Disease pathways at the Rat Genome Database Pathway Portal: genes in context-a network approach to understanding the molecular mechanisms of disease
© Petri et al.; licensee BioMed Central Ltd. 2014
Received: 5 August 2014
Accepted: 23 September 2014
Published: 30 September 2014
Biological systems are exquisitely poised to respond and adjust to challenges, including damage. However, sustained damage can overcome the ability of the system to adjust and result in a disease phenotype, its underpinnings many times elusive. Unraveling the molecular mechanisms of systems biology, of how and why it falters, is essential for delineating the details of the path(s) leading to the diseased state and for designing strategies to revert its progression. An important aspect of this process is not only to define the function of a gene but to identify the context within which gene functions act. It is within the network, or pathway context, that the function of a gene fulfills its ultimate biological role. Resolving the extent to which defective function(s) affect the proceedings of pathway(s) and how altered pathways merge into overpowering the system's defense machinery are key to understanding the molecular aspects of disease and envisioning ways to counteract it. A network-centric approach to diseases is increasingly being considered in current research. It also underlies the deployment of disease pathways at the Rat Genome Database Pathway Portal. The portal is presented with an emphasis on disease and altered pathways, associated drug pathways, pathway suites, and suite networks.
The Pathway Portal at the Rat Genome Database (RGD) provides an ever-increasing collection of interactive pathway diagrams and associated annotations for metabolic, signaling, regulatory, and drug pathways, including disease and altered pathways. A disease pathway is viewed from the perspective of networks whose alterations are manifested in the affected phenotype. The Pathway Ontology (PW), built and maintained at RGD, facilitates the annotations of genes, the deployment of pathway diagrams, and provides an overall navigational tool. Pathways that revolve around a common concept and are globally connected are presented within pathway suites; a suite network combines two or more pathway suites.
The Pathway Portal is a rich resource that offers a range of pathway data and visualization, including disease pathways and related pathway suites. Viewing a disease pathway from the perspective of underlying altered pathways is an aid for dissecting the molecular mechanisms of disease.
Pathways and the Pathway Ontology
Disease and altered pathways-a network approach to diseases
A disease pathway, as opposed to the clinical, gene-centric view of the condition, offers a network-centric view-an approach increasingly being considered by scientists. Interestingly, despite a wealth of information on mutated genes, the number of those considered `driver' genes in cancer (genes that can promote or `drive' tumorigenesis) is relatively small. Collectively, they are found in a set of important pathways such as the Ras-driven Erk1/2 and phosphatidylinositol 3-kinase-Akt signaling, those mediated by receptor tyrosine kinases (RTK), or those that are involved in cell cycle and apoptosis, DNA damage control, chromatin modification, and transcriptional regulation ,. Although the rest of the mutant genes are considered `passengers', their presence and faulty interactions could, at least in principle, augment in some fashion the negative impact of `driver' genes and, as such, contribute to the altered pathways leading to disease. Given the role these pathways normally play, their alterations can easily fuel the `hallmarks' of cancer proposed by Hanahan and Weinberg: sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, and resisting cell death . In addition to variant genes and their associated dysfunctional pathways, deregulations stemming from sources other than protein coding genes such as those associated with microRNAs (miRNAs) and other non-coding elements or from sources other than sequence variation such as those at the epigenetic level can and do contribute to the disease phenotype. Abnormal chromatin modification as well as the up- and down-regulated expression of miRNA in tumor tissues compared to normal ones have been reported ,. Systems level, high-throughput, and -omics approaches to the study and understanding of disease initiation and progression are being considered ,. Disease pathways are approached in a similar, network-centric vein at RGD, and they are presented as sets/collections of altered pathways.
Resources such as KEGG , the Small Molecule Pathway Database (SMPDB) , and Reactome  offer pathway diagrams, including disease pathways, along with links to gene entries and other pertinent information. However, the portrayal of disease pathways as the collection of altered pathways associated with a particular deviant phenotype, the use of a dedicated pathway ontology to annotate gene products and for use as a navigational tool conferring the ability to `travel' the road of connected pathways, along with the provision of pathway suites and suite networks, are all distinctive features of the RGD Pathway Portal.
Results and discussion
Pancreatic cancer pathway
Pancreatic cancer is one of the most aggressive cancer types which despite sustained scientific and clinical efforts continues to have a less than 5% overall 5-year survival rate. It is the fourth leading cause of cancer-related death and both men and women are affected. Pancreatic ductal adenocarcinoma (PDAC) is the predominant form with neoplastic precursor lesions such as pancreatic intraepithelial neoplasia (PanIN) graded stage I to III, converging into PDAC and ultimately invasion and metastasis. A major genetic driver is Kras of the Ras family believed to be an initiator of PDAC and a promoter of its development and progression. Activating mutations are present in >90% of PDAC and can be found as early as PanIN grade I and even in normal pancreas. KRAS activation found in the early stages of pancreatic cancer is followed by inactivation of the cell cycle regulator CDKN2A (95%) also in the earlier stages, and inactivation of TP53 (75%) and SMAD4 (55%) in the later stages. The CDKN2A gene codes for two non-identical proteins of which the p16 or p16/Ink4a product is the cyclin-dependent kinase inhibitor and cell cycle regulator and the p14 or p14/Arf product is a p53-activating tumor suppressor. The inactivating mutations in PDAC involve the p16/Ink4a gene product -. However, p14/Arf mutations are associated with other cancer types, and the two protein products act in connected pathways-p53 signaling promotes, as necessary, cell cycle arrest, apoptosis, or senescence and is also a negative regulator of p14/Arf expression ,. Studies, large-scale genomic studies in particular, indicate that many important cellular pathways are deregulated in pancreatic cancer, those involving the above mentioned genes as well as others - and references therein. These pathways are major players in the regulation of cell growth, differentiation, proliferation, and/or survival, such as the extracellular signal-regulated Raf/Mek/Erk (ERK1/2) pathway downstream of Kras, the Smad-dependent transforming growth factor-beta (TGF-beta) pathway, or the epidermal growth factor/neuregulin (EGF) signaling pathway. Other involved genes are known tumor suppressors such as Tp53 (P53), whose signaling bridges DNA damage response to cell cycle arrest or apoptosis, or important regulators such as Pten in the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) signaling pathway and Cdkn2a in the G1/S transition pathway of the cell cycle. PI3K-Akt may also be downstream of oncogenic Kras in PDAC. Signaling by Hedgehog proteins or hepatocyte growth factor (SF/HGF) play important developmental roles, and both pathways are deregulated in pancreatic cancer. Finally, other involved pathways are integrin-mediated signaling, with important roles in adhesion, and canonical Wnt signaling, with important roles in development. Alterations in components of chromatin modification and remodeling pathways have also been identified. Prominent pathways shown to be altered in the condition are represented in the `pancreatic cancer pathway' diagram page [see Figure 2]. While the substantial number of pathways observed to be affected may be the result of large-scale experimental approaches, it is nonetheless possible that this is a feature particular to pancreatic cancer and as such it may underlie the extreme aggressiveness of this malignancy. The combined effect of these altered pathways can `meet' most if not all the above mentioned `hallmarks' of cancer as put forward by Hanahan and Weinberg . A number of these pathways, particularly those involving Kras, Pten, or EGF, are also deregulated in many other cancer types. Ras proteins were the first oncogenes identified in human cancers, primarily Kras with frequent activating mutations and, to a much lesser extent, mutations in the closely related Hras or Nras genes. Kras confers stem-like properties on certain cell types, Kras deletion leads to death during embryogenesis in mice, and it is in pancreatic cancer that the activating Kras mutations are the most frequent . miRNAs, which primarily inhibit the translation of target genes, are aberrantly expressed in pancreatic cancer as well as other cancer types. Many miRNAs are shown to be both up- and down-regulated in pancreatic cancer resulting in multiple effects such as chemoresistance, proliferation, survival, invasion, and metastasis . Early detection of pancreatic cancer has proven difficult. Aberrant DNA methylation and other epigenetic alterations are observed in many cancer types, including pancreatic cancer. Epigenetic markers may provide a means for earlier detection of pancreatic cancer . Pancreatic cancer may be an extreme case but it is nonetheless intriguing why so many mutations and associated altered pathways converge on this organ and its malignancy and why they do display a preferential as well as a temporal pattern.
Prostate cancer pathway
Unlike pancreatic cancer with its plethora of altered pathways, in the case of prostate cancer, the main culprit is the androgen receptor (AR) of the androgen signaling pathway. A deregulated phosphatidylinositol 3-kinase-Akt pathway also contributes with loss or inactivating mutations in the Pten regulator and, to a lesser extent, amplification or activating mutations of the catalytic subunit Pik3ca. Deletions at the p53 locus in the p53 pathway have also been seen in prostate cancer samples . Normal androgen signaling plays an essential role in the development and maintenance of the male phenotype and reproductive functions and in a range of other processes. The steroid hormone AR belongs to the nuclear receptor family. Once activated by hormone binding-testosterone or its more potent metabolite dihydrotestosterone (DHT), AR translocates to the nucleus to regulate the expression of its target genes. In the altered pathway leading to prostate cancer, the androgen receptor displays an intriguing altered and mutational behavior, mostly treatment-induced. Reduction of testosterone levels leads to changes in gene copy number and also in increased transcription of the receptor. Thus, trace amounts of the ligand are enough to set its signaling pathway in motion. Complete elimination of plasma testosterone initially abrogates receptor activity, followed in time by various mechanisms which result in ligand-independent androgen receptor signaling. Increased phosphorylation of the receptor, expression of splice variants that do not have the ligand binding domain, mutations that allow the receptor to bind to and be activated by non-traditional ligands including antagonists, and altered expression of coregulators, steroid biosynthetic enzymes, and/or the receptor transcriptional program all contribute to testosterone-independent receptor activity -. Alterations in the NCOA2 coactivator and NCOR2 corepressor and in chromatin regulatory elements have been reported . Steroid hormones share a core biosynthetic pathway that branches into the individual steroid biosynthesis in given tissues via tissue-specific expression of terminal enzymes; in prostate cancer, changes in enzyme expression circumvent the initial testosterone depletion . Gene fusion between androgen receptor-regulated genes and members of the E26 transformation-specific (ETS) family of oncogenic transcription factors is a signature feature found in ~50% of cases. Fusion between the Tmprss2 gene and the Erg member of the ETS family is common in prostate cancer. The gene rearrangements have been mostly noticed in primary prostate cancer while the alterations/mutations of the receptor have been associated with the treatment-resistant, metastatic prostate tumors. The PI3K-Akt and p53 alterations are observed in both primary and metastatic prostate cancer. Mutations in a number of other elements are being unraveled and await further investigation with respect to their role in the initiation and/or progression of prostate tumors ,,. In the altered androgen signaling and prostate cancer pathways, the androgen receptor becomes a ligand-independent or antagonist-induced, constitutively active transcription factor.
Renal cell cancer pathway
In RCC, as in the case of prostate cancer with altered androgen signaling, HIF has become an unregulated, condition-independent, constitutively active transcription factor. However, unlike the androgen receptor pathway with its rather distinct expression and functional range, the HIF pathway is ubiquitous, yet its alteration is localized. VHL, the dominant contributor to RCC, is rarely mutated in other sporadic tumors.
Drug and drug/compound responses-axitinib, cisplatin, and bisphenol A
Like cisplatin, BPA can form DNA adducts, but its primary targets are nuclear and hormone receptors, mainly the estrogen receptors. BPA is used in the production of many types of plastics, the lining of food containers, medical and dental devices, and thermal paper. The high levels of BPA production are responsible for its widespread presence in the environment. In addition, BPA can also be found in food due to its leaching out of containers. BPA binds the ESR1 and ESR2 nuclear estrogen receptors and also the G protein-coupled estrogen receptor GPER. BPA can induce rapid activation of the Erk1/2 pathway via GPER in breast cancer; it may affect various immune responses and has been implicated in the etiology of many diseases and disorders  [Figure 8B]. Most compounds and drugs exert negative effects; the distinction between adverse effects and toxicity is one of response, i.e., the relative steepness of the response curve. As in the altered and disease pathways, the diagrams attempt to capture the molecular underpinnings of drug metabolism and of drug-target interactions or the implications of drug and/or chemical toxicity
Estrogen pathway suite
Conclusions and future developments
A disease pathway brings together associated altered pathways and culprit genes within, along with deregulated miRNAs and other putative candidate genes, to provide a unique view of the possible molecular mechanisms underlying the condition. Normal processes are hijacked, harnessed, and modulated by tumor cells to serve their proliferative and invasive needs, as posited by Hanahan and Weinberg . The case studies presented here centered on malignancies and featured a number of special examples: the extreme case of pancreatic cancer with its many altered pathways; prostate cancer with few contributors and whose main culprit, despite its intriguing therapy-induced resistance response, can be rationalized by virtue of specific expression and function; and renal cell cancer, also with few contributors, but whose main culprit cannot be readily explained by virtue of expression and function alone. Despite the identity of altered pathways being different, constitutive signaling as well as deregulated expression of coding and non-coding genes, activation of oncogenes, and silencing of tumor suppressors are shared features. However, there are also distinctive features and they raise questions. For instance, many of the pathways altered in pancreatic cancer are known to be oncogenic in other cancer types-as an example, TP53 is the most commonly mutated gene in cancer. However, it is KRAS that has the highest mutation incidence in pancreatic cancer-twice its occurrence in cancer of the colon or small intestine, followed in decreasing order by endometrium and lung cancers and much lower in neoplasms of other tissues. Why is KRAS preferentially mutated in pancreatic cancer and why does this member of Ras have the highest overall mutagenic propensities relative to the other two, closely related Ras members, HRAS and NRAS? Differential codon usage in KRAS might underlie its higher mutagenic rate than its Ras cousins and distinct mutations may confer distinct functional behaviors upon the mutant proteins and prompt different outcomes, but they do not explain what triggers the frequency of mutations in and their association with different tissues . In a similar vein, one may ask why somatic mutations in the VHL protein are primarily associated with renal cell cancer or why diminishing levels of testosterone prompt the kind of mutations that render the androgen receptor ligand-independent.
Interestingly, the pancreatic acinar cells and the most abundant cell type, under certain conditions such as injury and accompanying inflammation, can acquire plastic capabilities . Findings suggest that acinar cells may be the cells of origin for PanIN lesions and renal ductal adenocarcinoma. These findings await further investigation to be firmly established. However, one is tempted to wonder whether the proneness of KRAS to mutate may in some fashion be aided or activated within a challenged pancreatic tissue milieu, perhaps further promoting its plasticity and the instantiation of mutations in other genes. Likewise, do the unique features of the filtering system the kidney represents make it more vulnerable to unwanted hypoxic responses which would be easy to `satisfy', by just silencing VHL? Are the reproductive tissues more likely to be affected by infection, and does a yet to be identified infectious agent confer upon the androgen receptor its features, reminiscent of acquired resistance?
The provision of diagrams offers a means to quickly visualize the individual aspects of given pathways and, in the case of disease pathways, to inspect the underlying altered pathways, how their unfolding differs from the regular ones, what features are shared, and which ones may be unique. Having access to a large collection of disease and associated altered pathways enables the user to quickly inspect, compare, and identify aspects that may be unique or aspects that may be intriguing. As such, it can prompt asking new questions or redefining previous ones, lead to the search for new or revised venues of inquiry, and overall help further the efforts aimed at deciphering the mechanisms that determine the initiation and progression of disease. Future work will focus on expanding the repertoire of published diagrams for disease and altered pathways and associated drug and response pathways. Also, pathways underlying epigenetics and transcriptional programs, which are at the heart of differential gene expression in which genes get expressed and/or spliced at certain times in certain locations, likely play a role in the issues raised above. In addition, new pipelines and new features/entries of individual diagrams, such as those for genes with non-synonymous variants in the sequenced rat strains and genes and variant structural models, are scheduled to be implemented. The overall increase of the interactive diagram collection and associated pathway annotations for the rat, human, and mouse genes represent an ongoing process in the multifaceted Pathway Portal project.
The Pathway Ontology is being developed using the OBO ontology editor, developed by the Gene Ontology Consortium . The pathway diagrams are being built using Pathway Studio software, version 9, from Elsevier . The pathway diagram pages are made using a pathway curation tool web application developed at RGD . The methodology for building the pathway pipelines is detailed in Petri et al. .
VP wrote the manuscript, originated the PW ontology, composed most of the PW diagrams, and assisted with the portal design, diagram publications, and pathway pipeline construction. GTH composed some of the PW diagrams, assisted with the diagram publications, and reviewed the manuscript. MT assisted with the PW uploads, ftp file placement, and pipeline implementation. JRS assisted with the diagram publications. SJFL and SJW reviewed the manuscript. RN is part of the RGD team. JDP supervised the pipeline construction. MS supervised the PW portal and pipeline projects. MRD, EAW, and HJJ cosupervised the RGD projects. All authors read and approved the final manuscript.
The RGD project is funded by Grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the National Institutes of Health.
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