Hallmarks of cancer: of all cancer cells,all the time?

In two landmark articles, Hanahan and Weinberg synthesized into one conceptual framework 'the hallmarks of cancer', a massive amount of information describing the characteristics of a cancer cell. Although this is neither the intention nor the belief of the authors, hallmarks are often interpreted as applying to a canonic cancer cell, or equally to all cells within a cancer. In this article, we clarify the separate concepts of causes, oncogenic events, signal transduction programs, and hallmarks to show that there is no unimodal relation between these concepts but a complex network of interrelations that vary in different cells, between cells, and at different times in any given cell. We consider cancer as an evolving, dynamic, and heterogeneous system, explaining, at least in part, the difficulty of treating cancer and supporting the use of simultaneous, multitarget therapies.     

In silico analysis of expression pattern of a Wnt/β-catenin responsive gene ANLN in gastric cancer

Actin-binding protein anillin (ANLN) is primarily involved in the cytokinesis and known to be dysregulated in many cancers including gastric cancer (GC). However, the regulation and clinical significance of ANLN in GC are far less clear. In the present study, we aimed to investigate the clinical significance and possible regulators of ANLN in GC. We have identified the Wnt/β-catenin associated regulation of ANLN by analyzing the in vitro perturbed β-catenin mRNA expression profiles. Investigating the gastric tumors from publicly available genome-wide mRNA expression profiles, we have identified the over expression of ANLN in gastric tumors. Association between ANLN expression and clinical characteristics of GC showed elevated expression in intestinal type GC. Performing a single sample prediction method across GC mRNA expression profiles, we have identified the over expression of ANLN in proliferative type gastric tumors compared to the invasive and metabolic type gastric tumors. In silico pathway prediction analysis revealed the association between Wnt/β-catenin signaling and ANLN expression in gastric tumors. Our results highlight that expression of a Wnt/β-catenin responsive gene ANLN in GC is a molecular predictor of intestinal and proliferative type gastric tumors.     

Role of CSN5/JAB1 in Wnt/β-catenin activation in colorectal cancer cells

CSN5/JAB1 is a critical subunit of the COP9 signalosome (CSN) and is overexpressed in many human cancers, but little is known about the role of CSN5 in colorectal cancer (CRC). To explore the functional role of CSN5 in colorectal tumorigenesis, we applied siRNA technology to silence CSN5 in HeLa, SW480, HCT116, HT29, and CaCo2 cells. CSN5 knock-down led to reduced β-catenin and phospho-bcatenin levels and this was paralleled by reduced CRC cell proliferation and reduced apoptosis rates, whereas the short-term β-catenin protein stability was enhanced by CSN5 knock-down in SW480 cells. Together, these data implicate the CSN in the pathogenesis of CRC via regulation of the Wnt/β-catenin pathway     

Gastric cancer & prospects of cancer in Saudi Arabia peninsula

Gastric cancer is classified to be an aggressive disease with poor treatment outcome, as most cases remain undetected until later stages, wherein surgery and few chemotherapeutics become the only recommended treatment course. The process of cancer development is multistep involving many stages and types of precancerous lesions, and hence, routine monitoring becomes a necessity in those detected with these or exposed to risk factors. Studying the pattern of gastric cancer for any geographical region is also important to control mortality and focus on implementation of efficient management and treatment guidelines. The cause for gastric cancer can be genetic, racial as well as environmental, and hence the pattern of this malignancy differs across geographical regions and between the developing and the developed nations. In case of the Kindgom of Saudi Arabia, very few hospital-based reports have been published highlighting the pattern of gastric cancer, and the associated incidence and mortality rates. However, classified to be one of the most crucial cancer forms in Saudi Arabia, research pertaining to epidemiology, presentation and pathological features are limited. Studying gastric cancer occurrence from public health viewpoint is important also because eradication of causative agents like those that H. pylori has also shown been not reduce the risk of cancer development among individuals with atrophic metaplastic gastritis. In case of Saudi Arabia, many inherent risks for this malignancy exists like waterpipe smoking and shift in diet pattern from the traditional Mediterranean diet. Our review focusses on pattern of gastric cancer on a global scale in comparison to scenario in Saudi Arabia. The aim is to encompass all of the less stressed upon facts about this malignancy in the Kingdom, paving way for future work in this regards.     

Involvement of β-arrestins in cancer progression

β-arrestins, including β-arrestin1 and β-arrestin2, are ubiquitous cytosolic proteins which localize in the cytoplasm and plasma membrane, initially be regarded as an potential character in G protein-coupled receptors (GPCR) desensitization, sequestration, and internalization. Besides, recent many studies increasingly revealed that β-arrestins served widely as versatile adapter proteins for scaffolding many intracellular signaling networks to modulate the strength and duration of signaling by diverse types of receptors and downstream kinases. As we known, the biologic and clinical behaviors of many tumors are largely determined by multiple molecular signal pathways. More recently, accumulating evidences established that β-arrestins got widely involved in many cancer developmental signaling events which responsible for tumor viability and metastasis, suggesting an impressive role of β-arrestins in tumor progression. Because of the regulation and biological output of β-arrestins is so complex, the role of β-arrestins in cancer development still remains enigmatic. However, the further understanding with the clinical prognosis and oncogenic potential of β-arrestins might facilitate the identification of diagnosis biomarkers and development of drug targets in cancer. In this article, we reviewed a comprehensive summary of the β-arrestins-mediated functions in human cancers.     

Epigenomics of cancer – emerging new concepts

The complexity of the mammalian genome is regulated by heritable epigenetic mechanisms, which provide the basis for differentiation, development and cellular homeostasis. These mechanisms act on the level of chromatin, by modifying DNA, histone proteins and nucleosome density/composition. During the last decade it became clear that cancer is defined by a variety of epigenetic changes, which occur in early stages of disease and parallel genetic mutations. With the advent of new technologies we are just starting to unravel the cancer epigenome and latest mechanistic findings provide the first clue as to how altered epigenetic patterns might occur in different cancers. Here we review latest findings on chromatin related mechanisms and hypothesize how their impairment might contribute to the altered epigenome of cancer cells.     

Complexities of TGF-β targeted cancer therapy

Many advanced tumors produce excessive amounts of Transforming Growth Factor-β (TGF-β) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-β is often diverted along alternative pathways. Hence, TGF-β signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-β-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects. At late stages of malignancy, tumor progression is driven by TGF-β overload. The tumor microenvironment is a target of TGF-β action that stimulates tumor progression via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-β in the body and a common site for dissemination of breast cancer metastases. Osteoclastic degradation of bone matrix, which accompanies establishment and growth of metastases, triggers further release of bone-derived TGF-β. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-β released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-β signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-β therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-β inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-β inhibitors may be ill-advised, since this class of drug has potentially highly pleiotropic activity, and development of drug resistance might potentiate tumor progression. Current paradigms for the use of TGF-β inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic.     

miR-612 suppresses the stemness of liver cancer via Wnt/β-catenin signaling

Previous research showed that microRNA-612 (miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial–mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/β-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612.     

Cardiotoxicity of breast cancer radiotherapy – overview of current results

Adjuvant radiotherapy after breast cancer surgery is an important part of breast cancer treatment improving local control and overall survival. However, a higher risk of cardiac mortality was observed when conventional radiotherapy techniques were used. Cardiac morbidity and mortality after radiation therapy have been studied in many meta-analyses. In those focused on modern radiotherapy techniques, cardiac morbidity and mortality were no longer presented. However, an extremely long follow-up period is required. Importantly, the cardiac morbidity rates vary depending not only on the dose delivered to the heart, but also on the systemic therapies administrated and the pre-existing cardiac disease. Systematic heart dose monitoring is of great importance, as are efforts to constantly decrease doses, using advanced radiotherapy techniques. Nowadays, it is essential to individualize treatment according to tumor characteristics and anatomical predispositions, and to consider the cost and benefits.     

Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth

The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide’s anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.     

β-Mangostin inhibits the metastatic power of cervical cancer cells attributing to suppression of JNK2/AP-1/Snail cascade

β-Mangostin is a natural mangostin with potent anticancer activity against various cancers. In this study, we further explored the anticancer activity of β-mangostin on cervical cancer cells. β-Mangostin did not affect cell viability and cell cycle distribution in HeLa and SiHa cells; however, it dose-dependently inhibited the migration and invasion of both the human cervical cancer cell lines. In addition, we observed that β-mangostin suppressed the expression of integrin αV and β3 and the downstream focal adhesion kinase/Src signaling. We also found that Snail was involved in the β-mangostin inhibited cell migration and invasion of HeLa cell. Then, our findings showed that β-mangostin reduced both nuclear translocation and messenger RNA expression of AP-1 and demonstrated that AP-1 could target to the Snail promoter and induce Snail expression. Kinase cascade analysis and reporter assay showed that JNK2 was involved in the inhibition of AP-1/Snail axis by β-mangostin in HeLa cells. These results indicate that β-mangostin can inhibit the mobility and invasiveness of cervical cancer cells, which may attribute to the suppression of both integrin/Src signaling and JNK2-mediated AP-1/Snail axis. This suggests that β-mangostin has potential antimetastatic potential against cervical cancer cells.     

Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer

Casein kinase 1δ/ε have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1δ/ε inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative breast cancer cell line and have physical, in vitro and in vivo pharmacokinetic properties suitable for use in proof of principle animal xenograft studies against human cancers.     

ChIP-seq defined genome-wide map of TGFβ/SMAD4 targets: implications with clinical outcome of ovarian cancer

Deregulation of the transforming growth factor-β (TGFβ) signaling pathway in epithelial ovarian cancer has been reported, but the precise mechanism underlying disrupted TGFβ signaling in the disease remains unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate genome-wide screening of TGFβ-induced SMAD4 binding in epithelial ovarian cancer. Following TGFβ stimulation of the A2780 epithelial ovarian cancer cell line, we identified 2,362 SMAD4 binding loci and 318 differentially expressed SMAD4 target genes. Comprehensive examination of SMAD4-bound loci, revealed four distinct binding patterns: 1) Basal; 2) Shift; 3) Stimulated Only; 4) Unstimulated Only. TGFβ stimulated SMAD4-bound loci were primarily classified as either Stimulated only (74%) or Shift (25%), indicating that TGFβ-stimulation alters SMAD4 binding patterns in epithelial ovarian cancer cells. Furthermore, based on gene regulatory network analysis, we determined that the TGFβ-induced, SMAD4-dependent regulatory network was strikingly different in ovarian cancer compared to normal cells. Importantly, the TGFβ/SMAD4 target genes identified in the A2780 epithelial ovarian cancer cell line were predictive of patient survival, based on in silico mining of publically available patient data bases. In conclusion, our data highlight the utility of next generation sequencing technology to identify genome-wide SMAD4 target genes in epithelial ovarian cancer and link aberrant TGFβ/SMAD signaling to ovarian tumorigenesis. Furthermore, the identified SMAD4 binding loci, combined with gene expression profiling and in silico data mining of patient cohorts, may provide a powerful approach to determine potential gene signatures with biological and future translational research in ovarian and other cancers.