PharmStatus.com
Oncology Intelligence

TNF
TNF TNF(33)
TNFs are a group of cytokines regulating apoptosis.(1) TNFs can be grouped into a family on the basis of sequence, functional, and structural similarities. All members of the TNF family, with the exception of LT and a proliferation-inducing ligand (APRIL), are type II transmembrane proteins on immune cells. DRs are a subfamily of TNFs, which includes the TNFR1, TRAMP, DR3/APO-3, TRAIL-receptor 1 (TRAIL-R1/DR4), TRAIL-receptor 2 (TRAIL-R1/DR5), DR6, and CD95 (Fas/Apo-1).(2) Other TNFs include CD40L, CD27L, CD30L, FASL, 4-1BBL, and OX40L. TNFs form homotrimeric (or heterotrimeric in the case of LT-α/β) complexes. OX40L is a cytokine that co-stimulates T-cell proliferation and cytokine production. TNF or TNFα, is a monocyte-derived cytotoxin synthesized as a pro-hormone. TNFα can cause cytolysis of certain tumor cell lines, is involved in the induction of cachexia, and can stimulate cell proliferation and differentiation. LT-α or TNF-β, is a cytokine inhibited by IL-10. LT-α and LT-β are two related cytokines produced by lymphocytes cytotoxic for a wide range of tumor cells.(7, 21)
T-cell antigen gp39 (CD40L) is a cytokine important in B-cell development and activation. TRAF1, TRAF2, TRAF6, and possibly TRAF5 interact with CD40. An overexpression of CD40 results in expression microbicidal substances in the macrophage, including ROS and nitric oxide, leading to the destruction of ingested microbe. The B-cell can present antigens to HTCs. If an activated T-cell recognizes the peptide presented by the B-cell, the CD40L on the T-cell binds to the B-cell's CD40 receptor, causing resting B-cell activation. CD40 is constitutively expressed by antigen presenting cells, including DCs, B-cells, and macrophages. It can also be expressed by endothelial cells, smooth muscle cells, fibroblasts, bone marrow, T-cells, platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, and epithelial cells.(10-12) CD40 is expressed on a wide range of tumor cells, including NHL, HL, myeloma, and nasopharynx carcinoma, bladder cancer, cervical cancer, RCC and ovarian carcinoma.(11, 12)
CD154 is the ligand for CD40. CD40L has three binding partners: CD40, α5&betaa;1 INT and αIIbβ3. On TFH cells, CD154 promotes B-cell maturation and function by engaging CD40 on the B-cell surface and therefore facilitating cell-cell communication. In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L on the T-cell, which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface, which helps increase the level of activation. The activated macrophage can then destroy phagocytosed bacteria and produce more cytokines.(12)
CD27L is a cytokine that plays a role in T-cell activation. It induces the proliferation of co-stimulated T cells and enhances the generation of cytolytic T cells. It is present on the surface of resting memory B-cells. It binds to ligand CD70. CD27 transduces signals that lead to the activation of NFκB and MAPK8/JNK. Adaptor proteins TRAF2 and TRAF5 have been shown to mediate the signaling process of this receptor. CD27-binding protein (SIVA), a pro-apoptotic protein, can bind to this receptor and is thought to play an important role in the apoptosis induced by this receptor.(8) CD70 is a ligand for CD27 required for generation and long-term maintenance of T-cell immunity, and plays a key role in regulating B-cell activation and Ig synthesis.(13)
CD30L is a cytokine that induces proliferation of T cells. It binds to CD153. CD30+ T-cells are the hallmark of primary cutaneous ALCL and HL.(26) CD30 and CD15 are also expressed on classical HL Reed-Sternberg cells.(27, 28) Trx and CD30 alterations have been identified in various types of tumors such as CRC, NSCLC, and BC.(29)
Bax protein and TRAIL (TRAIL)-receptor 1/receptor 2 (DR4/DR5); and (iii) mitochondrial dysfunction.(31) It is not well understood why TRAIL kills tumor cells but leaves normal cells unharmed. Activating the DRs for TRAIL, DR4 and DR5, selectively kills cancer cells via induction of apoptosis while sparing normal cells. Compared to Fas, the frequencies of DR4 and DR5 mutations detected in cancers including lung, HNN, BC, bladder, gastric, HCC, NHL, and CML are very low. TRAIL and agonistic antibodies to DR4 and DR5 exhibit cancer therapeutic potential and their efficacies can be enhanced by small molecules.(32) Among patients with MM, RANKL activity was greatly increased. Therefore, RANKL is considered to be a key signal regulator for cancer-induce bone diseases.(22) TRAIL is a cytokine that induces apoptosis.(1, 3-9) TRAIL receptors are expressed in wide variety of normal tissues. c-Myc induces vulnerability to TRAIL and other death receptor ligands.(20)
RANKL is a protein encoded by the TNFSF11 gene.(22) RANKL is a type II membrane protein.(23) RANKL is expressed in several tissues and organs including: thymus, liver, colon, small intestine, adrenal gland, osteoclast, mammary gland epithelial cells, prostate, pancreas, lung, lymph nodes, bone marrow, stomach, peripheral blood, spleen, placenta, leukocytes, heart, thyroid, and skeletal muscle.(24) RANKL regulates bone regeneration and remodeling, is involved in the regulation of T cell-dependent immune response, and is involved in DC maturation. RANKL is a DC survival factor.(22, 25) RANKL may be used as an apoptosis regulator gene, a binding partner of OPG. RANKL activates anti-apoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and TNF receptor-associated factor 6 (TRAF6), which indicated this protein may have a role in the regulation of cell apoptosis. The upstream of AKAP11 may suggest there is a complex regulator process that regulates the level of RANKL expression.(22)
4-1BBL is an inducible T cell surface molecule that contributes to T-cell stimulation. CD137 (or TNFRSF9, 4-1BB, or ILA) can be expressed by activated T-cells, but to a larger extent on CD8 than on CD4 T-cells. CD137 expression is found on DCs, follicular DCs, NK cells, granulocytes and cells of blood vessel walls at sites of inflammation. Crosslinking of CD137 enhances T-cell proliferation, IL-2 secretion survival, and cytolytic activity.(14)
FASL is a cytokine involved in cell death. FAS (or CD95, APO-1, APT, or TNFRSF6) is an extrinsic apoptotic signal protein. FasR is a DR located on chromosome 10. Fas is divided into 3 domains: an extracellular domain, a transmembrane domain, and a cytoplasmic domain.(15) Fas forms the DISC upon ligand binding. Membrane-anchored Fas ligand oligomer on the surface of an adjacent cell causes oligomerization of Fas.(16) Upon ensuing death domain aggregation, the adaptor molecule FADD to bind the death domain of Fas through its own death domain.(15, 17) FADD also contains a death effector domain near its amino terminus, which facilitates binding to the death effector domain of caspase-8. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA degradation, membrane blebbing, and other hallmarks of apoptosis. Extrinsic Fas pathway may be sufficient to induce complete apoptosis in certain cell types through DISC assembly and subsequent caspase-8 activation. These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of the Bcl-2 family (Bcl-2 and Bcl-xL) to protect from Fas-mediated apoptosis. Evidence for crosstalk between the extrinsic and intrinsic pathways exists in the Fas signal cascade.(15) Fas receptor has been shown to interact with a number of proteins, including caspase 8, caspase 10, FADD, and FasR.(15, 18, 19) Fas has been shown to promote tumor growth. Cancer cells in general, regardless of their Fas apoptosis sensitivity, depend on constitutive activity of Fas. This is stimulated by cancer-produced Fas ligand for optimal growth.(15, 30) In the late stage of endoreduplication, the effects of PTX-2 on different cancer cells involves: (i) down-regulation of anti- apoptotic Bcl-2 members and IAP family proteins; (ii) up-regulation of pro-apoptotic signals.

Drugs/Indications
Marketed Drugs
Generic Code Old Code Brand Company Indication trials
brentuximab vedotin SGN-35 Adcetris Seattle Genetics Mkt: HL, large cell lymphoma; P3: NHL; P2: germ trials
denosumab AMG 162 XGeva, Prolia Amgen Mkt: bone mets, MM, giant cell; P3: BC, PC, hem, NSCLC trials
lenalidomide CC-5013 ENMD-0997, CDC-501,IMiD3 Revlimid Abraxis Mkt: MDS, MM, AML; P3: CLL, PC, NHL, lymphoma; P2: CRC, bladder, HCC, NSCLC, pancreatic, RCC, melanoma, thyroid, hem, CLL, squamous, WM, GBM, gliomas, HL, leukemia, HCC, PC, solid; P1/2: fallopian, ovarian, peritoneal, ureteral, Kaposis trials
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
golnerminogene pradenovec TNFerade GenVec P3: pancreatic; P2: CRC, esophageal, melanoma; P1/2: HNN; P1: PC trials
conatumumab AMG 655 TL32711 Birinapant Amgen P2: CRC, solid; P1/2: pancreatic, NSCLC, sarcoma; P1: HL, lymphoma, MCL, NHL trials
lucatumumab HCD122 Novartis P2: MM; P1/2: NHL, HL; P1: lymphoma, CLL (terminated) trials
mapatumumab HGS (GSK) P2: HCC, NSCLC, lymphoma, MM; P1/2: cervical trials
tigatuzumab CS-1008 Daiichi Sankyo P2: HCC, pancreatic, ovarian, NSCLC, CRC, BC, HCC; P1: lymphoma, solid trials
urelumab BMS-663513 BMS P2: melanoma, leukemia; P1/2: various (terminated); P1: NSCLC (terminated), solid, NHL, CRC, HNN trials
AFM13 CHIR-12.12 TandAb Affimed P2: HL trials
CD40L Noncorporate P2: melanoma, lymphoma, Ewings's, rhabdomyosarcoma; P1/2: lung, esophageal, solid, bladder, CLL; P1: RCC, leukemia trials
CMVpp65-A*0201 noncorporate P2: CML trials
ISF35 Memgen P2: CLL, lymphoma, NHL trials
OX40 noncorporate P2: melanoma: P1/2: PC, lung, BC, HCC; P1: solid, rhabdomyosarcoma, Ewing's, neuroblastoma trials
varlilumab Celldex P1/2: melanoma, NSCLC, RCC trials
CD40-ligand noncorporate P1/2: melanoma; P1: RCC, CLL trials
A2/4-1BBL noncorporate P1/2: melanoma trials
CCL21 Noncorporate P1/2: lung; P1: melanoma trials
ARGX-110 arGEN-X P1: various trials
CP-870,893 Pfizer P1: solid, pancreatic, melanoma trials
Chi Lob 7/4 noncorporate P1: solid, lymphoma, NHL trials
MEDI-6469 MedImmune P1: solid, lymphoma trials
MDX-1203 BMS P1: NHL trials
rhTNF noncorporate P1: Kaposi, lymphoma, solid trials
urocanic acid noncorporate P1: bladder cancer trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
etanercept TNFR:Fc Enbrel Pfizer Failed for cancer due to increased risk of infection and development of skin cancer including melanoma; P3: solid, melanoma, non-melanoma skin; ; P2/3: lung, PC, bone; P2: CML, leukemia, MDS; P1: solid trials
leflunomide SU101 Arava Pfizer suspended; P3: Brain, CNS; P2/3: PC; P1/2: melanoma (suspended); P1: sarcoma trials
apomab PRO95780 RG7425 Roche Last new trial started in 2009; P2: NSCLC, chondrosarcoma (terminated), NHL; P1: CRC trials
dacetuzumab SGN-40 Seattle Last new trial started in 2008; P2: B-Cell Lymphoma, NHL, MM; P1: CLL trials
dulanermin AMG 951 RG3639 Amgen Last new trial started in 2007; P2: NSCLC trials
iratumumab MDX-060 BMS; Pfizer withdrawn; P2: HL, large cell lymphoma; P1/2: lymphoma trials
tasonermine TNFa noncorporate Last trial started 2004; P2: sarcoma trials
SGN-30 Seattle Last new trial started in 2007; P2: HL, large cell lymphoma (terminated) trials
TRAIL-R1 mAb TRM-1 Human Genome Sciences Inc. Last trial started 2004; P2: NHL, NSCLC trials
NGR-TNF MolMed S.p.A. Last trial started 2007; P2: CRC, HCC, mesothelioma; P1: solid, RCC, HNN trials
VML 295 LY293111 Eli Lilly Last new trial started in 2003; P2: NSCLC, pancreatic; P1: solid trials
L19TNFa Philogen Last new trial started in 2007; P1/2: solid, CRC trials
MCS110 Novartis terminated; P1/2: bone mets -- PC trials
lexatumumab ETR2-ST01 HGS-ETR2 HGS (GSK) Last new trial started in 2006; P1: solid trials
HeFi-1 noncorporate Last new trial started in 2002; P1: lymphoma, various trials
Lym-1 Peregrine Last new trial started in 2001; P1: lymphoma trials
MDX-1401 BMS Last new trial started in 2008; P1: HL trials
MDX-1411 BMS withdrawn; P1: CLL, mantle cell, RCC trials
SGN-75 Seattle terminated; P1: RCC, NHL trials
XmAb2513 Xencor Last new trial started in 2007; P1: HL, lymphoma trials
CC-11006 Abraxis last new trial 2007; P1: MDS trials
diltiazem APO010 TopoTarget A/S Last new trial 2007; P1: solid trials
News
References

1. Haiat S BC, Quiney C, Ajchenbaum-Cymbalista F, Kolb JP. Role of BAFF and APRIL in human B-cell chronic lymphocytic leukaemia. Immunology. 2006;118(3):281-92. PMCID: 16827889.

2. Sancho-Martinez I M-VA. Tyrosine phosphorylation and CD95: a FAScinating switch. Cell Cycle. 2009;8(6):838-42. PMCID: 19221505.

3. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang C-P, Nicholl JK, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. immunity. 1995;3(6):673-82.

4. Bazan JF. Emerging families of cytokines and receptors. Current Biology. 1993;3(9):603-6.

5. Baum PR, Gayle 3rd R, Ramsdell F, Srinivasan S, Sorensen R, Watson M, et al. Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34. The EMBO journal. 1994;13(17):3992.

6. Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75(6):1169-78.

7. Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Pingchang Chow E, et al. Lymphotoxin ?, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell. 1993;72(6):847-56.

8. Kim PG, Albacker CE, Lu Y-f, Jang I-h, Lim Y, Heffner GC, et al. Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition. Proceedings of the National Academy of Sciences. 2013;110(2):E141-E50.

9. Fukamachi S SK, Sawada Y, Bito T, Nakamura M, Tokura Y. Drug-induced CD30+ T cell pseudolymphoma. Eur J Dermatol. 2009;19(3):292-4. PMCID: 19336342.

10. Akhdar H, Legendre C, Aninat C, More F. Anticancer drug metabolism: chemotherapy resistance and new therapeutic approaches. 2012.

11. Schnbeck U, Libby P. The CD40/CD154 receptor/ligand dyadRID="" ID="" Review. Cellular and Molecular Life Sciences CMLS. 2001;58(1):4-43.

12. Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene. 2008;27(50):6407-18.

13. Lim SH BS, French RR, Johnson PW, Glennie MJ, Cragg MS. Anti-CD20 monoclonal antibodies: historical and future perspectives. Haematologica. 2010;95(1):135-43. PMCID: 19773256.

14. Yea SS, Fruman DA. Achieving cancer cell death with PI3K/mTOR?targeted therapies. Annals of the New York Academy of Sciences. 2013;1280(1):15-8.

15. Schaller MD. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. Journal of Cell Science. 2010;123(7):1007-13.

16. Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, et al. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nature structural & molecular biology. 2010;17(11):1324-9.

17. Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW. NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. 1996.

18. Gajate C, Mollinedo F. Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. Journal of Biological Chemistry. 2005;280(12):11641-7.

19. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, et al. The receptor for the cytotoxic ligand TRAIL. Science. 1997;276(5309):111-3.

20. Nieminen AI PJ, Klefstrom J. c-Myc blazing a trail of death: coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc. Cell Cycle. 2007;6(20):2464-72. PMCID: 17914284.

21. Lymphotoxin_?. [cited]; Available from: http://en.wikipedia.org/wiki/Lymphotoxin_?.

22. RANKL. [cited]; Available from: http://en.wikipedia.org/wiki/RANKL.

23. Hanada R, Hanada T, Sigl V, Schramek D, Penninger JM. RANKL/RANK-beyond bones. Journal of molecular medicine. 2011;89(7):647-56.

24. Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends in molecular medicine. 2006;12(1):17-25.

25. Castellano D, Sepulveda JM, Garca-Escobar I, Rodriguez-Antoln A, Sundlv A, Cortes-Funes H. The role of RANK-ligand inhibition in cancer: the story of denosumab. The oncologist. 2011;16(2):136-45.

26. W K. CD30+ lymphoproliferative disorders histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol. 2006;1(33 Suppl):58-70.

27. Gorczyca W, Tsang P, Liu Z, Wu CD, Dong HY, Goldstein M, et al. CD30-positive T-cell lymphomas co-expressing CD15: an immunohistochemical analysis. International journal of oncology. 2003;22(2):319-24.

28. Sharma VM, Draheim KM, Kelliher MA. The Notch1/c-Myc pathway in T cell leukemia. Cell Cycle. 2007;6(8):927-30.

29. Berghella AM PP, Del Beato T, Ciccone F, Contasta I. The potential role of thioredoxin 1 and CD30 systems as multiple pathway targets and biomarkers in tumor therapy. Cancer Immunol Immunother. 2011;60(10):1373-81. PMCID: 21739118.

30. Chen L, Park S-M, Tumanov AV, Hau A, Sawada K, Feig C, et al. CD95 promotes tumour growth. Nature. 2010;465(7297):492-6.

31. Kim GY KW, Choi YH. Pectenotoxin-2 from marine sponges: a potential anti-cancer agent-a review. Mar Drugs. 2011;9(11):2176-87. PMCID: 22163180.

32. Elrod HA SS. Modulation of death receptors by cancer therapeutic agents. Cancer Biol Ther. 2008;7(2):163-73. PMCID: 18059181.

33. Brunelle JK LA. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122(Pt 4):437-41. PMCID: 19193868.



News
Tuesday, September 20, 2016 6:00 PM|Shuomeng Xiao|Public Health & Healthcare|Labels: TNF, CRC
We examined colon cancer patients who received soluble dietary fiber enteral nutrition (SDFEN) to evaluate the feasibility and potential benefit of early SDFEN compared to EN. Sixty patients who were confirmed as having colon cancer with histologically and accepted radical resection of colon cancer were randomized into an SDFEN group and an EN group. The postoperative complications, length of hospital stay (LOH), days for first fecal passage, and the difference in nutritional status, immune function and inflammatory reaction between pre-operation and post-operation were all recorded. The statistical analyses were performed using the t-test and the chi square test. Statistical significance was defined as p < 0.05. After the nutrition support, differences in the levels of albumin, prealbumin and transferrin in each group were not statistically significant (p > 0.05); the levels of CD4+, IgA and IgM in the SDFEN group were higher than that of the EN group at seven days (p < 0.05); the levels of TNF-α and IL-6 in the SDFEN group were lower than that of the EN group at seven days (p < 0.05); and patients in the SDFEN group had a significantly shorter first flatus time than the EN group (p < 0.05). Early post-operative SDFEN used in colon cancer patients was feasible and beneficial in immune function and reducing inflammatory reaction, gastrointestinal function and speeding up the recovery.
Thursday, September 15, 2016 6:45 AM|Liu, J., Blake, S. J., Harȷunpaa, H., Fairfax, K. A., Yong, M. C. R., Allen, S., Kohrt, H. E., Takeda, K., Smyth, M. J., Teng, M. W. L.|Cancer Research recent issues|Labels: PD-1/PD-L1, TNF
New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137–treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288–301. ©2016 AACR.
This is a signaling study to assess whether nivolumab in combination with brentuximab vedotin is safe and effective in certain subtypes of non-hodgkin lymphomas.
Wednesday, September 14, 2016 11:10 AM|Marwa Kamel, Samia Shouman, Mahmoud El-Merzebany, Gokhan Kilic, Timothy Veenstra, Muhammad Saeed, Mohamed Wagih, Concepcion Diaz-Arrastia, Deepa Patel, Salama Salama|Journal of Cancer|Labels: TNF, breast cancer

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-β estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer.

Tuesday, September 13, 2016 11:38 PM|M Mego, H Gao, EN Cohen, S Anfossi, A Giordano, T Sanda, TM Fouad, U De Giorgi, M Giuliano, WA Woodward, RH Alvarez, V Valero, NT Ueno, GN Hortobagyi, M Cristofanilli, JM Reuben|Journal of Cancer|Labels: TNF, breast cancer

Background: Circulating tumor cells (CTCs) play a crucial role in tumor dissemination and are prognostic in primary and metastatic breast cancer. Peripheral blood (PB) immune cells contribute to an unfavorable microenvironment for CTC survival. This study aimed to correlate CTCs with the PB T-cell immunophenotypes and functions of patients with inflammatory breast cancer (IBC).

Methods: This study included 65 IBC patients treated at the MD Anderson Cancer Center. PB was obtained from patients prior to starting a new line of chemotherapy for CTCs enumeration by CellSearch®, and T cell phenotype and function by flow cytometry; the results were correlated with CTCs and clinical outcome.

Results: At least 1 CTC (≥1) or ≥5 CTCs was detected in 61.5% or 32.3% of patients, respectively. CTC count did not correlate with total lymphocytes; however, patients with ≥1 CTC or ≥5 CTCs had lower percentages (%) of CD3+ and CD4+ T cells compared with patients with no CTCs or <5 CTCs, respectively. Patients with ≥1 CTC had a lower percentage of T-cell receptor (TCR)-activated CD8+ T cells synthesizing TNF-α and IFN-γ and a higher percentage of T-regulatory lymphocytes compared to patients without CTCs. In multivariate analysis, tumor grade and % CD3+ T-cells were associated with ≥1 CTC, whereas ≥5 CTC was associated with tumor grade, stage, % CD3+ and % CD4+ T cells, and % TCR-activated CD8 T-cells synthesizing IL-17.

Conclusions: IBC patients with CTCs in PB had abnormalities in adaptive immunity that could potentially impact tumor cell dissemination and initiation of the metastatic cascade.

Tuesday, September 13, 2016 8:19 PM|Sen Wang, Weifang An, Yunhong Yao, Renhuai Chen, Xiaoxuan Zheng, Wanyong Yang, Yi Zhao, Xinrong Hu, Enping Jiang, Yanhong Bie, Zhangquan Chen, Ping Ouyang, He Zhang, Hui Xiong|Journal of Cancer (RSS 2.0)|Labels: STAT, TNF, cervical cancer

Objectives: The most recently discovered cytokine interleukin 37 (IL-37) received growing attention. Its function on tumor is largely unknown. Here, we investigated the biological function of IL-37 on cervical cancer (CC).

Materials and methods: HPV+ Hela cells and HPV- C33A cells were used. RT-qPCR was performed to detect the transcription of IL-37, STAT3, TNF-αand IL-1β. Western blotting was used for protein detection. CCK-8 assay and transwell assay were employed for cell proliferation and invasion detection, respectively.

Results: Successful gene transfection of IL-37 suppressed the proliferation and invasion of CC. Interestingly, IL-37 showed higher anticancer ability in HPV+ Hela cells than that in HPV- C33A cells. Then, the molecular mechanism of IL-37 anticancer was explored. Firstly, we found that IL-37 inhibited STAT3 expression at both mRNA and protein levels. IL-37 also down regulated the phosphorylation of STAT3. Secondly, blockage of STAT3 using siRNAs reduced significantly the ability of IL-37 to suppress cell proliferation and invasion. Thirdly, STAT3 knockdown reduced markedly the inhibition of IL-37 on the transcription of tumor-derived TNF-α and IL-1β, indicating the contribution of STAT3 for the cancer associated antiinflammation of IL-37. Finally, STAT3 up regulation restored the ability of cell proliferation, cell invasion and the expression of inflammatory cytokines, TNF-α and IL-1β.

Conclusions: IL-37 suppressed cell proliferation and invasion of CC and STAT3 is involved in this process. Thus, IL-37 emerges as a new anticancer cytokine for CC. This study demonstrated a new biological function of IL-37 and offered a potential molecule for CC treatment.

Tuesday, September 13, 2016 8:19 PM|Teodora Mocan, Cristian Matea, Flaviu Tabaran, Cornel Iancu, Remus Orasan, Lucian Mocan|Journal of Cancer (RSS 2.0)|Labels: TNF, IL

Therapeutic cancer vaccines (or active immunotherapy) aim to guide the patient's personal immune system to eradicate cancer cells. An exciting approach to cancer vaccines has been offered by nanoscale drug delivery systems containing tumor associated antigens (TAAs). Their capacity to stimulate the immune system has been suggested during late years. However, the role of the macrophages as key-elements in antigen-presentation process following TAAs-containing nanosystems is not completely understood. We aimed to evaluate the effect of gold nanoparticles functionalized with mucin-1 peptide (MUC-1) on murine peritoneal macrophages.

Gold nanoparticles, obtained using a modified Turkevich method, were functionalized with MUC-1 protein using Clealand's reagent. The obtained GNP-MUC-1 solution was used to treat at various concentrations monolayers of peritoneum-derived macrophages that were further analyzed using confocal and hyperspectral microscopy, ELISA assays and spectroscopic techniques. The GNP-MUC-1 nano-construct had proven to function as a powerful macrophage activator with consequent release of cytokines such as: TNF-ɑ, IL-6, IL-10 and IL-12 on peritoneal macrophages we have isolated from mice. Our results demonstrate optimization of antigen-presenting process and predominant M1 polarization following exposure GNP-MUC-1. To our best knowledge this is the first study to evaluate the anticancer effects of a newly designed nano-biocompound on the complex antigen- processing apparatus of peritoneal macrophages.

Tuesday, September 13, 2016 8:19 PM|Anna Kiyomi, Masujiro Makita, Takuji Iwase, Sachiko Tanaka, Kenji Onda, Kentaro Sugiyama, Hironori Takeuchi, Toshihiko Hirano|Journal of Cancer (RSS 2.0)|Labels: TNF, breast cancer

Introduction: Aromatase inhibitor use for postmenopausal hormone-sensitive breast cancer patients often results in drug-induced osteoarthropathy, while its accurate mechanism has not been clarified. We investigated the implication of female hormones and several cytokines in osteoarthropathy complicated with aromatase inhibitor treatment, and the efficacy of vitamin E on the severity of osteoarthropathy, in breast cancer patients.

Methods: Sixty two breast cancer patients treated with aromatase inhibitor for average of 1.77 years were included. These patients were orally administered vitamin E (150mg/day) for 29.8 days to alleviate aromatase inhibitor-related osteoarthropathy. Severity of osteoarthropathy was scored, and the patients were grouped based on the severity or vitamin E efficacy. Serum estradiol, progesterone, vitamin E, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), IL-2, IL-4, IL-6, IL-10, and IL-17A concentrations were measured by ELISA or beads array procedures followed by flow cytometry.

Results: There was no significant difference in serum concentrations of the biomarkers between the severe and the mild osteoarthropathy groups before vitamin E administration. The osteoarthropathy scores significantly decreased after vitamin E administration (p=0.0243), while serum-estradiol concentrations did not change. The serum-estradiol concentrations before vitamin E administration in the group sensitive to the vitamin E efficacy were significantly lower, as compared with those in the insensitive group (p=0.0005). The rate of the highly sensitive patients to the vitamin E efficacy in those exhibiting low serum-estradiol concentrations was significantly higher than that in the high serum-estradiol group (p=0.0004). In the sensitive group, serum-estradiol concentrations after taking vitamin E were significantly higher than those before taking vitamin E (p=0.0124).

Conclusions: Vitamin E administration seemed to be a potential way for relieving osteoarthropathy complicated with aromatase inhibitor use. Using serum-estradiol concentration, it would be possible to select out the breast cancer patients who will respond well to the vitamin E therapy for osteoarthropathy complicated with aromatase inhibitor.

Monday, September 12, 2016 4:30 AM|Wood, M. B., Rios, D., Williams, I. R.|AJP: Cell Physiology current issue|Labels: TNF

Microfold (M) cells are phagocytic intestinal epithelial cells in the follicle-associated epithelium of Peyer's patches that transport particulate antigens from the gut lumen into the subepithelial dome. Differentiation of M cells from epithelial stem cells in intestinal crypts requires the cytokine receptor activator of NF-B ligand (RANKL) and the transcription factor Spi-B. We used three-dimensional enteroid cultures established with small intestinal crypts from mice as a model system to investigate signaling pathways involved in M cell differentiation and the influence of other cytokines on RANKL-induced M cell differentiation. Addition of RANKL to enteroids induced expression of multiple M cell-associated genes, including Spib, Ccl9 [chemokine (C-C motif) ligand 9], Tnfaip2 (TNF-α-induced protein 2), Anxa5 (annexin A5), and Marcksl1 (myristoylated alanine-rich protein kinase C substrate) in 1 day. The mature M cell marker glycoprotein 2 (Gp2) was strongly induced by 3 days and expressed by 11% of cells in enteroids. The noncanonical NF-B pathway was required for RANKL-induced M cell differentiation in enteroids, as addition of RANKL to enteroids from mice with a null mutation in the mitogen-activated protein kinase kinase kinase 14 (Map3k14) gene encoding NF-B-inducing kinase failed to induce M cell-associated genes. While the cytokine TNF-α alone had little, if any, effect on expression of M cell-associated genes, addition of TNF-α to RANKL consistently resulted in three- to sixfold higher levels of multiple M cell-associated genes than RANKL alone. One contributing mechanism is the rapid induction by TNF-α of Relb and Nfkb2 (NF-B subunit 2), genes encoding the two subunits of the noncanonical NF-B heterodimer. We conclude that endogenous activators of canonical NF-B signaling present in the gut-associated lymphoid tissue microenvironment, including TNF-α, can play a supportive role in the RANKL-dependent differentiation of M cells in the follicle-associated epithelium.

Sunday, September 11, 2016 11:00 PM|Guo, Xiaoqing; Meng, Yue; Sheng, Xiaotong; Guan, Yuan; Zhang, Fenglei; Han, Zhen; Kang, Yuying; Tai, Guihua; Zhou, Yifa; Cheng, Hairong|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: EGFR, Jnk, TNF, CRC
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively induces apoptosis in many tumor cells while leaving normal cells intact and is thus an attractive candidate for antitumor therapies. This paper reports that the combination of tunicamycin plus TRAIL produced a strong synergistic effect in TRAIL-sensitive human colon cancer HCT116 cells and TRAIL-resistant HT-29 cells. On a cellular mechanistic level, tunicamycin-enhanced TRAIL-induced apoptosis by death receptor (DR) 5 upregulation and DR4 deglycosylation. Knockdown of DR5 but not DR4 expression by specific shRNAs or siRNAs significantly increased tunicamycin-mediated and TRAIL-mediated cell viability. DR5 induction was regulated by C/EBP homologous protein (CHOP) and JNK as CHOP siRNA or JNK inhibitor SP600125 considerably abolished the DR5 induction. In addition, tunicamycin inhibited epidermal growth factor receptor glycosylation and the downstream signaling pathways, Akt and extracellular signal-regulated kinases activation, which might also be required for TRAIL sensitization by tunicamycin. In summary, tunicamycin effectively enhanced TRAIL-induced apoptosis might through JNK-CHOP-mediated DR5 upregulation and the inhibition of the epidermal growth factor receptor pathway. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Sunday, July 31, 2016 10:05 PM|Richmond, J., Robbins, A., Evans, K., Beck, D., Kurmasheva, R. T., Billups, C. A., Carol, H., Heatley, S., Sutton, R., Marshall, G. M., White, D., Pimanda, J., Houghton, P. J., Smith, M. A., Lock, R. B.|Cancer Research recent issues|Labels: SMAC, TNF, ALL
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579–91. ©2016 AACR.
Sunday, July 31, 2016 10:05 PM|Joseph, A. M., Srivastava, R., Zabaleta, J., Davila, E.|Cancer Immunology Research recent issues|Labels: TNF

The activation of TLR-MyD88 (Toll-like receptor-myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1–TLR2-stimulated and unstimulated T-cell receptor transgenic "pmel" and MyD88–/– pmel CD8+ T cells and identified changes in the expression of several TNF family members. In particular, TLR stimulation increased 4-1BB levels in pmel but not in MyD88–/–pmel T cells. A link between 4-1BB and TLR1–TLR2 signaling in CD8+ T cells was highlighted by the suboptimal responses of 4-1BB–/– T cells to TLR1–TLR2 agonist, but their normal response to CD28 or OX40 costimulation. Blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1–TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1–TLR2-stimulated cells were not due to increased mRNA stability nor increased histone activation, but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1–TLR2 ligand with an agonistic antibody to 4-1BB enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1–TLR2 signaling in CD8+ T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. Cancer Immunol Res; 4(8); 708–16. ©2016 AACR.

Thursday, July 28, 2016 7:56 AM|Yan, L., Sundaram, S.|Cancer Research recent issues|Labels: TNF, VEGF, lung cancer
Obesity is a risk factor for cancer. Adipose tissue is considered an endocrine organ that produces pro-inflammatory adipokines, e.g. monocyte chemotactic protein-1 (MCP-1), that may contribute to obesity-related malignant progression. This study investigated effects of MCP-1 deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice using a spontaneous metastasis model. The high-fat diet (45% of energy from fat) significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet (16% of energy from fat). Deficiency of MCP-1 reduced the number of lung metastases by 37% (p < 0.05) in high-fat diet-fed mice; it reduced metastatic cross-sectional area by 46% (p < 0.05) and volume by 69% (p < 0.05) compared to wild-type mice. Adipose and plasma concentrations of MCP-1 were significantly higher in high-fat diet-fed wild-type mice than in their AIN93G-fed counterparts, but they were not detectable in MCP-1 deficient mice regardless of diets. Plasma concentrations of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly higher in MCP-1 deficient mice than in wild-type mice. We conclude that adipose-produced MCP-1, at least partly, contributes to high-fat diet-enhanced metastasis and suggest that the overproduction of inflammatory cytokines (PAI-1, TNF-α) and angiogenic factors (VEGF, TIMP-1) in the absence of MCP-1 may support the metastatic development and growth of LLC in MCP-1 deficient mice.Citation Format: Lin Yan, Sneha Sundaram. Effects of monocyte chemotactic protein-1 deficiency on spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C33.
Thursday, July 28, 2016 7:56 AM|Soukup, K., Halfmann, A., Poyer, F., Martin, K., Blauensteiner, B., Huber, B., Kuttke, M., Schabbauer, G., Zopf, L., Zinnanti, J., Dohnal, A. M.|Cancer Research recent issues|Labels: MapK, TNF
The MAPK signaling pathway represents a central player in inflammatory processes. As a downstream target of p38, MAPK-activated protein kinase 2 (MK2) contributes to signal transduction regulating the expression and translation of various targets, among them several cytokines such as tumor necrosis factor (TNF) α. While MK2 was shown to promote an inflammatory macrophage phenotype, we have reported its Th1-attenuating function in dendritic cells (DCs). These observations of differential regulatory functions prompted us to investigate MK2 in the context of DCs and other myeloid cells in the tumor microenvironment.Murine DCs lacking MK2 activity exhibit an enhanced potential to differentiate Th1 cells upon Toll-like receptor (TLR) ligation in vitro and in vivo. In line with this finding, we observe significantly reduced B16.F10 melanoma growth in CD11cCre-MK2fl/fl mice upon DC activation by administration of lipopolysaccharide (LPS) together with whole tumor cell lysate as compared to wildtype littermate controls. Interestingly, CD11cCre-MK2fl/fl mice show an overall reduced myeloid cell tumor infiltration. Looking at MK2 expression in DCs isolated from orthotopic B16.F10 tumor-bearing mice, we find elevated MK2 levels in tumor-resident as opposed to splenic DCs, which has also been confirmed in a model of intracranial glioma (GL-261). This MK2 up-regulation in glioma-infiltrating DCs is associated with an enhanced expression of IL-10. Furthermore, tumor-resident myeloid-derived suppressor cells (MDSCs) show elevated MK2 expression, further underlining its potential involvement in immunosuppressive mechanisms in the myeloid lineage. In DCs we have observed cross-regulation of MAPK signaling by MK2, which promotes ERK1/2 while attenuating p38 activation and is further implicated to enhance STAT3 phosphorylation – all together contributing to a tolerogenic DC phenotype. Therefore we are now looking to unravel mechanisms by which MK2 impacts on signaling networks involved in myeloid immunosuppression in the tumor microenvironment.Our data contrast the previously described role of MK2 in pro-inflammatory mechanisms of the p38 signaling route and suggest an additional immunosuppressive feedback function in myeloid cells, which might be exploited by tumor cells to escape immune recognition and elimination. These indications are particularly interesting with regard to glioma, since the glioma microenvironment has been shown to be rich in various cytokines promoting favourable conditions for tumor growth. Finally, MK2 represents a promising target for combination therapy, as it has been reported to mediate chemo- as well as radioresistance in different types of tumors. Nevertheless, its function in tumor-infiltrating immune cells remains to be elucidated. We therefore aim to contribute to a deeper understanding of the complex interplay between extra- and intracellular signaling molecules regulating tumor as well as immune cell phenotypes.Citation Format: Klara Soukup, Angela Halfmann, Fiona Poyer, Katharina Martin, Bernadette Blauensteiner, Bastien Huber, Mario Kuttke, Gernot Schabbauer, Lydia Zopf, Jelena Zinnanti, Alexander Michael Dohnal. MAPK-activated protein kinase MK2 exerts immune regulatory functions in the microenvironment of orthotopic tumors. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A43.
Thursday, July 28, 2016 7:56 AM|Ray, A. L., Castillo, E. F., Nofchissey, R. A., Beswick, E. J.|Cancer Research recent issues|Labels: TNF, CRC
Chronic inflammation is a known risk factor for colorectal cancer (CRC). Cancers in patients with increased inflammatory cytokines in tumor tissue are associated with increased drug resistance, metastasis, and mortality. We have identified mitogen-activated protein kinase-activated protein kinase 2 (MK2) as a regulator of pro-inflammatory cytokines and promoter of proliferation in CRC progression. MK2 signaling induces IL-1, IL-6, and TNF-alpha production, which have been associated with CRC development and progression. We investigated this pathway in an inflammation-related model of CRC. This model relies on an initial dose of the carcinogen azoxymethane, followed by administration of dextran sodium sulfate to model chronic inflammation. C57BL/6 mice were found to develop colon tumors by day 54 in this model. Thus, we treated mice with MK2 inhibitors starting at this time point, 3 times a week for 3 weeks. At day 80, neoplasm number and size were measured, as well as pro-inflammatory cytokines and immune cell profiles in the colon using flow cytometry and multiplex bead-based arrays. MK2 inhibition drastically reduced colon pro-inflammatory cytokines, influx of immune cells, and tumor burden compared to vehicle control treated mice. Upon testing two separate MK2 inhibitors, 6/7 and 5/7 mice were completely free of tumors after treatment. We conclude that this pathway is an important contributor to CRC and could be a promising therapeutic target.Citation Format: Anita L. Ray, Eliseo F. Castillo, Robert A. Nofchissey, Ellen J. Beswick. Inhibition of MK2 reduces chronic inflammation and regresses tumors in a mouse model of colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A19.
Sunday, July 17, 2016 10:05 PM|Romeo, C., Weber, M. C., Zarei, M., DeCicco, D., Chand, S. N., Lobo, A. D., Winter, J. M., Sawicki, J. A., Sachs, J. N., Meisner-Kober, N., Yeo, C. J., Vadigepalli, R., Tykocinski, M. L., Brody, J. R.|Molecular Cancer Research recent issues|Labels: TNF, pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. TRAIL directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3'-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR's role in affecting TRAIL apoptotic resistance. NanoString analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in antiapoptotic processes. Taken together, these data extend HuR's role as a key regulator of TRAIL-induced apoptosis.

Implications: Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAIL-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients. Mol Cancer Res; 14(7); 599–611. ©2016 AACR.

Wednesday, June 15, 2016 10:56 AM|Almeida, A. R., Correia, D. V., Fernandes-Platzgummer, A., da Silva, C. L., Gomes da Silva, M., Anjos, D. R., Silva-Santos, B.|Clinical Cancer Research Online First Articles|Labels: TNF, CLL

Purpose: The V1+ subset of T lymphocytes is a promising candidate for cancer immunotherapy but the lack of suitable expansion/ differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a V1+ T cell-based protocol that is GMP-compatible and devoid of feeder cells for prompt clinical translation. Experimental design: We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (over 2-3 weeks) V1+ T cells from the peripheral blood of healthy donors and chronic lymphocytic leukemia (CLL) patients. We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL). Results: We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinical-grade cell culture bags) and differentiation of cytotoxic V1+ (DOT) cells. These expressed the Natural Cytotoxicity Receptors (NCRs), NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro. When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss-of-function; indeed, DOT cells proliferated and produced abundant IFN- and TNF-α, but importantly no IL-17, in vivo. Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL. Conclusions: We provide a clinical-grade method and the preclinical proof-of-principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL.

Sunday, February 21, 2016 4:00 PM|British Journal of Pharmacology|MedWorm: Cancer Therapy|Comments|Labels: TNF, lung cancer
Conclusions and ImplicationsROS generation by decursin selectively activated the PERK/ATF4 axis of the endoplasmic reticulum stress signalling pathway, leading to enhanced TRAIL sensitivity in TRAIL‐resistant NSCLC cell lines, partly via up‐regulation of DR5. (Source: British Journal of Pharmacology)
Thursday, January 28, 2016 4:00 PM|Clinical Oral Investigations|MedWorm: Cancer Therapy|Comments|Labels: TNF, pharyngeal
Conclusions We showed for the first time that PEITC overcomes TRAIL resistance in oral cancer cells and enhance the therapeutic potential of TRAIL in vivo. Clinical relevance PEITC, either alone or in combination with TRAIL, can be used as a new therapeutic approach for the treatment of oral cancers. (Source: Clinical Oral Investigations)
Wednesday, January 13, 2016 8:49 PM|Postepy higieny i medycyny doswiadczalnej|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: TNF
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces carcinoma cell death through the extrinsic pathway of apoptosis. Preclinical trials of gene therapy have been conducted using viral transfer of the TRAIL transgene into prostate, bladder, breast, kidney, liver, non-small cell lung cancer and also glioblastoma cells. Experiments in vitro demonstrated the extensive apoptosis of target cells as well as frequent disease regression or remission. TRAIL transfer did not show any side effects, opposite to chemotherapy. Encouraging results of TRAIL-related gene therapy were observed in rheumatoid arthritis and type 1 diabetes. Adenoviral vectors (AdV) encoding TRAIL are the most promising tool in anti-tumor therapy. They have undergone numerous modifications by incr...
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: TNF, lung cancer, IL
The CBP501 calmodulin-binding peptide is an anti-cancer drug candidate that has completed a Phase II clinical trial for patients with non-small cell lung carcinoma (NSCLC). CBP501 was also previously identified as a unique G2 checkpoint-directed agent and as an enhancer of cisplatin (CDDP) uptake.In a post-trial analysis of the NSCLC patients, it was found that the survival was statistically significantly different between subpopulations with normal white blood cell counts (WBC) (WBC < 8000) and high WBC (WBC > 8000). Notably, treatment by CDDP with or without CBP501 had no effect on the neutrophil oxidative burst or phagocytosisHere, we show that CBP501 inhibits several functions of macrophages. The LPS-stimulated production of several cytokines (IL-6. TNF-alpha and IL-10) by macrop...