Pathway of the Month
Axl Receptor Axis: A New Therapeutic Target in Lung CancerAxl belongs to the TAM family of receptor tyrosine kinases, which consists of Tyro3, Axl, and Mer. All three family members have similar structures and share a number of ligands, including the vitamin K–dependent ligands growth arrest protein 6 (Gas6) and protein S. In normal tissues, TAM receptor tyrosine kinases contribute to immune response regulation, including clearance of apoptotic cells and inhibition of cytotoxic immune activation in response to apoptosis. When cells undergo apoptosis, the polarity of the plasma membrane lipid bilayer is altered, externalizing the anionic phospholipid phosphatidylserine (PS).
Functional Analysis of the Adrenomedullin Pathway in Malignant Pleural MesotheliomaMalignant pleural mesothelioma (MPM) grows aggressively within the thoracic cavity and has a very low cure rate, thus highlighting the need for identification of new therapeutic targets. Adrenomedullin (AM) is a multifunctional peptide that is highly expressed in several tumors and plays an important role in angiogenesis and tumor growth after binding to its receptors, calcitonin receptor–like receptor/receptor activity–modifying protein 2 (CLR/RAMP2) and calcitonin receptor–like receptor/receptor activity–modifying protein 3 (CLR/RAMP3).
The mTOR Pathway in Lung Cancer and Implications for Therapy and Biomarker AnalysisMammalian target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulatory protein in normal cell growth, survival, metabolism, development, and angiogenic pathways. Deregulation of these processes is a required hallmark of cancer, and dysregulation of mTOR signaling frequently occurs in a wide variety of malignancies, including lung cancer. Targeting of mTOR is thus an attractive strategy in the development of therapeutic agents against lung cancer. In this review, the mTOR-signaling pathway is described, highlighting opportunities for therapeutic intervention and biomarker analysis, and clinical trials in lung cancer including both non–small cell lung cancer and small cell lung cancer.
OPG/RANKL/RANK Pathway as a Therapeutic Target in CancerBone metastases play an important role in the morbidity and mortality of patients with malignant disease. Despite therapeutic advances in the treatment of solid organ malignancy such as lung cancer, less development on metastasis interventions has been forthcoming. More recent research has focused on molecular pathway manipulation in the prevention and treatment of metastatic bone disease and associated complications such as bone pain and hypercalcemia. The osteoprotegerin/receptor activator of nuclear factor-кβ ligand/receptor activator of nuclear factor-кβ pathway, which is physiologically involved in bone turnover, has been of considerable interest, and recent promising data have been revealed.
The Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Lung Cancer: Still Following the Right TRAIL?Tumor necrosis factor-related apoptosis-inducing ligand is a type II membrane-bound protein whose C-terminal extracellular domain shows clear homology to other tumor necrosis factor family members. It is constitutively expressed on macrophages, T cells, natural killer cells, and dendritic cells and selectively kills transformed cells leaving most of the normal cells alone. This selectivity has led to great interest in it use as a therapeutic agent for the treatment of malignancy. In this review, this critical pathway is described, highlighting its mechanistic manipulation for therapeutic benefit and the recent phase I and II trials in lung cancer that have been performed or are currently ongoing are also discussed.
GPC5 Gene and Its Related Pathways in Lung CancerRecently, a five-center collaborative study1 reported that genetic variations of glypican-5 (GPC5) may significantly contribute to an increased risk of lung cancer in never smokers. GPC5 gene expression levels in normal lung tissues were found significantly lower in individuals who carry high-risk alleles, and the GPC5 expression level in adenocarcinoma tissue was significantly lower than in matched normal lung tissue. Reduction of expression of GPC5 may lead to the development of lung cancer, suggesting that this gene normally functions as a tumor suppressor.
LKB1 Regulated Pathways in Lung Cancer Invasion and MetastasisMetastasis is characterized by the ability of cancer cells to invade into adjacent tissue, intravasate into blood or lymphatic vessels, and extravasate into a distant tissue. Metastatic disease is primarily responsible for the low 5-year survival rate of non-small cell lung cancer (NSCLC), and therefore, an understanding of the molecular mechanisms that regulate NSCLC metastasis is clearly warranted. The serine/threonine kinase and tumor suppressor LKB1 is mutated in 30% of NSCLC tumors, and recent evidence points to a prominent role in NSCLC metastasis.
TGF-² Signaling and the Role of Inhibitory Smads in Non-small Cell Lung CancerThe signaling pathway mediated by transforming growth factor-² (TGF-²) participates in various biologic processes, including cell growth, differentiation, angiogenesis, apoptosis, and extracellular matrix remodeling. In the context of cancer, TGF-² signaling can inhibit tumor growth in early-stage tumors. However, in late-stage tumors, the very same pathway promotes tumor invasiveness and metastasis. This paradoxical effect is mediated through similar to mothers against decapentaplegic or Smad protein dependent and independent mechanisms and provides an opportunity for targeted cancer therapy.
RBM5 as a Putative Tumor Suppressor Gene for Lung CancerRBM5 is one member of a group of structurally related genes that includes RBM6 and RBM10. RBM10 maps to Xp11.23, and one allele is inactivated as a result of X chromosome inactivation. Both RBM5 and RBM6 map to 3p21.3, a tumor suppressor region that experiences loss of heterozygosity in the majority of lung cancers. Overexpression of RBM5, which encodes an RNA-binding protein involved in the regulation of alternative splicing and retards ascites associated tumor growth in immunocompromised mice, a phenomenon that may be related to an associated ability to modulate apoptosis.
TGF-² Signaling Pathway in Lung Adenocarcinoma InvasionThe histologic distinction between bronchioloalveolar carcinoma and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in nonmucinous bronchioloalveolar carcinoma is significantly lower than that of pure invasive tumors and in tumors with greater than 0.5 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-² signaling was identified as an important mediator of tumor invasion.
Acetylcholine Receptor Pathway and Lung CancerGenome-wide association studies revealed chromosome regions 15q24-25 were associated with a higher risk for development of lung cancer. The 15q24-25 region encompasses the nicotinic acetylcholine receptor subunit genes (nAchR ±3, ±5, and ²4) that play a role in nicotine addiction. This review reports information of the acetylcholine receptor and lung cancer. In patients diagnosed with smoking-related lung cancer and who continue smoking, a negative correlation with lung cancer survival has been shown.
Class IA Phosphatidylinositol 3-Kinase Signaling in Non-small Cell Lung CancerClass IA phosphatidylinositol-3 kinases (PI3Ks) together with AKT and mammalian target of rapamycin (mTOR) comprise the central axis of a complex, interconnected signaling network that integrates signals from growth factors, insulin, nutrients and oxygen to play a critical role in controlling cell growth, proliferation, metabolism, survival, and tumor angiogenesis. De-regulation of these processes is a required hallmark of cancer1 and aberrant activation of the class IA PI3K signaling occurs frequently in many malignancies including non-small cell lung cancer (NSCLC).
Alternative Splicing in Lung CancerAlterations in alternative splicing affect essential biologic processes and are the basis for a number of pathologic conditions, including cancer. In this review we will summarize the evidence supporting the relevance of alternative splicing in lung cancer. An example that illustrates this relevance is the altered balance between Bcl-xL and Bcl-xS, two splice variants of the apoptosis regulator Bcl-x. Splice modifications in cancer-related genes can be associated with modifications either in cis-acting splicing regulatory sequences or in trans-acting splicing factors.
MET Pathway as a Therapeutic TargetDysregulation of mesenchymal-epithelial transition factor receptor tyrosine kinase pathway leads to cell proliferation, protection from apoptosis, angiogenesis, invasion, and metastasis. It can be dysregulated through overexpression, constitutive activation, gene amplification, ligand-dependent activation or mutation. New drugs targeting various mesenchymal-epithelial transition factor pathways are being investigated with promising results.
The CTC-Chip: An Exciting New Tool to Detect Circulating Tumor Cells in Lung Cancer PatientsCirculating tumor cells (CTCs) are rare cells that originate from a malignancy and circulate freely in the peripheral blood. The ability to capture and study CTCs is an emerging field with implications for early detection, diagnosis, determining prognosis and monitoring of cancer, as well as for understanding the fundamental biology of the process of metastasis. Here, we review the development and initial clinical studies with a novel microfluidic platform for isolating these cells, the CTC-chip, and discuss its potential uses in the study of lung cancer.
EGFR T790M Mutation: A Double Role in Lung Cancer Cell Survival?Even though lung cancer patients harboring a mutation in the epidermal growth factor receptor (EGFR) gene exhibit an initial dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs), acquired resistance is almost inevitable after a progression-free period of approximately 10 months. A secondary point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) is a molecular mechanism that produces a drug-resistant variant of the targeted kinase. The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs.
The CXCR4/SDF-1 Chemokine Receptor Axis: A New Target Therapeutic for Non-small Cell Lung CancerChemokines are proinflammatory chemoattractant cytokines that regulate cell trafficking and adhesion. The CXCR4 chemokine receptor and its ligand, stromal cell derived factor (SDF-1), constitute a chemokine/receptor axis that has attracted great interest because of an increasing understanding of its role in cancer, including lung cancer. The CXCR4/SDF-1 complex activates several pathways that mediate chemotaxis, migration and secretion of angiopoietic factors. Neutralization of SDF-1 by anti-SDF-1 or anti-CXCR4 monoclonal antibody in preclinical in vivo studies results in a significant decrease of non-small cell lung cancer metastases.
Telomeres and Telomerase in Lung CancerProtected telomeres ensure normal chromosomal segregation during mitosis but at the same time can endow genetically abnormal cancer cells with immortality. Telomerase has a pivotal role in telomere protection, both in normal and cancer cells. Understanding the functional interplay between telomere shortening and telomerase expression in cancer cells is of critical importance to elucidating the precise mechanisms by which these cells are able to bypass telomere crisis and become immortal.
The Insulin-Like Growth Factor Pathway in Lung CancerThe insulin-like growth factor (IGF) pathway is involved in the normal control of fetal development, tissue growth, and metabolism. Two distinct ligands (insulin-like growth factor-1 [IGF-1] and IGF-2) plus insulin, and two receptors (insulin-like growth factor receptor-1 [IGF-1R] and the insulin receptor) capable of both homo- and heteropolymerization mediate the actions of this pathway. Cellular functions of IGF-regulated signaling are influenced by the expression of a variety of receptor docking proteins, including four different insulin receptor substrate proteins.
Role of Chromosome 3q Amplification in Lung CancerChromosome abnormalities often correlate with molecular abnormalities and provide a starting point for gene discovery and characterization in the context of a specific disorder. In cancer biology, chromosomal abnormalities carry diagnosis, prognostic, and predictive value of response to treatment. Recently, methodologies such as array comparative genomic hybridization and oligonucleotide microarrays allow discovery of regions of frequent alterations with high resolution. Genomic gain at chromosome 3q location has been recognized as one the most prevalent and significant alterations in lung cancer.
Inflammation, Epithelial to Mesenchymal Transition, and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ResistanceInflammation is an important contributor to lung tumor development and progression. In addition, inflammatory signaling may promote epithelial to mesenchymal transition, development of aggressive metastatic tumor phenotypes, and play a role in resistance to targeted therapies. New insights in inflammatory signaling have led to the evaluation of combination therapies that target these specific pathways. In addition to developing the optimal combination of targeted agents, biomarker-based selection of patients who will likely benefit will be critical to the success of this strategy.
Platinum Resistance Related to a Functional NER PathwayTobacco carcinogens induce DNA adducts that are repaired by the nucleotide excision repair (NER) pathway.1 Inhaled combustion-derived particles, such as cigarette smoke, cause a local pulmonary inflammatory response that is characterized by the influx of neutrophils into the airways. On entering the lung, neutrophils are activated and release reactive oxygen species and an array of proteins, such as myeloperoxidase. A significant reduction of NER in human alveolar epithelial cells was observed when they were cocultured with activated neutrophils.
Role of the Wnt Signaling Pathway and Lung CancerThe Wnt pathway plays an important role in development and in regulating adult stem cell systems. A variety of cellular processes are mediated by Wnt signaling, including proliferation, differentiation, survival, apoptosis and cell motility.1 Loss of regulation of these pathways can lead to tumorigenesis and the Wnt pathway has been implicated in the development of several types of cancers, including colon, lung, leukemia, breast, thyroid, and prostate.2–6
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Pathway SignalingTumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo1L is a death ligand, a cytokine that activates apoptosis through cell surface death receptors. TRAIL is thought to be important in host tumor surveillance and metastasis suppression, and various therapeutic agonists that activate TRAIL receptors to induce tumor cell apoptosis are in clinical development. This review discusses recent findings about TRAIL pathway signaling and relates the signaling mechanisms to issues that need to be considered as we try to manipulate TRAIL signaling to treat cancer.
Lymphangiogenesis and Lung CancerThe lymphatic vasculature maintains tissue homeostasis and sustains immune function by guiding leukocytes and activated antigen presenting cells toward the lymph nodes. The lymphatic system is also relevant in cancer progression because cancer cells frequently spread out of the original tumor through the lymphatic capillaries.1 The detection of cancer cells in lymphatic vessels and regional lymph nodes is a key criterion in the staging of many human tumors, including lung cancer, and is used as decisive element for therapeutic intervention.