patient. For both the phantom and patient, the neutron equivalent doses were small but non-negligible and extended far beyond the therapeutic field. The time required for neutron equivalent dose calculation was 1.6 times longer than that required for proton dose calculation, with a total calculation time of less than 1 h on one processor for both treatment plans. Our results demonstrate that it is feasible to predict neutron equivalent dose distributions using an analytical dose algorithm for individual patients with irregular surfaces and internal tissue heterogeneities. Eventually, personalized estimates of neutron equivalent dose to organs far from the treatment field may guide clinicians to create treatment plans that reduce the risk of late effects. Full article

(This article belongs to the Special Issue Proton Therapy for Cancer)

► Show Figures

Graphical abstract

1253 KiB

Open AccessArticle

Inter-Institutional Comparison of Personalized Risk Assessments for Second Malignant Neoplasms for a 13-Year-Old Girl Receiving Proton versus Photon Craniospinal Irradiation

by Phillip J. Taddei, Nabil Khater, Rui Zhang, Fady B. Geara, Anita Mahajan, Wassim Jalbout, Angélica Pérez-Andújar, Bassem Youssef and Wayne D. Newhauser

Cancers 2015, 7(1), 407-426; https://doi.org/10.3390/cancers7010407 - 10 Mar 2015

Cited by 16 | Viewed by 7652

Abstract

Children receiving radiotherapy face the probability of a subsequent malignant neoplasm (SMN). In some cases, the predicted SMN risk can be reduced by proton therapy. The purpose of this study was to apply the most comprehensive dose assessment methods to estimate the reduction [...] Read more.

Children receiving radiotherapy face the probability of a subsequent malignant neoplasm (SMN). In some cases, the predicted SMN risk can be reduced by proton therapy. The purpose of this study was to apply the most comprehensive dose assessment methods to estimate the reduction in SMN risk after proton therapy vs. photon therapy for a 13-year-old girl requiring craniospinal irradiation (CSI). We reconstructed the equivalent dose throughout the patient’s body from therapeutic and stray radiation and applied SMN incidence and mortality risk models for each modality. Excluding skin cancer, the risk of incidence after proton CSI was a third of that of photon CSI. The predicted absolute SMN risks were high. For photon CSI, the SMN incidence rates greater than 10% were for thyroid, non-melanoma skin, lung, colon, stomach, and other solid cancers, and for proton CSI they were non-melanoma skin, lung, and other solid cancers. In each setting, lung cancer accounted for half the risk of mortality. In conclusion, the predicted SMN risk for a 13-year-old girl undergoing proton CSI was reduced vs. photon CSI. This study demonstrates the feasibility of inter-institutional whole-body dose and risk assessments and also serves as a model for including risk estimation in personalized cancer care. Full article

(This article belongs to the Special Issue Proton Therapy for Cancer)

► Show Figures

Figure 1

1061 KiB

Open AccessReview

Tumor and Stromal-Based Contributions to Head and Neck Squamous Cell Carcinoma Invasion

by Steven M. Markwell and Scott A. Weed

Cancers 2015, 7(1), 382-406; https://doi.org/10.3390/cancers7010382 - 27 Feb 2015

Cited by 41 | Viewed by 13254

Abstract

Head and neck squamous cell carcinoma (HNSCC) is typically diagnosed at advanced stages with evident loco-regional and/or distal metastases. The prevalence of metastatic lesions directly correlates with poor patient outcome, resulting in high patient mortality rates following metastatic development. The progression to metastatic [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is typically diagnosed at advanced stages with evident loco-regional and/or distal metastases. The prevalence of metastatic lesions directly correlates with poor patient outcome, resulting in high patient mortality rates following metastatic development. The progression to metastatic disease requires changes not only in the carcinoma cells, but also in the surrounding stromal cells and tumor microenvironment. Within the microenvironment, acellular contributions from the surrounding extracellular matrix, along with contributions from various infiltrating immune cells, tumor associated fibroblasts, and endothelial cells facilitate the spread of tumor cells from the primary site to the rest of the body. Thus far, most attempts to limit metastatic spread through therapeutic intervention have failed to show patient benefit in clinic trails. The goal of this review is highlight the complexity of invasion-promoting interactions in the HNSCC tumor microenvironment, focusing on contributions from tumor and stromal cells in order to assist future therapeutic development and patient treatment. Full article

(This article belongs to the Special Issue Cancer Cell Invasion)

► Show Figures

Figure 1

1168 KiB

Open AccessReview

Proton Radiobiology

by Francesco Tommasino and Marco Durante

Cancers 2015, 7(1), 353-381; https://doi.org/10.3390/cancers7010353 - 12 Feb 2015

Cited by 219 | Viewed by 15331

Abstract

In addition to the physical advantages (Bragg peak), the use of charged particles in cancer therapy can be associated with distinct biological effects compared to X-rays. While heavy ions (densely ionizing radiation) are known to have an energy- and charge-dependent increased Relative Biological [...] Read more.

In addition to the physical advantages (Bragg peak), the use of charged particles in cancer therapy can be associated with distinct biological effects compared to X-rays. While heavy ions (densely ionizing radiation) are known to have an energy- and charge-dependent increased Relative Biological Effectiveness (RBE), protons should not be very different from sparsely ionizing photons. A slightly increased biological effectiveness is taken into account in proton treatment planning by assuming a fixed RBE of 1.1 for the whole radiation field. However, data emerging from recent studies suggest that, for several end points of clinical relevance, the biological response is differentially modulated by protons compared to photons. In parallel, research in the field of medical physics highlighted how variations in RBE that are currently neglected might actually result in deposition of significant doses in healthy organs. This seems to be relevant in particular for normal tissues in the entrance region and for organs at risk close behind the tumor. All these aspects will be considered and discussed in this review, highlighting how a re-discussion of the role of a variable RBE in proton therapy might be well-timed. Full article

(This article belongs to the Special Issue Proton Therapy for Cancer)

► Show Figures

Graphical abstract

1738 KiB

Open AccessArticle

Complex of MUC1, CIN85 and Cbl in Colon Cancer Progression and Metastasis

by Sandra Cascio and Olivera J. Finn

Cancers 2015, 7(1), 342-352; https://doi.org/10.3390/cancers7010342 - 10 Feb 2015

Cited by 26 | Viewed by 8055

Abstract

We previously reported that CIN85, an 85 KDa protein known to be involved in tumor cell migration and metastasis through its interaction with Cbl, associates with MUC1 in tumor cells. MUC1/CIN85 complex also regulates migration and invasion of tumor cells in vitro. [...] Read more.

We previously reported that CIN85, an 85 KDa protein known to be involved in tumor cell migration and metastasis through its interaction with Cbl, associates with MUC1 in tumor cells. MUC1/CIN85 complex also regulates migration and invasion of tumor cells in vitro. Here, we examined specifically human colon carcinoma tissue microarrays (TMA) by immunohistochemistry for the expression of MUC1 and CIN85 and their potential role in cancer progression and metastasis. We detected a significant increase in expression of both MUC1 and CIN85 associated with advanced tumor stage and lymph node metastasis. We further investigated if Cbl could also be present in the MUC1/CIN85 complex. Co-immunoprecipitation assay showed that Cbl co-localized both with CIN85 and with MUC1 in a human colon cancer cell line. To begin to investigate the in vivo relevance of MUC1 overexpression and association with CIN85 and Cbl in cancer development and progression, we used human MUC1 transgenic mice that express MUC1 on the colonic epithelial cells, treated with azoxymethane to initiate and dextran sulfate sodium (AOM/DSS) to promote colorectal carcinogenesis. MUC1.Tg mice showed higher tumor incidence and decreased survival when compared with wild-type mice. Consistent with the in vitro data, the association of MUC1, CIN85 and Cbl was detected in colon tissues of AOM/DSS-treated MUC1 transgenic mice. MUC1/CIN85/Cbl complex appears to contribute to promotion and progression of colon cancer and thus increased expression of MUC1, CIN85 and Cbl in early stage colon cancer might be predictive of poor prognosis. Full article

(This article belongs to the Special Issue Cancer Cell Invasion)

► Show Figures

Figure 1

710 KiB

Open AccessReview

Collagenolytic Matrix Metalloproteinases in Chronic Obstructive Lung Disease and Cancer

by Denzel Woode, Takayuki Shiomi and Jeanine D'Armiento

Cancers 2015, 7(1), 329-341; https://doi.org/10.3390/cancers7010329 - 5 Feb 2015

Cited by 8 | Viewed by 6796

Abstract

Chronic obstructive pulmonary disease (COPD) and lung cancer result in significant morbidity and mortality worldwide. In addition to the role of environmental smoke exposure in the development of both diseases, recent epidemiological studies suggests a connection between the development of COPD and lung [...] Read more.

Chronic obstructive pulmonary disease (COPD) and lung cancer result in significant morbidity and mortality worldwide. In addition to the role of environmental smoke exposure in the development of both diseases, recent epidemiological studies suggests a connection between the development of COPD and lung cancer. Furthermore, individuals with concomitant COPD and cancer have a poor prognosis when compared with individuals with lung cancer alone. The modulation of molecular pathways activated during emphysema likely lead to an increased susceptibility to lung tumor growth and metastasis. This review summarizes what is known in the literature examining the molecular pathways affecting matrix metalloproteinases (MMPs) in this process as well as external factors such as smoke exposure that have an impact on tumor growth and metastasis. Increased expression of MMPs provides a unifying link between lung cancer and COPD. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Cancer Progress)

► Show Figures

Figure 1

406 KiB

Open AccessReview

Immunreconstitution and Infectious Complications After Rituximab Treatment in Children and Adolescents: What Do We Know and What Can We Learn from Adults?

by Jennifer Worch, Olga Makarova and Birgit Burkhardt

Cancers 2015, 7(1), 305-328; https://doi.org/10.3390/cancers7010305 - 29 Jan 2015

Cited by 43 | Viewed by 9162

Abstract

Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after [...] Read more.

Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials. Full article

(This article belongs to the Special Issue Lymphoma)

► Show Figures

Figure 1

778 KiB

Open AccessArticle

FDG-PET Response Prediction in Pediatric Hodgkin’s Lymphoma: Impact of Metabolically Defined Tumor Volumes and Individualized SUV Measurements on the Positive Predictive Value

by Amr Elsayed M. Hussien, Christian Furth, Stefan Schönberger, Patrick Hundsdoerfer, Ingo G. Steffen, Holger Amthauer, Hans-Wilhelm Müller and Hubertus Hautzel

Cancers 2015, 7(1), 287-304; https://doi.org/10.3390/cancers7010287 - 28 Jan 2015

Cited by 22 | Viewed by 8513

Abstract

Background: In pediatric Hodgkin’s lymphoma (pHL) early response-to-therapy prediction is metabolically assessed by (18)F-FDG PET carrying an excellent negative predictive value (NPV) but an impaired positive predictive value (PPV). Aim of this study was to improve the PPV while keeping the optimal [...] Read more.

Background: In pediatric Hodgkin’s lymphoma (pHL) early response-to-therapy prediction is metabolically assessed by (18)F-FDG PET carrying an excellent negative predictive value (NPV) but an impaired positive predictive value (PPV). Aim of this study was to improve the PPV while keeping the optimal NPV. A comparison of different PET data analyses was performed applying individualized standardized uptake values (SUV), PET-derived metabolic tumor volume (MTV) and the product of both parameters, termed total lesion glycolysis (TLG); Methods: One-hundred-eight PET datasets (PET1, n = 54; PET2, n = 54) of 54 children were analysed by visual and semi-quantitative means. SUVmax, SUVmean, MTV and TLG were obtained the results of both PETs and the relative change from PET1 to PET2 (Δ in %) were compared for their capability of identifying responders and non-responders using receiver operating characteristics (ROC)-curves. In consideration of individual variations in noise and contrasts levels all parameters were additionally obtained after threshold correction to lean body mass and background; Results: All semi-quantitative SUV estimates obtained at PET2 were significantly superior to the visual PET2 analysis. However, ΔSUVmax revealed the best results (area under the curve, 0.92; p < 0.001; sensitivity 100%; specificity 85.4%; PPV 46.2%; NPV 100%; accuracy, 87.0%) but was not significantly superior to SUVmax-estimation at PET2 and ΔTLGmax. Likewise, the lean body mass and background individualization of the datasets did not impove the results of the ROC analyses; Conclusions: Sophisticated semi-quantitative PET measures in early response assessment of pHL patients do not perform significantly better than the previously proposed ΔSUVmax. All analytical strategies failed to improve the impaired PPV to a clinically acceptable level while preserving the excellent NPV. Full article

(This article belongs to the Special Issue Lymphoma)

► Show Figures

Figure 1

467 KiB

Open AccessReview

Desmoglein 3: A Help or a Hindrance in Cancer Progression?

by Louise Brown and Hong Wan

Cancers 2015, 7(1), 266-286; https://doi.org/10.3390/cancers7010266 - 26 Jan 2015

Cited by 36 | Viewed by 7292

Abstract

Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the intermediate filaments of adjacent cells and confer strong cell adhesion thus are essential in the maintenance of tissue architecture and [...] Read more.

Desmoglein 3 is one of seven desmosomal cadherins that mediate cell-cell adhesion in desmosomes. Desmosomes are the intercellular junctional complexes that anchor the intermediate filaments of adjacent cells and confer strong cell adhesion thus are essential in the maintenance of tissue architecture and structural integrity. Like adherens junctions, desmosomes function as tumour suppressors and are down regulated in the process of epithelial-mesenchymal transition and in tumour cell invasion and metastasis. However, recently several studies have shown that various desmosomal components, including desmoglein 3, are up-regulated in cancer with increased levels of expression correlating with the clinical stage of malignancy, implicating their potentiality to serve as a diagnostic and prognostic marker. Furthermore, in vitro studies have demonstrated that overexpression of desmoglein 3 in cancer cell lines activates several signal pathways that have an impact on cell morphology, adhesion and locomotion. These additional signalling roles of desmoglein 3 may not be associated to its adhesive function in desmosomes but rather function outside of the junctions, acting as a key regulator in the control of actin based cellular processes. This review will discuss recent advances which support the role of desmoglein 3 in cancer progression. Full article

(This article belongs to the Special Issue Cancer Cell Invasion)

942 KiB

Open AccessReview

Extracellular Molecules Involved in Cancer Cell Invasion

by Theodora Stivarou and Evangelia Patsavoudi

Cancers 2015, 7(1), 238-265; https://doi.org/10.3390/cancers7010238 - 26 Jan 2015

Cited by 49 | Viewed by 12072

Abstract

Nowadays it is perfectly clear that understanding and eradicating cancer cell invasion and metastasis represent the crucial, definitive points in cancer therapeutics. During the last two decades there has been a great interest in the understanding of the extracellular molecular mechanisms involved in [...] Read more.

Nowadays it is perfectly clear that understanding and eradicating cancer cell invasion and metastasis represent the crucial, definitive points in cancer therapeutics. During the last two decades there has been a great interest in the understanding of the extracellular molecular mechanisms involved in cancer cell invasion. In this review, we highlight the findings concerning these processes, focusing in particular on extracellular molecules, including extracellular matrix proteins and their receptors, growth factors and their receptors, matrix metalloproteinases and extracellular chaperones. We report the molecular mechanisms underlying the important contribution of this pool of molecules to the complex, multi-step phenomenon of cancer cell invasion. Full article

(This article belongs to the Special Issue Cancer Cell Invasion)

► Show Figures

Figure 1

2383 KiB

Open AccessReview

Targeting Cyclin-Dependent Kinases in Human Cancers: From Small Molecules to Peptide Inhibitors

by Marion Peyressatre, Camille Prével, Morgan Pellerano and May C. Morris

Cancers 2015, 7(1), 179-237; https://doi.org/10.3390/cancers7010179 - 23 Jan 2015

Cited by 260 | Viewed by 24065

Abstract

Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation [...] Read more.

Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported. Full article

(This article belongs to the Collection Kinases and Cancer)

► Show Figures

Graphical abstract

947 KiB

Open AccessArticle

Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

by Ana M. Santander, Omar Lopez-Ocejo, Olivia Casas, Thais Agostini, Lidia Sanchez, Eduardo Lamas-Basulto, Roberto Carrio, Margot P. Cleary, Ruben R. Gonzalez-Perez and Marta Torroella-Kouri

Cancers 2015, 7(1), 143-178; https://doi.org/10.3390/cancers7010143 - 15 Jan 2015

Cited by 85 | Viewed by 13439

Abstract

The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) [...] Read more.

The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity. Full article

(This article belongs to the Special Issue Tumor Associated Macrophages)

► Show Figures

Figure 1

1115 KiB

Open AccessReview

Chromatinization of the KSHV Genome During the KSHV Life Cycle

by Timsy Uppal, Hem C. Jha, Subhash C. Verma and Erle S. Robertson

Cancers 2015, 7(1), 112-142; https://doi.org/10.3390/cancers7010112 - 14 Jan 2015

Cited by 35 | Viewed by 15176

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family and is the causative agent of various lymphoproliferative diseases in humans. KSHV, like other herpesviruses, establishes life-long latent infection with the expression of a limited number of viral genes. Expression of these genes [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family and is the causative agent of various lymphoproliferative diseases in humans. KSHV, like other herpesviruses, establishes life-long latent infection with the expression of a limited number of viral genes. Expression of these genes is tightly regulated by both the viral and cellular factors. Recent advancements in identifying the expression profiles of viral transcripts, using tilling arrays and next generation sequencing have identified additional coding and non-coding transcripts in the KSHV genome. Determining the functions of these transcripts will provide a better understanding of the mechanisms utilized by KSHV in altering cellular pathways involved in promoting cell growth and tumorigenesis. Replication of the viral genome is critical in maintaining the existing copies of the viral episomes during both latent and lytic phases of the viral life cycle. The replication of the viral episome is facilitated by viral components responsible for recruiting chromatin modifying enzymes and replication factors for altering the chromatin complexity and replication initiation functions, respectively. Importantly, chromatin modification of the viral genome plays a crucial role in determining whether the viral genome will persist as latent episome or undergo lytic reactivation. Additionally, chromatinization of the incoming virion DNA, which lacks chromatin structure, in the target cells during primary infection, helps in establishing latent infection. Here, we discuss the recent advancements on our understating of KSHV genome chromatinization and the consequences of chromatin modifications on viral life cycle. Full article

(This article belongs to the Special Issue DNA Viruses in Human Cancer)

► Show Figures

Figure 1

1672 KiB

Open AccessArticle

The Roles of Akt Isoforms in the Regulation of Podosome Formation in Fibroblasts and Extracellular Matrix Invasion

by Robert Eves, Robyn Oldham, Lilly Jia and Alan S. Mak

Cancers 2015, 7(1), 96-111; https://doi.org/10.3390/cancers7010096 - 7 Jan 2015

Cited by 10 | Viewed by 7091

Abstract

Mesenchymal cells employ actin-based membrane protrusions called podosomes and invadopodia for cross-tissue migration during normal human development such as embryogenesis and angiogenesis, and in diseases such as atherosclerosis plaque formation and cancer cell metastasis. The Akt isoforms, downstream effectors of phosphatidylinositol 3 kinase [...] Read more.

Mesenchymal cells employ actin-based membrane protrusions called podosomes and invadopodia for cross-tissue migration during normal human development such as embryogenesis and angiogenesis, and in diseases such as atherosclerosis plaque formation and cancer cell metastasis. The Akt isoforms, downstream effectors of phosphatidylinositol 3 kinase (PI3K), play crucial roles in cell migration and invasion, but their involvement in podosome formation and cell invasion is not known. In this study, we have used Akt1 and/or Akt2 knockout mouse embryonic fibroblasts and Akt3-targeted shRNA to determine the roles of the three Akt isoforms in Src and phorbol ester-induced podosome formation, and extracellular matrix (ECM) digestion. We found that deletion or knockdown of Akt1 significantly reduces Src-induced formation of podosomes and rosettes, and ECM digestion, while suppression of Akt2 has little effect. In contrast, Akt3 knockdown by shRNA increases Src-induced podosome/rosette formation and ECM invasion. These data suggest that Akt1 promotes, while Akt3 suppresses, podosome formation induced by Src, and Akt2 appears to play an insignificant role. Interestingly, both Akt1 and Akt3 suppress, while Akt2 enhances, phorbol ester-induced podosome formation. These data show that Akt1, Akt2 and Akt3 play different roles in podosome formation and ECM invasion induced by Src or phorbol ester, thus underscoring the importance of cell context in the roles of Akt isoforms in cell invasion. Full article

(This article belongs to the Special Issue Cancer Cell Invasion)

► Show Figures

Figure 1

278 KiB

Open AccessEditorial

Acknowledgement to Reviewers of Cancers in 2014

by Cancers Editorial Office

Cancers 2015, 7(1), 92-95; https://doi.org/10.3390/cancers7010092 - 7 Jan 2015

Viewed by 4133

Abstract

The editors of Cancers would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2014:[...] Full article

1114 KiB

Open AccessReview

Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

by Holli A. Loomans and Claudia D. Andl

Cancers 2015, 7(1), 70-91; https://doi.org/10.3390/cancers7010070 - 30 Dec 2014

Cited by 115 | Viewed by 17850

Abstract

In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation [...] Read more.

In recent years, a significant amount of research has examined the controversial role of activin A in cancer. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, is best characterized for its function during embryogenesis in mesoderm cell fate differentiation and reproduction. During embryogenesis, TGFβ superfamily ligands, TGFβ, bone morphogenic proteins (BMPs) and activins, act as potent morphogens. Similar to TGFβs and BMPs, activin A is a protein that is highly systemically expressed during early embryogenesis; however, post-natal expression is overall reduced and remains under strict spatiotemporal regulation. Of importance, normal post-natal expression of activin A has been implicated in the migration and invasive properties of various immune cell types, as well as endometrial cells. Aberrant activin A signaling during development results in significant morphological defects and premature mortality. Interestingly, activin A has been found to have both oncogenic and tumor suppressor roles in cancer. Investigations into the role of activin A in prostate and breast cancer has demonstrated tumor suppressive effects, while in lung and head and neck squamous cell carcinoma, it has been consistently shown that activin A expression is correlated with increased proliferation, invasion and poor patient prognosis. Activin A signaling is highly context-dependent, which is demonstrated in studies of epithelial cell tumors and the microenvironment. This review discusses normal activin A signaling in comparison to TGFb and highlights how its dysregulation contributes to cancer progression and cell invasion. Full article

(This article belongs to the Special Issue Cancer Cell Invasion)

► Show Figures

Figure 1

1218 KiB

Open AccessReview

p53 Acetylation: Regulation and Consequences

by Sara M. Reed and Dawn E. Quelle

Cancers 2015, 7(1), 30-69; https://doi.org/10.3390/cancers7010030 - 23 Dec 2014

Cited by 262 | Viewed by 26747

Abstract

Post-translational modifications of p53 are critical in modulating its tumor suppressive functions. Ubiquitylation, for example, plays a major role in dictating p53 stability, subcellular localization and transcriptional vs. non-transcriptional activities. Less is known about p53 acetylation. It has been shown to govern p53 [...] Read more.

Post-translational modifications of p53 are critical in modulating its tumor suppressive functions. Ubiquitylation, for example, plays a major role in dictating p53 stability, subcellular localization and transcriptional vs. non-transcriptional activities. Less is known about p53 acetylation. It has been shown to govern p53 transcriptional activity, selection of growth inhibitory vs. apoptotic gene targets, and biological outcomes in response to diverse cellular insults. Yet recent in vivo evidence from mouse models questions the importance of p53 acetylation (at least at certain sites) as well as canonical p53 functions (cell cycle arrest, senescence and apoptosis) to tumor suppression. This review discusses the cumulative findings regarding p53 acetylation, with a focus on the acetyltransferases that modify p53 and the mechanisms regulating their activity. We also evaluate what is known regarding the influence of other post-translational modifications of p53 on its acetylation, and conclude with the current outlook on how p53 acetylation affects tumor suppression. Due to redundancies in p53 control and growing understanding that individual modifications largely fine-tune p53 activity rather than switch it on or off, many questions still remain about the physiological importance of p53 acetylation to its role in preventing cancer. Full article

(This article belongs to the Special Issue Cell Cycle Deregulation in Cancers)

► Show Figures

Figure 1

943 KiB

Open AccessReview

Regulation of the Tumor-Suppressor Function of the Class III Phosphatidylinositol 3-Kinase Complex by Ubiquitin and SUMO

by Christina Reidick, Fouzi El Magraoui, Helmut E. Meyer, Harald Stenmark and Harald W. Platta

Cancers 2015, 7(1), 1-29; https://doi.org/10.3390/cancers7010001 - 23 Dec 2014

Cited by 29 | Viewed by 12729

Abstract

The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes—autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic [...] Read more.

The occurrence of cancer is often associated with a dysfunction in one of the three central membrane-involution processes—autophagy, endocytosis or cytokinesis. Interestingly, all three pathways are controlled by the same central signaling module: the class III phosphatidylinositol 3-kinase (PI3K-III) complex and its catalytic product, the phosphorylated lipid phosphatidylinositol 3-phosphate (PtdIns3P). The activity of the catalytic subunit of the PI3K-III complex, the lipid-kinase VPS34, requires the presence of the membrane-targeting factor VPS15 as well as the adaptor protein Beclin 1. Furthermore, a growing list of regulatory proteins associates with VPS34 via Beclin 1. These accessory factors define distinct subunit compositions and thereby guide the PI3K-III complex to its different cellular and physiological roles. Here we discuss the regulation of the PI3K-III complex components by ubiquitination and SUMOylation. Especially Beclin 1 has emerged as a highly regulated protein, which can be modified with Lys11-, Lys48- or Lys63-linked polyubiquitin chains catalyzed by distinct E3 ligases from the RING-, HECT-, RBR- or Cullin-type. We also point out other cross-links of these ligases with autophagy in order to discuss how these data might be merged into a general concept. Full article

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cancers, Volume 7, Issue 1 (March 2015) – 23 articles , Pages 1-537

Further Information

Guidelines

MDPI Initiatives

Follow MDPI