Novel insights into the molecular origins and treatment of lung cancer

Lung cancer remains the foremost cause of cancer deaths worldwide. Despite advances in both detection and treatment, diagnosis is often late and the prognosis for patients poor. Our understanding of the molecular basis and progression of lung cancer remains incomplete, hampering the design and development of more effective diagnostic tools and therapies for this devastating disease. However, the last twelve months have witnessed the publication of several studies that represent significant advances in our knowledge of lung cancer, and may represent important steps on the road to effective new therapies. In this review we aim to summarize these recent developments, and give our perspectives on the therapeutic possibilities they may offer in the future.     

Small cell lung cancer: New insights into origins

Comment on: Park K, et al. Cell Cycle 2011; 10:2806-15.     

Structural insights into the origins of DNA polymerase fidelity

DNA polymerases discriminate from a pool of structurally similar molecules to insert the correct nucleotide to preserve Watson-Crick base pairing rules. The ability to choose between "right and wrong" is highly dependent on the identity of the polymerase. Because naturally occurring polymerases with divergent fidelities insert incorrect nucleotides with comparable efficiencies, fidelity is primarily governed by the ability to insert the correct nucleotide. DNA polymerases generally bind the correct nucleotide with similar affinities, but low-fidelity polymerases insert correct nucleotides more slowly than higher fidelity enzymes. A comparison of crystallographic ternary substrate complexes of DNA polymerases from five families exhibiting a range of nucleotide insertion rates reveals possible structural features that lead to rapid, efficient, and faithful DNA synthesis.     

Branching morphogenesis of the lung: new molecular insights into an old problem

It has been known for decades that branching morphogenesis of the lung is mediated through reciprocal interactions between the epithelium and its underlying mesenchyme. In recent years, several key players, in particular members of the major signaling pathways that mediate this interaction, have been identified. Here, we review the genetic and molecular studies of these key components, which have provided a conceptual framework for understanding the interactions of these major signaling pathways in branching morphogenesis. The future challenge is to translate understanding of the signaling cascade into knowledge of the cellular responses, including cell proliferation, migration and differentiation, that lead to the stereotyped branching.*     

Novel insights into the implication of the IGF-1 network in prostate cancer

Nearly a decade has passed since the hypothesis that the insulin-like growth factor (IGF) signalling cascade is involved in prostate carcinogenesis. Recent research has outlined the association of circulating IGF-1 and prostate cancer risk, and studies have elucidated the implication of the IGF network in the early stages of prostate carcinogenesis. Moreover, it has been suggested that IGF-1 induces ligand-independent activation of the androgen receptor and enhances the expression of matrix metalloproteinase-2 and urokinase plasminogen activator. Furthermore, progression to androgen independence has been linked to deregulation of the IGF-1-IGF-1-receptor axis. Here, we report on updated studies that contribute to the unravelling of the IGF 'circuitry' in prostate cancer cells, with the anticipation that relevant pharmacological 'rewiring' might offer novel therapeutic regimens.     

Turtle origins: insights from phylogenetic retrofitting and molecular scaffolds

Adding new taxa to morphological phylogenetic analyses without substantially revising the set of included characters is a common practice, with drawbacks (undersampling of relevant characters) and potential benefits (character selection is not biased by preconceptions over the affinities of the ‘retrofitted’ taxon). Retrofitting turtles (Testudines) and other taxa to recent reptile phylogenies consistently places turtles with anapsid‐grade parareptiles (especially Eunotosaurus and/or pareiasauromorphs), under both Bayesian and parsimony analyses. This morphological evidence for turtle–parareptile affinities appears to contradict the robust genomic evidence that extant (living) turtles are nested within diapsids as sister to extant archosaurs (birds and crocodilians). However, the morphological data are almost equally consistent with a turtle–archosaur clade: enforcing this molecular scaffold onto the morphological data does not greatly increase tree length (parsimony) or reduce likelihood (Bayesian inference). Moreover, under certain analytic conditions, Eunotosaurus groups with turtles and thus also falls within the turtle–archosaur clade. This result raises the possibility that turtles could simultaneously be most closely related to a taxon traditionally considered a parareptile (Eunotosaurus) and still have archosaurs as their closest extant sister group.     

New insights into the phylogenetic distribution and evolutionary origins of the septins

Until recently, it had appeared that the septin family of proteins was restricted to the opisthokont eukaryotes (the fungi and animals and their close relatives the microsporidia and choanoflagellates). It has now become apparent that septins are also present in several other widely divergent eukaryotic lineages (chlorophyte algae, brown algae, and ciliates). This distribution and the details of the non-opisthokont septin sequences appear to require major revisions to hypotheses about the origins and early evolution of the septins.     

Systems biology analysis reveals new insights into invasive lung cancer

Background

Adenocarcinoma in situ (AIS) is a pre-invasive lesion in the lung and a subtype of lung adenocarcinoma. The patients with AIS can be cured by resecting the lesion completely. In contrast, the patients with invasive lung adenocarcinoma have very poor 5-year survival rate. AIS can develop into invasive lung adenocarcinoma. The investigation and comparison of AIS and invasive lung adenocarcinoma at the genomic level can deepen our understanding of the mechanisms underlying lung cancer development.

Results

In this study, we identified 61 lung adenocarcinoma (LUAD) invasive-specific differentially expressed genes, including nine long non-coding RNAs (lncRNAs) based on RNA sequencing techniques (RNA-seq) data from normal, AIS, and invasive tissue samples. These genes displayed concordant differential expression (DE) patterns in the independent stage III LUAD tissues obtained from The Cancer Genome Atlas (TCGA) RNA-seq dataset. For individual invasive-specific genes, we constructed subnetworks using the Genetic Algorithm (GA) based on protein-protein interactions, protein-DNA interactions and lncRNA regulations. A total of 19 core subnetworks that consisted of invasive-specific genes and at least one putative lung cancer driver gene were identified by our study. Functional analysis of the core subnetworks revealed their enrichment in known pathways and biological progresses responsible for tumor growth and invasion, including the VEGF signaling pathway and the negative regulation of cell growth.

Conclusions

Our comparison analysis of invasive cases, normal and AIS uncovered critical genes that involved in the LUAD invasion progression. Furthermore, the GA-based network method revealed gene clusters that may function in the pathways contributing to tumor invasion. The interactions between differentially expressed genes and putative driver genes identified through the network analysis can offer new targets for preventing the cancer invasion and potentially increase the survival rate for cancer patients.

     

Novel insights into the mitochondrial permeability transition

Alavian and colleagues recently provided further evidence in support of the notion that the c subunit of the mitochondrial F₁F_O ATP synthase constitutes the long-sought pore-forming unit of the supramolecular complex responsible for the so-called ‘mitochondrial permeability transition’ (MPT). Besides shedding new light on the molecular mechanisms that underlie the MPT, these findings corroborate the notion that several components of the cell death machinery, including cytochrome c and the F₁F_O ATP synthase, mediate critical metabolic activities.     

Dyskeratosis congenita: molecular insights into telomerase function, ageing and cancer

Dyskeratosis congenita (DC) is a severe, inherited, bone marrow failure syndrome, with associated cutaneous and noncutaneous abnormalities. DC patients also show signs of premature ageing and have an increased occurrence of cancer. DC can originate through: (1) mutations in DKC1, which result in X-linked recessive DC; (2) mutations in the RNA component of telomerase (TERC), which result in autosomal dominant DC (AD-DC); and (3) mutations in other, currently uncharacterized, genes, which result in autosomal recessive DC (AR-DC). As DKC1 encodes dyskerin, a protein component of small nucleolar ribonucleoprotein (snoRNP) particles, which are important in ribosomal RNA processing, DC was initially described as a disorder of defective ribosomal biogenesis. Subsequently, dyskerin and TERC were shown to closely associate with each other in the telomerase complex, and DC has since come to be regarded as a telomerase deficiency disorder characterised by shorter telomeres. These findings demonstrate the importance of telomerase in humans and highlight how its deficiency (through DKC1 and TERC mutations) results in multiple abnormalities including premature ageing, bone marrow failure and cancer. Identification of the gene(s) involved in AR-DC will help to define the pathophysiology of DC further, as well as expand our insights into telomere function, ageing and cancer.     

Novel insights into the aetiology and pathogenesis of hypopituitarism

Recent advances in our knowledge of pituitary development, acquired mainly from animal models, have enhanced our understanding of the aetiology of isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD), as well as several syndromic forms of growth hormone deficiency (GHD). A number of developmental genes known to be important for organ commitment and cell differentiation and proliferation (HESX1, LHX3, LHX4, PROP1 and PIT1) have been implicated in CPHD with or without other syndromic features. Phenotypes associated with these genetic mutations and their inheritance may be highly variable. Functional analyses of these mutations reveal valuable insights into the function of the proteins and hence into the effect of these mutations on phenotype. Novel insights have been gained into the mechanisms whereby these genes are associated with particular phenotypes as a result of murine transgenesis, e.g. type II autosomal dominant GHD. Mutations within known genes account for a small proportion of cases of IGHD and CPHD, suggesting the role of other as yet unidentified genetic and environmental factors. Hence, genetic testing will in the future have a greater role to play in understanding the mechanisms leading to particular hypopituitary phenotypes and also in predicting the evolution of these disorders. There is, however, no substitute for careful delineation of the phenotype prior to undertaking genetic studies.     

New insights into small‐cell lung cancer development and therapy

Small‐cell lung cancer (SCLC) accounts for approximately 15% of lung cancer cases; however, it is characterized by easy relapse and low survival rate, leading to one of the most intractable diseases in clinical practice. Despite decades of basic and clinical research, little progress has been made in the management of SCLC. The current standard first‐line regimens of SCLC still remain to be cisplatin or carboplatin combined with etoposide, and the adverse events of chemotherapy are by no means negligible. Besides, the immunotherapy on SCLC is still in an early stage and novel studies are urgently needed. In this review, we describe SCLC development and current therapy, aiming at providing useful advices on basic research and clinical strategy.     

A novel classification of lung cancer into molecular subtypes

The remarkably heterogeneous nature of lung cancer has become more apparent over the last decade. In general, advanced lung cancer is an aggressive malignancy with a poor prognosis. The discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer, however, has created new opportunities for targeted therapy and improved outcome. In this paper, we define "molecular subtypes" of lung cancer based on specific actionable genetic aberrations. Each subtype is associated with molecular tests that define the subtype and drugs that may potentially treat it. We hope this paper will be a useful guide to clinicians and researchers alike by assisting in therapy decision making and acting as a platform for further study. In this new era of cancer treatment, the 'one-size-fits-all' paradigm is being forcibly pushed aside-allowing for more effective, personalized oncologic care to emerge.