Special Issue "System Biology in Cancer Research"

Guest Editor
Dr. Bernard Corfe
Department of Oncology, The Medical School, Beech Hill Road, Sheffield, S10 2RX, UK
Website: http://www.shef.ac.uk/oncology/staffprofiles/corfe
E-Mail: b.m.corfe@sheffield.ac.uk

Dear Colleagues,

Systems biology is an emerging interdisciplinary approach to biological research deliberately embracing a suite of divergent approaches. It seeks to incorporate substantive bodies of literature, high throughput (omics)data, mathemetical modelling to generate in silico models with predictive capacity to improve understanding of biology. In essence it is anti-reductionist. Systems biology is being applied to cancer research at a number of levels and from a number of perspectives, network modelling is applied to large datasets to reveal novel markers or targets of disease (1,2) and also from a ground-up perspective in the modelling of pathways previously described purely qualitatively (3). It is perhaps naive to treat a cancer as behaving like the host organism and the application of models of competition in ecosystems and game theory have also been applied to modelling the behaviour of tumours (4,5).

This special edition of Cancers gives an opportunity to describe recent original research in the application of any systems-biology approach in cancer research, the development or application of new platforms or insights, and is open to reviews of the field and benefits of application. If you would like to discuss an idea for a paper before committing please contact the guest editor.

Dr. Bernard Corfe
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 500 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Wolfgang Brozek, Teresa Manhardt, Enikö Kállay, Meinrad Peterlik and Heide S. Cross Article: Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis Cancers 2012, 4(3), 763-776; doi:10.3390/cancers4030763 Received: 22 May 2012; in revised form: 6 July 2012 / Accepted: 13 July 2012 / Published: 26 July 2012 Show/Hide Abstract | Download PDF Full-text (207 KB) | Download XML Full-text Abstract: Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1a-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression.

---

Marija Milacic, Robin Haw, Karen Rothfels, Guanming Wu, David Croft, Henning Hermjakob, Peter D'Eustachio and Lincoln Stein Article: Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome Cancers 2012, 4(4), 1180-1211; doi:10.3390/cancers4041180 Received: 8 October 2012; in revised form: 31 October 2012 / Accepted: 2 November 2012 / Published: 8 November 2012 Show/Hide Abstract | Download PDF Full-text (1361 KB) | Download XML Full-text Abstract: Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics.

---

Claudio L. Battaglini, Anthony C. Hackney and Matthew L. Goodwin Commentary: Cancer Cachexia: Muscle Physiology and Exercise Training Cancers 2012, 4(4), 1247-1251; doi:10.3390/cancers4041247 Received: 11 September 2012; in revised form: 17 November 2012 / Accepted: 21 November 2012 / Published: 29 November 2012 Show/Hide Abstract | Download PDF Full-text (308 KB) | Download XML Full-text Abstract: Cachexia in cancer patients is a condition marked by severe tissue wasting and a myriad of quality of life and health consequences. Cachexia is also directly linked to the issues of morbidity and survivability in cancer patients. Therapeutic means of mitigating cachexia and its effects are thus critical in cancer patient treatment. We present a discussion on the use of physical exercise activities in the context of such treatment as a means to disruption the tissue wasting effects (i.e., muscle tissue losses via anorexigenic pro-inflammatory cytokines) of cachexia. In addition we propose a theoretical model (Exercise Anti-Cachectic Hypothetical—“EACH” model) as to how exercise training may promote a disruption in the cycle of events leading to advancing cachexia and in turn promote an enhanced functionality and thus improved quality of life in cancer patients.

---

Type of Paper: Article
Title: Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome
Author: Peter G D'Eustachio
Affiliation: 550 First Avenue, Dept. of Biochemistry, Floor 3, Room 328, Medical Science Building, New York, NY 10016 USA; E-Mail: Peter.D'Eustachio@nyumc.org
Abstract: Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Two recent extensions of our data model accommodate the annotation of disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the mutant proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that accepts disease ontology terms, e.g., from the Human Disease Ontology. From the perspective of Reactome’s data model, the changes in protein struc-ture and function that lead to disease fall into three groups: i) ones in which the protein function is unaltered but the amount of its activity changes, altering the quantitative ex-tent of the normal process; ii) ones in which a protein’s function is changed, enabling ab-normal processes to occur; and iii) ones in which foreign proteins introduced into the cell mediate abnormal processes. Diseases due to loss-of-function mutant variants are cap-tured by our expression-overlay data analysis tool. We can annotate diseases due to gain-of-function mutant proteins by creating a “disease” reaction, and associating it with the normal pathway.
Using the Epidermal Growth Factor Receptor (EGFR) as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR mutant va-riants due to their altered kinase and ligand-binding properties. We can represent the mode of action and specificity of anti-cancer therapeutics and monoclonal antibodies like Gefitinib and Cetuximab, respectively. To support the graphical representation of “cancer” pathways, we have adapted the Reactome Pathway Browser to display each of these va-riants in a way that allows comparison with the wild type pathway and connections be-tween perturbations in EGFR signaling and cancer related changes in other biological pathways, such as PI3K/AKT signaling.
Annotation strategies for diseases due to the introduction of foreign proteins are al-ready well established in Reactome. We have annotated the life cycles of HIV and in-fluenza viruses, as well as the TLR-mediated signaling cascades of the innate immune system triggered by microbial proteins. The curation of pathways associated with cancer coupled with our efforts to create other disease-specific pathways, will open up additional opportunities to support the annotation activities of the Gene Ontology (GO) and Protein Ontology (PRO) Consortia.

Type of Paper: Review
Title: Systems Biology in Breast Cancer Research
Author: Binnaz Demirkan
Affiliation: Department of Internal Medicine, Division of Medical Oncology, Dokuz Eylul University, School of Medicine, Izmir; E-Mail: binnaz.demirkan@deu.edu.tr
Abstract: Breast cancer imposes a significant healthcare burden on women worldwide. Systems biology in breast cancer research is the  study of breast cancer viewed as an integrated and interacting network of genes, proteins and biochemical reactions within the tumor and microenviroment and it does not only require the integration of cell biology, molecular biology, genetics, biochemistry, technology, computation and medicine, but also a strong cross-disciplinary team of researchers. Breast cancer research is an ideal example of how systems biology can be applied to better understand a specific clinical issue. Today, we can better understand the concept of breast cancer development, heterogeneity, and its treatment by integrating vast data sets from tumor-derived expression arrays, genome-wide transcription factor/chromatin interactions, proteomics and computational analyses. In this review, the current status of  studies and the challenges as well as promises will be described and discussed in order to fully understand the new concept, P4 Medicine:  Predictive, Preventive, Personalized and Participatory.

Type of the Paper: Article
Title: Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 is a Determinant of Human Colorectal Cancer Heterogeneity: Results from Factor and Cluster Analysis
Authors: Wolfgang Brozek, Teresa Manhardt, Enikö Kállay, Meinrad Peterlik and Heide S. Cross
Affiliation: Department of Pathophysiology, Medical University of Vienna, Vienna, Austria; E-Mail: meinrad.peterlik@meduniwien.ac.at
Abstract: Colorectal carcinomas display a high degree of heterogeneity. Incidence, malignancy and clinical outcome differ widely in relation to age, gender and tumor location in the colorectum. Previous studies on the significance of vitamin D insufficiency and chronic inflammation on colorectal cancer development clearly indicated that maintenance of cellular homeostasis requires balancing of growth promoting signals from prostaglandin E2 by anti-mitogenic signaling via the 1,25-dihydroxyvitamin D3/Vitamin D Receptor (1,25-(OH)2D3/VDR) pathway. We therefore studied whether observed differences in susceptibility for colorectal cancer reflect changes in the activity of gut-located vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1a-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, since these control the synthesis of 1,25-(OH)2D3, and of inflammation-induced cyclo-oxygenase-2 (COX-2). Data from 105 cancer patients on mRNA expression of CYP27B1, VDR, CYP24A1, and COX-2 in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Identical results were obtained by the principal factor and the maximum likelihood method and were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were identified, which are associated with different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancers is solely associated with a rise in CYP24A1 expression. Our study suggests that modulation of vitamin D metabolism leading to stimulation of CYP27B1 and inhibition of CYP24A1 activity could specifically complement the efficiency of COX-2 inhibitors in prevention of colorectal cancer.