Integrative Multi-Omics Approaches in Cancer Research: From Biological Networks to Clinical Subtypes

Multi-omics approaches are novel frameworks that integrate multiple omics datasets generated from the same patients to better understand the molecular and clinical features of cancers. A wide range of emerging omics and multi-view clustering algorithms now provide unprecedented opportunities to further classify cancers into subtypes, improve the survival prediction and therapeutic outcome of these subtypes, and understand key pathophysiological processes through different molecular layers. In this review, we overview the concept and rationale of multi-omics approaches in cancer research. We also introduce recent advances in the development of multi-omics algorithms and integration methods for multiple-layered datasets from cancer patients. Finally, we summarize the latest findings from large-scale multi-omics studies of various cancers and their implications for patient subtyping and drug development.     

Rapid assessment of drug resistance of cancer cells to gefitinib and carboplatin using optical imaging

The overall goal of this study was to evaluate optical molecular imaging approaches to determine the drug response of chemotherapy and molecular targeted agents in drug sensitive and drug resistant cell lines. The optical molecular imaging approaches selected in this study were based on changes in intracellular uptake and retention of choline and glucose molecules. The breast cancer cell lines were treated with a molecular targeted anti-EGFR therapy. The bladder cancer cell lines were treated with a conventional chemotherapy approach. Sensitivity of optical molecular imaging approach was also compared with conventional cell viability and cell growth inhibition assays. Results demonstrate that optical molecular imaging of changes in intracellular uptake of metabolites was effective in detecting drug susceptibility for both molecular targeted therapy in breast cancer cells and chemotherapy in bladder cancer cells. Between the selected metabolites for optical molecular imaging, changes in glucose metabolic activity showed higher sensitivity in discrimination between the drug sensitive and drug resistant cell lines. The results demonstrated that optical molecular imaging approaches more significantly sensitive as compared to the conventional cell viability and growth assays. Overall, the results demonstrate potential of optical molecular imaging of metabolic activity to improve sensitivity of in-vitro drug response assays.     

Systems biology and cancer stem cells

The identification, purification, and characterization of cancer stem cells holds tremendous promise for improving the treatment of cancer. Mounting evidence is demonstrating that only certain tumor cells (i.e. the cancer stem cells) can give rise to tumors when injected and that these purified cell populations generate heterogeneous tumors. While the cell of origin is still not determined definitively, specific molecular markers for populations containing these cancer stem cells have been found for leukemia, brain cancer, and breast cancer, among others. Systems approaches, particularly molecular profiling, have proven to be of great utility for cancer diagnosis and characterization. These approaches also hold significant promise for identifying distinctive properties of the cancer stem cells, and progress is already being made.     

From modules to medicine: How modular domains and their associated networks can enable personalized medicine

Unveiling of cancer genomes is unleashing new therapeutic strategies for cancer. With cancer parts lists in hand, new approaches to personalized medicine can be developed by understanding the assembly of cancer machines using modular domains in proteins and their associated networks. Using the Src-homology-2 (SH2) domain as an example, new profiling approaches can discern global patterns of tyrosine phosphorylation in cancer cells that can enable molecular cancer medicine. Identifying and quantifying protein-protein interactions also has the potential to subtype tumors and guide clinical decision making. These approaches should extend the impact of genomics through viewing the architecture of cancer systems and improve predictions of patient outcome and therapeutic response, as well as guide combination therapy approaches that attack cancer systems.     

Focus: A Multifaceted Battle Against Cancer: Approaches to Identifying Synthetic Lethal Interactions in Cancer

Targeting synthetic lethal interactions is a promising new therapeutic approach to exploit specific changes that occur within cancer cells. Multiple approaches to investigate these interactions have been developed and successfully implemented, including chemical, siRNA, shRNA, and CRISPR library screens. Genome-wide computational approaches, such as DAISY, also have been successful in predicting synthetic lethal interactions from both cancer cell lines and patient samples. Each approach has its advantages and disadvantages that need to be considered depending on the cancer type and its molecular alterations. This review discusses these approaches and examines case studies that highlight their use.     

Molecular mechanisms of drug resistance and its reversal in cancer

Chemotherapy is the main strategy for the treatment of cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance. The resistance can be intrinsic or acquired. The resistance phenotype is associated with the tumor cells that gain a cross-resistance to a large range of drugs that are structurally and functionally different. Multidrug resistance arises via many unrelated mechanisms, such as overexpression of energy-dependent efflux proteins, decrease in uptake of the agents, increase or alteration in drug targets, modification of cell cycle checkpoints, inactivation of the agents, compartmentalization of the agents, inhibition of apoptosis and aberrant bioactive sphingolipid metabolism. Exact elucidation of resistance mechanisms and molecular and biochemical approaches to overcome multidrug resistance have been a major goal in cancer research. This review comprises the mechanisms guiding multidrug resistance in cancer chemotherapy and also touches on approaches for reversing the resistance.     

Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications—The Role of Molecular Dynamics Simulation

Theranostics cover emerging technologies for cell biomarking for disease diagnosis and targeted introduction of drug ingredients to specific malignant sites. Theranostics development has become a significant biomedical research endeavor for effective diagnosis and treatment of diseases, especially cancer. An efficient biomarking and targeted delivery strategy for theranostic applications requires effective molecular coupling of binding ligands with high affinities to specific receptors on the cancer cell surface. Bioaffinity offers a unique mechanism to bind specific target and receptor molecules from a range of non‐targets. The binding efficacy depends on the specificity of the affinity ligand toward the target molecule even at low concentrations. Aptamers are fragments of genetic materials, peptides, or oligonucleotides which possess enhanced specificity in targeting desired cell surface receptor molecules. Aptamer–target binding results from several inter‐molecular interactions including hydrogen bond formation, aromatic stacking of flat moieties, hydrophobic interaction, electrostatic, and van der Waals interactions. Advancements in Systematic Evolution of Ligands by Exponential Enrichment (SELEX) assay has created the opportunity to artificially generate aptamers that specifically bind to desired cancer and tumor surface receptors with high affinities. This article discusses the potential application of molecular dynamics (MD) simulation to advance aptamer‐mediated receptor targeting in targeted cancer therapy. MD simulation offers real‐time analysis of the molecular drivers of the aptamer‐receptor binding and generate optimal receptor binding conditions for theranostic applications. The article also provides an overview of different cancer types with focus on receptor biomarking and targeted treatment approaches, conventional molecular probes, and aptamers that have been explored for cancer cells targeting.     

Helicobacter and Gastric Malignancies

Individuals infected with Helicobacter pylori , a stomach colonizing bacteria, have an increased risk of developing gastric malignancies. The risk for developing cancer relates to the physiologic and histologic changes that H. pylori infection induces in the stomach. In the last year numerous studies have been conducted in order to characterize the association between H. pylori infection and gastric cancer. These studies range from epidemiologic approaches aiming at the identification of environmental, host genetic, and bacterial factors associated with risk of gastric cancer, to molecular and cell biology approaches aiming at understanding the interaction between H. pylori and the transforming epithelial cell. In this review an account of the last year's research activity on the relationship between H. pylori and gastric cancer will be given.     

Molecular modelling and simulations in cancer research

The complexity of cancer and the vast amount of experimental data available have made computer-aided approaches necessary. Biomolecular modelling techniques are becoming increasingly easier to use, whereas hardware and software are becoming better and cheaper. Cross-talk between theoretical and experimental scientists dealing with cancer-research from a molecular approach, however, is still uncommon. This is in contrast to other fields, such as amyloid-related diseases, where molecular modelling studies are widely acknowledged. The aim of this review paper is therefore to expose some of the more common approaches in molecular modelling to cancer scientists in simple terms, illustrating success stories while also revealing the limitations of computational studies at the molecular level.     

Thyroid tumors: novel insights from proteomic studies

Several genomics-based techniques have been applied in the last decade to the molecular characterization of cancer, which has led to a variety of applications suitable for improved diagnosis, prognosis and prediction of outcome to treatment. Proteomics-based approaches have also been seen as crucial to the discovery of biomarkers for early diagnosis and prognosis of tumors, as well as for a better understanding of the molecular bases of cancer. Accordingly, proteomic techniques have been used extensively for a better molecular characterization of thyroid tumors. In this field, three main directions have been preceded: first, proteomic studies of model systems; second, proteomics of thyroid tumor specimens; and third, serum proteomics. In this review, we describe the most relevant results that have been obtained for tumors derived from thyroid follicular cells using various proteomic approaches.     

The role of probiotics and natural bioactive compounds in modulation of the common molecular pathways in pathogenesis of atherosclerosis and cancer

Atherosclerosis and cancer are ranked among the most serious health problems in human medicine. Various predictive and etiological factors, biomarkers and molecular pathways of disease development and progression common to atherosclerosis and cancer suggest that the two most common diseases in worldwide dimension are far more closely aligned than previously believed. It is hypothesized that atherosclerosis and cancer are variants of a similar disease process. Shared disease progression in atherosclerosis and cancer is the emergence of similar novel approaches to therapy. On previous knowledge, it may be hypothesized that not only common approaches to therapy but also preventive strategies could be efficacious in both diseases. The results of in vitro and in vivo animal experiments, clinical and epidemiological studies and also the results of our experiments using animal experimental models of atherosclerosis and carcinogenesis indicate that probiotics, prebiotics, plants and their extracts and poly-unsaturated fatty acids could be effectively used in prevention of both atherosclerosis and colorectal cancer and decrease the disease risk. Future research should answer the question whether probiotic microorganisms and natural bioactive substances could effectively influence the molecular mechanisms in pathogenesis of atherosclerosis and cancer.     

胰腺癌发病的分子机制和诊断

胰腺癌是高度恶性肿瘤,起病隐匿,早期诊断困难,临床疗效差,是预后最差的恶性肿瘤之一。目前临床上尚缺乏有效的非 创伤早期筛查手段,多数患者确诊时已失去手术切除的机会。因此探讨胰腺癌发病的分子机制,特别是寻找在胰腺癌组织中高度 特异性表达的基因,对于胰腺癌的早期诊断和治疗具有重要的意义。本文就胰腺癌发病的分子机制和早期诊断进行综述。     

Contemporary molecular-biological methods of cancer diagnosis and monitoring based on the humoral immune response to tumor-associated antigens

Humoral immune response to tumor-associated antigens in cancer patients can be used as a basis for disease diagnosis and monitoring. Moreover, identification of molecular targets of such response may be used to develop antigen-specific anticancer vaccines. Here, we review the main approaches to identification and study of tumor-associated antigens recognized by serum antibodies. We also focus on the challenges that must be met before serological antigens can be used in clinical cancer diagnostics.     

Killing cells by targeting mitosis

Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis. As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.     

The role of the CXCR4/CXCL12 axis and its clinical implications in gastric cancer

Gastric cancer is the second leading cause of cancer deaths worldwide. Despite the extensive body of research on gastric cancer, the prognosis of patients with advanced gastric cancer remains poor, and therapy for advanced gastric cancer relies largely on cytotoxic chemotherapy. Therefore, identifying the distinct molecular pathways underlying disease progression and treatment resistance may lead to novel therapeutic approaches, as well as improve the quality of life and survival of patients. The chemokine CXCL12 and its receptor CXCR4 are now known to play an important role in cancer development and progression. Here, we review the expression and function of CXCR4 and CXCL12, as well as their clinical relevance in gastric cancer. We also cover the current molecular mechanism, specifically the cell-signaling pathway, by which gastric cancer progresses through the CXCR4/CXCL12 axis, and discuss the potential of that axis as a therapeutic target in the treatment of gastric cancer.