Tumor Necrosis Factor Apoptosis-inducing Ligand Research Articles

Interferon beta increases NK cell cytotoxicity against tumor cells in patients with nasopharyngeal carcinoma via tumor necrosis factor apoptosis-inducing ligand.

Nasopharyngeal carcinoma (NPC) is an EBV-associated neoplasm occurring endemically in Southeast Asia and sporadically all over the world. In children and adolescents, high cure rates have been obtained using chemotherapy, radiochemotherapy and maintenance therapy with interferon beta (IFNβ). The mechanism by which IFNβ contributes to a low systemic relapse rate has not yet been fully revealed. NK cells and serum samples from two patients with NPC were analyzed before and at different time points during IFNβ therapy, for assessment of TRAIL expression and NK cell cytotoxicity. Cytotoxicity was measured using the calcein release assay and the contribution of different death effector pathways was analyzed using specific inhibitors. Treatment with IFNβ induced TRAIL expression on patients' NK cells and increased their cytotoxicity against NPC targets in vitro. NK cell-mediated cytotoxicity was predominately mediated via TRAIL. IFNβ also induced the production of soluble TRAIL (sTRAIL) by NK cells and its release upon contact with NPC cells. IFNβ treatment increased serum levels of sTRAIL in patients. Moreover, sTRAIL concentrated from patients' serum samples induced apoptosis ex vivo in NPC cells from a patient-derived xenograft. Increased cytotoxicity of NK cells against NPC cells and increased serum levels of biologically active TRAIL in patients treated with IFNβ could be a means to eliminate micrometastatic disease and explain the low systemic relapse rate in this patient group.

Uncommon low-grade brain tumors.

The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I-II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.

LB06 - Mesenchymal stem cells shuttle micrornas via extracellular vesicles and prime resistant GBM to caspase mediated apoptosis

Mesenchymal stem cell (MSC)-based therapies have yielded beneficial effects in a broad range of animal models of disease and human clinical trials. MSC shed extracellular vesicles and microvesicles into the extracellular space that contain small non-coding RNA molecules, microRNAs (miR). In this study, we engineered MSC to shed exosomes containing microRNA that control cell proliferation and apoptosis in tumors and investigated their potential to prime resistant tumor cells to apoptosis in glioblastoma (GBM) brain tumors. We show that exosomes isolated from engineered MSC are enriched in miR-1 and miR-7and are efficiently transferred into the GMB stem cells (GSC) via exosomes. In order to develop a therapeutic strategy utilizing miRs,,we created constitutive and regulatable miR-7 expression vectors and utilized pharmacological inhibition of caspases and genetic loss of function to study the effect of forced expression of miR-7 on death receptor (DR) pathways in a cohort of death receptor ligand (DRL) resistant established GBM and patient-derived primary GSC. We show that expression of miR-7 results in the up-regulation of death receptor (DR) 5 and primes DRL resistant GBM cells to DRL, tumor necrosis factor apoptosis inducing ligand (TRAIL) mediated apoptotic cell death. In an effort to explore the mechanism underlying the cross talk between miR-7 targeted cell proliferation pathway and TRAIL/death receptor (DR) 4/5 mediated extrinsic apoptotic pathway; we show the interaction between various downstream players involving the NF-kB signaling and their role in up-regulating death receptors thereby priming them to DRLmediated apoptotic cell death. In vivo, we show that miR-7 significantly decreases tumor volumes and when combined with MSC-S-TRAIL, impairs tumor progression and significantly prolongs of mice bearing patient-derived GBM. In conclusion, our findings shed light on the presence anti-tumorgenic miRs in MSC shed exosomes and a unique role of miR-7 in priming resistant GBM cells to DRL mediated apoptosis. This study serves as a foundation for developing therapies utilizing engineered MSC to deliver a combination of microRNA and receptor targeted ligands for cancer therapy.

TRAIL Deficient Mice Are Protected from Sugen/Hypoxia Induced Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive lung disease diagnosed by an increase in pulmonary arterial blood pressure that is driven by a progressive vascular remodelling of small pulmonary arterioles. We have previously reported that tumor necrosis factor apoptosis-inducing ligand (TRAIL) protein expression is increased in pulmonary vascular lesions and pulmonary artery smooth muscle cells (PASMC) of patients with idiopathic PAH. The addition of recombinant TRAIL induces the proliferation and migration of PASMCs in vitro. TRAIL is required for hypoxia-induced pulmonary hypertension in mice, and blockade of TRAIL prevents and reduces disease development in other rodent models of PAH. Due to the availability of knockout and transgenic mice, murine models of disease are key to further advances in understanding the complex and heterogeneous pathogenesis of PAH. However, murine models vary in their disease severity, and are often criticized for lacking the proliferative pulmonary vascular lesions characteristic of PAH. The murine Sugen-hypoxic (SuHx) mouse model has recently been reported to have a more severe PAH phenotype consisting advanced pulmonary vascular remodelling. We therefore aimed to determine whether TRAIL was also required for the development of PAH in this model. C57BL/6 and TRAIL−/− mice were exposed to normoxia, Sugen5416 alone, hypoxia or both Sugen5416 and hypoxia (SuHx). We report here that SuHx treated C57BL/6 mice developed more severe PAH than hypoxia alone, and that TRAIL−/− mice were protected from disease development. These data further emphasise the importance of this pathway and support the use of the SuHx mouse model for investigating the importance of potential mediators in PAH pathogenesis.

Characterization of the role of tumor necrosis factor apoptosis inducing ligand (TRAIL) in spermatogenesis through the evaluation of trail gene-deficient mice.

TRAIL (TNFSF10/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily of proteins and is expressed in human and rodent testis. Although the functional role of TRAIL in spermatogenesis is not known, TRAIL is recognized to induce apoptosis via binding to its cognate receptors; DR4 (TRAIL-R1/TNFRSF10A) and DR5 (TRAIL-R2/TNFRSF10B). Here, we utilize Trail gene-deficient (Trail −/−) mice to evaluate the role of TRAIL in spermatogenesis by measuring testis weight, germ cell apoptosis, and spermatid head count at postnatal day (PND) 28 (pubertal) and PND 56 (adult). Trail−/− mice have significantly reduced testis to body weight ratios as compared to wild-type C57BL/6J at both ages. Also, Trail −/− mice (PND 28) show a dramatic increase in basal germ cell apoptotic index (AI, 16.77) as compared to C57BL/6J (3.5). In the testis of adult C57BL/6J mice, the AI was lower than in PND 28 C57BL/6J mice (2.2). However, in adult Trail −/− mice, the AI was still higher than that of controls (9.0); indicating a relative high incidence of germ cell apoptosis. Expression of cleaved caspase-8 (CC8) and cleaved caspase-9 (CC9) (markers of the extrinsic and intrinsic apoptotic pathway, respectively) revealed a two-fold increase in the activity of both pathways in adult Trail −/− mice compared to C57BL/6J. Spermatid head counts in adult Trail −/− mice were dramatically reduced by 54% compared to C57BL/6J, indicating these animals suffer a marked decline in the production of mature spermatozoa. Taken together, these findings indicate that TRAIL is an important signaling molecule for maintaining germ cell homeostasis and functional spermatogenesis in the testis.

Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors.

Therapeutically engineered stem cells (SC) are emerging as an effective tumor-targeted approach for different cancer types. However, the assessment of the long-term fate of therapeutic SC post-tumor treatment is critical if such promising therapies are to be translated into clinical practice. In this study, we have developed an efficient SC-based therapeutic strategy that simultaneously allows killing of tumor cells and assessment and eradication of SC after treatment of highly malignant glioblastoma multiforme (GBM). Mesenchymal stem cells (MSC) engineered to co-express the prodrug converting enzyme, herpes simplex virus thymidine kinase (HSV-TK) and a potent and secretable variant of tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) induced caspase-mediated GBM cell death and showed selective MSC sensitization to the prodrug ganciclovir (GCV). A significant decrease in tumor growth and a subsequent increase in survival were observed when mice bearing highly aggressive GBM were treated with MSC coexpressing S-TRAIL and HSV-TK. Furthermore, the systemic administration of GCV post-tumor treatment selectively eliminated therapeutic MSC expressing HSV-TK in vitro and in vivo, which was monitored in real time by positron emission-computed tomography imaging using 18F-FHBG, a substrate for HSV-TK. These findings demonstrate the development and validation of a novel therapeutic strategy that has implications in translating SC-based therapies in cancer patients.

Fluid shear stress sensitizes cancer cells to receptor-mediated apoptosis via trimeric death receptors

Cancer metastasis, the process of cancer cell migration from a primary to distal location, typically leads to a poor patient prognosis. Hematogenous metastasis is initiated by intravasation of circulating tumor cells (CTCs) into the bloodstream, which are then believed to adhere to the luminal surface of the endothelium and extravasate into distal locations. Apoptotic agents such as tumor necrosis factor apoptosis-inducing ligand (TRAIL), whether in soluble ligand form or expressed on the surface of natural killer cells, have shown promise in treating CTCs to reduce the probability of metastasis. The role of hemodynamic shear forces in altering the cancer cell response to apoptotic agents has not been previously investigated. Here, we report that human colon cancer COLO 205 and prostate cancer PC-3 cells exposed to a uniform fluid shear stress in a cone-and-plate viscometer become sensitized to TRAIL-induced apoptosis. Shear-induced sensitization directly correlates with the application of fluid shear stress, and TRAIL-induced apoptosis increases in a fluid shear stress force- and time-dependent manner. In contrast, TRAIL-induced necrosis is not affected by the application fluid shear stress. Interestingly, fluid shear stress does not sensitize cancer cells to apoptosis when treated with doxorubicin, which also induces apoptosis in cancer cells. Caspase inhibition experiments reveal that shear stress-induced sensitization to TRAIL occurs via caspase-dependent apoptosis. These results suggest that physiological fluid shear forces can modulate receptor-mediated apoptosis of cancer cells in the presence of apoptotic agents.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models

The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133(+) glioma-initiating cells and explored the potential of combining PI-103 with stem cell-delivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G(0)-G(1) arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell-delivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanism-based systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas.

Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

Background:Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1).Methods:This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. All patients received two loading doses of mapatumumab (20 mg kg−1 every 14 days), followed by maintenance therapy with 10 mg kg−1 infused every 14 days.Results:A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab.Conclusion:No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.

Abstract A137: Chemotherapy molecule delivered by tumor-targeted salmonella enterica serovar typhimurium under the control of integrated modular gate

Abstract Several strictly or facultative anaerobic bacteria have attracted more and more attention in cancer therapeutics because of their targeting and accumulating abilities in solid tumors, and Salmonella enterica serovar Typhimurium is one of them. These bacteria were also adapted to deliver therapeutic factors and were applied alone or in combination with conventional therapeutics. The aim of this study is to test a new integrated gene expression system in S. Typhimurim SL1344, and the benefit of the new system in amplifying therapeutic molecule production during bacterium targeting and accumulating in solid tumor. We have constructed a synthetic genetic gate in S. Typhimurim SL1344 that integrates information from two promoters as inputs and actives a promoter output only when both input promoters are induced. The integration occurs via an interaction between L-arabinose concentration and bacterium cell density. When certain amount of L-arabinose were added in the system and bacterium population were higher enough, the tumor necrosis factor apoptosis inducing ligand(TRAIL) and fluorescent protein ZsGreen as the control were produced by bacteria. LS174T colon carcinoma cells were processed to form cylindroids between the bottom surface of a 96-well plate and the top surface of a set of polycarbonate cylindrical plugs attached to a polycarbonate lid to mimic solid tumor, and then cylindroid cultures were inoculated with S. typhimurium SL1344 carrying TRAIL or ZsGreen expression system. 0.2% (w/v) L-arabinose was added into the well after 12hr inoculation, and then washed out after 2hr induced. Extents of apoptosis in cylindroids were tested by caspase-3 activity assay. Results showed that the bacteria accumulated inside cylindroids indicated by ZsGreen expression, and the average normalized intensity of apoptotic cell was higher in the cylindroids inoculated by the bacteria carrying the TRAIL than those inoculated by the bacteria carrying the ZsGreen. It can be concluded that the constructed integrated modular gate could effectively control bacteria to produce functional chemotherapy molecule in solid tumor at desirable time and places. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A137.

Is TRAIL the holy grail of cancer therapy?

Inducing apoptosis has become an important approach in the development of new anti-cancer treatments. Tumour necrosis factor apoptosis inducing ligand (TRAIL) based therapies have emerged as one of the most promising examples of this as they selectively induce apoptosis in tumour cells. However, many primary tumours are inherently resistant to TRAIL-mediated apoptosis and require additional sensitisation. Here we review apoptotic and non-apoptotic TRAIL-signalling, and the therapeutic effects of TRAIL-based treatments both as monotherapy and in combination with sensitising agents.

A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death

Evasion of death receptor ligand-induced apoptosis is an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule N-[4-chloro-3-(trifluoromethyl)phenyl]-3-oxobutanamide (fasentin) was identified as a chemical sensitizer to the death receptor stimuli FAS and tumor necrosis factor apoptosis-inducing ligand, but its mechanism of action was unknown. Here, we determined that fasentin alters expression of genes associated with nutrient and glucose deprivation. Consistent with this finding, culturing cells in low-glucose medium recapitulated the effects of fasentin and sensitized cells to FAS. Moreover, we showed that fasentin inhibited glucose uptake. Using virtual docking studies with a homology model of the glucose transport protein GLUT1, fasentin interacted with a unique site in the intracellular channel of this protein. Additional chemical studies with other GLUT inhibitors and analogues of fasentin supported a role for partial inhibition of glucose transport as a mechanism to sensitize cells to death receptor stimuli. Thus, fasentin is a novel inhibitor of glucose transport that blocks glucose uptake and highlights a new mechanism to sensitize cells to death ligands.

Interferon-γ Sensitizes Resistant Ewing's Sarcoma Cells to Tumor Necrosis Factor Apoptosis-Inducing Ligand-Induced Apoptosis by Up-Regulation of Caspase-8 Without Altering Chemosensitivity

Ewing's sarcoma cells are highly susceptible to apoptosis via tumor necrosis factor apoptosis-inducing ligand (TRAIL). Resistance to TRAIL has been linked to deficient expression of caspase-8 in vitro. Here, we report on the status of caspase-8 expression in tumors from patients with Ewing's sarcoma, the effect of interferon-gamma on caspase-8 expression and apoptosis, and the role of caspase-8 for TRAIL- and chemotherapy-mediated apoptosis in Ewing's sarcoma. Using immunohistochemistry, we show that low expression of caspase-8 is seen in about 24% of tumors. Interferon-gamma induces expression of caspase-8 at concentrations achievable in humans and sensitizes cells to TRAIL. Transfection of wild type but not mutant caspase-8 into caspase-8-deficient Ewing's sarcoma cells restored sensitivity to TRAIL, indicating that up-regulation of caspase-8 is sufficient to restore TRAIL sensitivity. In contrast, no role for caspase-8 in chemotherapy-induced apoptosis was identified, because 1) transfection of caspase-8 or treatment with interferon-gamma did not alter the sensitivity of caspase-8-deficient cells to chemotherapeutics, 2) application of chemotherapy did not select for caspase-8-negative tumor cells in vivo, and 3) the caspase-8 status of tumors did not influence survival after chemotherapy-based protocols. In conclusion, our data provide a rationale for the inclusion of interferon-gamma in upcoming clinical trials with TRAIL.

Physiological Smooth Muscle Cell Apoptosis Contributes to the Uterine Vascular Remodeling in Human Early Pregnancy

See related article, pages 834–841 Although equipped with the entire machinery driving cell proliferation and cell death, the turnover of the vascular smooth muscle cell (VSMC) layer within the vascular wall is quite low throughout the adult normal body. Vascular wall remodeling with VSMC apoptosis is routinely considered as associated with vascular diseases. This includes the development and regression of vascular thickening in hypertension, in advanced atherosclerotic plaques where VSMC apoptosis promotes plaque rupture, after angioplasty-induced arterial injury, as well as in arterial aneurysm where apoptosis is responsible for excessive slackening and rupture of the vessel media.1 Furthermore, in several animal studies, early pregnancy is a physiological situation where vessel wall remodeling plays a vital role. Indeed, in the first trimester of human pregnancy, vascular wall remodeling through degenerative changes converts the uterine spiral arteries located within the decidua basilis into toneless, widely opened arteries, thus enabling abundant blood supply to the maternal-fetal exchange area within the placenta. It is known that extravillous cytotrophoblasts deriving from fetal cytotrophoblastic shell migrate into segments of the spiral artery wall, through retrograde endovascular (intravasation) and interstitial migratory pathways (extravasation) into the decidua basilis to trigger the disappearance of endothelial and VSMC. In this process, trophoblasts become buried intramurally within a fibrinoid layer, which replaces the original muscular medial layer. Such trophoblast invasion converts the ends of spiral arteries into a wide caliber vessel that can better deliver maternal blood to the expanding intervillous space of the placenta (Figure 1A). Defective or incomplete trophoblast invasion can result in pathological pregnancies, including preeclampsia and intrauterine growth restriction.2,3 Therefore, understanding the cellular mechanisms governing the interaction between intramural trophoblast and vascular wall cells is yet to be determined. Oversimplified schematic depicting the trophoblasts invading the spiral artery traveling from myometrium up to …

HIV and liver disease forum: Conference proceedings

Liver disease has emerged as one of the major causes of morbidity and mortality among patients infected with the human immunodeficiency virus (HIV), particularly in regions where highly active antiretroviral therapy (ART) is widely available. This dramatic change in disease epidemiology is attributable to a complex interaction between etiologic factors that appear to increase the rate of hepatic fibrosis and accelerate progression to end-stage liver disease. Key factors include ART related hepatoxicity, frequent coinfection with hepatitis B and C, and possibly the direct interaction of HIV virus or soluble protein viral products that interact with hepatocytes and other liver resident cell types. Additionally, there is some evidence that gut permeability is altered during active HIV replication, which affects the complex mix of toxins and growth factors present in the portal circulation. It is critical that hepatologists maintain a strong knowledge base to provide the best possible guidance to HIV-infected patients and their healthcare providers. To this end, the second international forum on HIV and Liver Disease was convened in Jackson Hole, WY in September 2008. The first forum, held two years earlier was previously summarized in Hepatology, and has been widely cited by experts in the field.1 However, the fast moving nature of this critical health issue led to development of a second meeting, supported by grants from three institutes of the National Institutes of Health (NIAID, NIDDK, NIAAA) and by unrestricted grants provided by the pharmaceutical industry. As before, the meeting sought to bring together basic and clinical researchers representing multiple disciplines including hepatology, infectious diseases, epidemiology, virology, and drug development as well as governmental experts in health policy, research and research funding. This document provides a summary of key presentations and highlights the current state of knowledge and future directions this field will take.

Downregulation of VLA-4 on T cells as a marker of long term treatment response to interferon beta-1a in MS

We determined longitudinally the expression of a panel of adhesion molecules on T cells and soluble ICAM-1, VCAM-1 and tumor necrosis factor apoptosis inducing ligand (TRAIL) in serum during first year of the PRISMS Study with IFNβ1a in MS. Clinical data and quantitative MRI data were available for 4 years. VLA-4 was down-regulated on T cells and VCAM-1 was up-regulated in serum during the first 3 to 6 months of therapy in patients with favorable long-term treatment response (EDSS progression ≤ 1.0 in 4 years). Short disease duration and low EDSS were clinical pre-treatment characteristics related to good long-term response to therapy.

Coming Back at You with PI3K

The treatment of many solid cancers involves surgical removal of the primary tumor, a process that, dismayingly, may itself potentiate the growth of residual disease. Coffey et al. developed a model system in which they generated flank tumors in mice and measured the growth of primary tumors and recurrent tumors after surgical removal of most of the tumor. In immunocompromised mice with tumors of human origin and non-immunocompromised mice with tumors derived from the murine 3LL cell line, recurrent tumors grew more rapidly than primary tumors. Apoptosis (determined by morphological changes and TUNEL immunohistochemistry or by propidium iodide uptake) was reduced in recurrent compared with primary tumors, and the growth and metastatic capability of cells isolated from recurrent tumors was greater than that of cells isolated from primary tumors. Moreover, epithelial cells isolated from recurrent tumors showed greater resistance to tumor necrosis factor apoptosis-inducing ligand (TRAIL). Gene expression profiling indicated that expression of the gene encoding the phosphoinositide 3-kinase (PI3K) p85α inhibitory subunit ( Pik3r1 ) was decreased in recurrent tumors when compared with its expression in primary tumors. However, expression of the gene encoding the PI3K p110γ catalytic subunit ( Pik3CA ) was increased in recurrent tumors. Consistent with a shift in PI3K activity, phosphorylation of Akt was increased in recurrent tumors. LY294002, an inhibitor of PI3K, increased the susceptibility of recurrent tumor cells to TRAIL without affecting that of primary tumor cells and, when administered postoperatively, slowed recurrent tumor growth and prolonged survival. Thus, accelerated growth of tumors following surgery may involve increased PI3K activity, and inhibition of PI3K activity in the immediate postoperative period could potentially mitigate this effect. J. C. Coffey, J. H. Wang, M. J. F. Smith, A. Laing, D. Bouchier-Hayes, T. G. Cotter, H. P. Redmond, Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis: Novel role for an old enemy. J. Biol. Chem. 280 , 20968-20977 (2005). [Abstract] [Full Text]

Phosphoinositide 3-Kinase Accelerates Postoperative Tumor Growth by Inhibiting Apoptosis and Enhancing Resistance to Chemotherapy-induced Apoptosis: NOVEL ROLE FOR AN OLD ENEMY

Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.

Following a TRAIL: Update on a ligand and its five receptors

Identification of tumour necrosis factor apoptosis inducing ligand (TRAIL), a TNF family ligand, sparked a torrent of research, following an initial observation that it could kill tumour cells, but spare normal cells. Almost a decade after its discovery, and with five known receptors, the true physiological role of TRAIL is still debated and its anti-tumorigenic properties limited by potential toxicity. This review takes a comprehensive look at the story of this enigmatic ligand, addressing its remaining potential as a therapeutic and providing an overview of the TRAIL receptors themselves.