Top

Published in:

01-02-2018 | Original Article

Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells

Authors: Olexandr Fedorchuk, Yaroslav Susak, Mariia Rudyk, Nataliia Senchylo, Nataliia Khranovska, Oksana Skachkova, Larysa Skivka

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2018

Abstract

Purpose

Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.

Methods

Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.

Results

When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.

Conclusion

Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

Hamilton G, Rath B (2014) A short update on cancer chemoresistance. Wien Med Wochenschr 164(21–22):456–460. https://doi.org/10.1007/s10354-014-0311-zCrossRefPubMed

Gómez-Miragaya J, Palafox M, Paré L, Yoldi G, Ferrer I, Vila S, Galván P, Pellegrini P, Pérez-Montoyo H, Igea A, Muñoz P, Esteller M, Nebreda AR, Urruticoechea A, Morilla I, Pernas S, Climent F, Soler-Monso MT, Petit A, Serra V, Prat A, González-Suárez E (2017) Resistance to taxanes in triple-negative breast cancer associates with the dynamics of a CD49f+ tumor-initiating population. Stem Cell Rep 8(5):1392–1407. https://doi.org/10.1016/j.stemcr.2017.03.026CrossRef

Bilen MA, Hess KR, Campbell MT, Wang J, Broaddus RR, Karam JA, Ward JF, Wood CG, Choi SL, Rao P, Zhang M, Naing A, General R, Cauley DH, Lin SH, Logothetis CJ, Pisters LL, Tu SM (2016) Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis. Oncotarget 7(52):86280–86289. https://doi.org/10.18632/oncotarget.13380CrossRefPubMedPubMedCentral

Senthebane DA, Rowe A, Thomford NE, Shipanga H, Munro D, Mazeedi MAMA., Almazyadi HAM, Kallmeyer K, Dandara C, Pepper MS, Parker MI, Dzobo K (2017) The role of tumor microenvironment in chemoresistance: to survive, keep your enemies closer. Int J Mol Sci 18(7):E1586. https://doi.org/10.3390/ijms18071586CrossRefPubMed

Hölzel M, Bovier A, Tüting T (2013) Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 13(5):365–376. https://doi.org/10.1038/nrc3498CrossRefPubMed

Fouad YA, Aanei C (2017) Revisiting the hallmarks of cancer. Am J Cancer Res 7(5):1016–1036PubMedPubMedCentral

Chacon JA, Schutsky K, Powell DJ (2016) The impact of chemotherapy, radiation and epigenetic modifiers in cancer cell expression of immune inhibitory and stimulatory molecules and anti-tumor efficacy. Vaccines (Basel) 4(4)E43. https://doi.org/10.3390/vaccines4040043CrossRef

Triba MN, Starzec A, Bouchemal N, Guenin E, Perret GY, Le Moyec L (2010) Metabolomic profiling with NMR discriminates between biphosphonate and doxorubicin effects on B16 melanoma cells. NMR Biomed 23(9):1009–1016. https://doi.org/10.1002/nbm.1516CrossRefPubMed

Zub KA, Sousa MM, Sarno A, Sharma A, Demirovic A, Rao S, Young C, Aas PA, Ericsson I, Sundan A, Jensen ON, Slupphaug G (2015) Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells. PLoS One 10(3):e0119857. https://doi.org/10.1371/journal.pone.0119857CrossRefPubMedPubMedCentral

10.

Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22(47):7265–7279CrossRefPubMed

11.

Gottesman MM, Lavi O, Hall MD, Gillet JP (2016) Towards a better understanding of the complexity of cancer drug resistance. Annu Rev Pharmacol Toxicol 56:85–102. https://doi.org/10.1146/annurev-pharmtox-010715-103111CrossRefPubMed

12.

Shen DW, Pouliot LM, Hall MD, Gottesman MM (2012) Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev 64(3):706–721. https://doi.org/10.1124/pr.111.005637CrossRefPubMedPubMedCentral

13.

Wangpaichitr M, Kandemir H, Li YY, Wu C, Nguyen D, Feun LG, Kuo MT, Savaraj N (2017) Relationship of metabolic alterations and PD-L1 expression in cisplatin resistant lung cancer. Cell Dev Biol 6(2):183. https://doi.org/10.4172/2168-9296.1000183PubMedPubMedCentral

14.

Barr MP, Gray SG, Hoffmann AC, Hilger RA, Thomale J, O’Flaherty JD, Fennell DA, Richard D, O’Leary JJ, O’Byrne KJ (2013) Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS One 8(1):e54193. https://doi.org/10.1371/journal.pone.0054193CrossRefPubMedPubMedCentral

15.

Zhang Q, Cai DJ, Li B (2015) Ovarian cancer stem-like cells elicit the polarization of M2 macrophages. Mol Med Rep 11(6):4685–4693. https://doi.org/10.3892/mmr.2015.3323CrossRefPubMed

16.

Raggi C, Mousa HS, Correnti M, Sica A, Invernizzi P (2016) Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies. Oncogene 35(6):671–682. https://doi.org/10.1038/onc.2015.132CrossRefPubMed

17.

Levina V, Su Y, Nolen B, Liu X, Gordin Y, Lee M, Lokshin A, Gorelik E (2008) Chemotherapeutic drugs and human tumor cells cytokine network. Int J Cancer 123(9):2031–2040. https://doi.org/10.1002/ijc.23732CrossRefPubMedPubMedCentral

18.

Zhang F, Duan S, Tsai Y, Keng PC, Chen Y, Lee SO, Chen Y (2016) Cisplatin treatment increases stemness through upregulation of hypoxia-inducible factors by interleukin-6 in non-small cell lung cancer. Cancer Sci 107(6):746–754. https://doi.org/10.1111/cas.12937CrossRefPubMedPubMedCentral

19.

Castells M, Thibault B, Delord JP, Couderc B (2012) Implication of tumor microenvironment in chemoresistance: tumor-associated stromal cells protect tumor cells from cell death. Int J Mol Sci 13(8):9545–9571. https://doi.org/10.3390/ijms13089545CrossRefPubMedPubMedCentral

20.

Wang W, Kryczek I, Dostál L, Lin H, Tan L, Zhao L, Lu F, Wei S, Maj T, Peng D, He G, Vatan L, Szeliga W, Kuick R, Kotarski J, Tarkowski R, Dou Y, Rattan R, Munkarah A, Liu JR, Zou W (2016) Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165(5):1092–1105. https://doi.org/10.1016/j.cell.2016.04.009CrossRefPubMedPubMedCentral

21.

Solyanik GI, Pyaskovskaya ON, Garmanchouk LV (2003) Cisplatin-resistant Lewis lung carcinoma cells possess increased level of VEGF secretion. Exp Oncol 25(4):260–265

22.

Pyaskovskaya ON, Dasyukevich OI, Kolesnik DL, Garmanchouk LV, Solyanik GI (2007) Changes in VEGF level and tumor growth characteristics during Lewis lung carcinoma progression towards cis-DDP resistance. Exp Oncol 29:197–202PubMed

23.

Solyanik GI, Fedorchuk AG, Pyaskovskaya ON, Dasyukevich OI, Khranovskaya NN, Aksenov GN, Sobetsky VV (2004) Anticancer activity of aconitine-containing herbal extract BC1. Exp Oncol 26:307–311PubMed

24.

Kolesnik DL, Pyaskovskaya ON, Dasyukevich OI, Solyanik GI (2010) Significant antimetastatic efficacy of metronomic low-dose oral cyclophosphamide against highly angiogenic variant of Lewis lung carcinoma. Tumor Host Novel Asp Old Prob Int Conf (Kiev, 21–24 Sept., 2010) Exp Oncol 32(Suppl.):94

25.

Fedorchuk OG, Pyaskovskaya OM, Skivka LM, Gorbik GV, Trompak OO, Solyanik GI (2012) Paraneoplastic syndrome in mice bearing high-angiogenic variant of Lewis lung carcinoma: Relations with tumor derived VEGF. Cytokine 57(1):81–88. https://doi.org/10.1016/j.cyto.2011.10.022CrossRefPubMed

26.

Engblom C, Pfirschke C, Pittet MJ (2016) The role of myeloid cells in cancer therapies. Nat Rev Cancer 16(7):447–462. https://doi.org/10.1038/nrc.2016.54CrossRefPubMed

27.

Levina V, Marrangoni AM, DeMarco R, Gorelik E, Lokshin AE (2008) Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS One 3:e3077. https://doi.org/10.1371/journal.pone.0003077CrossRefPubMedPubMedCentral

28.

Skivka LM, Fedorchuk OG, Rudyk MP, Pozur VV, Khranovska NM, Grom MY, Nowicky JW (2013) Antineoplastic drug NSC631570 modulates functions of hypoxic macrophages. Tsitol Genet 47(5):70–82PubMed

29.

Sánchez A, Factor VM, Espinoza LA, Schroeder IS, Thorgeirsson SS (2004) In vitro differentiation of rat liver derived stem cells results in sensitization to TNFalpha-mediated apoptosis. Hepatology 40(3):590–599. https://doi.org/10.1002/hep.20363CrossRefPubMed

30.

Prylutska SV, Skivka LM, Didenko GV, Prylutskyy YI, Evstigneev MP, Potebnya GP, Panchuk RR, Stoika RS, Ritter U, Scharff P (2015) Complex of C60 fullerene with doxorubicin as a promising agent in antitumor therapy. Nanoscale Res Lett 10(1):499. https://doi.org/10.1186/s11671-015-1206-7CrossRefPubMedPubMedCentral

31.

Robinson SP, Stagg AJ (2001) Dendritic cell protocol, Humana Press Inc, New York, p 270CrossRef

32.

Maldonado-López R, De Smedt T, Pajak B, Heirman C, Thielemans K, Leo O, Urbain J, Maliszewski CR, Moser M (1999) Role of CD8alpha + and CD8alpha- dendritic cells in the induction of primary immune responses in vivo. J Leukoc Biol 66(2):242–246CrossRefPubMed

33.

Yoo PS, Mulkeen AL, Cha CH (2006) Post-transcriptional regulation of vascular endothelial growth factor: implications for tumor angiogenesis. World J Gastroenterol 12(31):4937–4942CrossRefPubMedPubMedCentral

34.

Arcondéguy T, Lacazette E, Millevoi S, Prats H, Touriol C (2013) VEGF-A mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post-transcriptional level. Nucleic Acids Res 41(17):7997–8010. https://doi.org/10.1093/nar/gkt539CrossRefPubMedPubMedCentral

35.

Segura E, Nicco C, Lombard B, Véron P, Raposo G, Batteux F, Amigorena S, Théry C (2005) ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood 106(1):216–223. https://doi.org/10.1182/blood-2005-01-022CrossRefPubMed

36.

Kodaira Y, Nair SK, Wrenshall LE, Gilboa E, Platt JL (2000) Phenotypic and functional maturation of dendritic cells mediated by heparan sulfate. J Immunol 165(3):1599–1604CrossRefPubMed

37.

Wicki A, Mandalà M, Massi D, Taverna D, Tang H, Hemmings BA, Xue G (2016) Acquired resistance to clinical cancer therapy: a twist in physiological signaling. Physiol Rev 96(3):805–829. https://doi.org/10.1152/physrev.00024.2015CrossRefPubMed

38.

De Palma M, Lewis CE (2011) Cancer: macrophages limit chemotherapy. Nature 472(7343):303–304. https://doi.org/10.1038/472303aCrossRefPubMed

39.

Buck MD, Sowell RT, Kaech SM, Pearce EL (2017) Metabolic instruction of immunity. Cell 169(4):570–586. https://doi.org/10.1016/j.cell.2017.04.004CrossRefPubMed

40.

Kareva I, Hahnfeldt P (2013) The emerging “hallmarks” of metabolic reprogramming and immune evasion: distinct or linked? Cancer Res 73(9):2737–2742. https://doi.org/10.1158/0008-5472CrossRefPubMed

41.

Jinushi M (2012) Chronic activation of DNA damage signals causes tumor immune evasion in the chemoresistant niche. Oncoimmunology 1(3):400–402. https://doi.org/10.4161/onci.19123CrossRefPubMedPubMedCentral

42.

Mocellin S, Panelli M, Wang E, Rossi CR, Pilati P, Nitti D, Lise M, Marincola FM (2004) IL-10 stimulatory effects on human NK cells explored by gene profile analysis. Genes Immun 5(8):621–630CrossRefPubMed

43.

Terme M, Colussi O, Marcheteau E, Tanchot C, Tartour E, Taieb J (2012) Modulation of immunity by antiangiogenic molecules in cancer. Clin Dev Immunol. 2012:492920. https://doi.org/10.1155/2012/492920CrossRefPubMedPubMedCentral

44.

Voron T, Marcheteau E, Pernot S, Colussi O, Tartour E, Taieb J, Terme M (2014) Control of the immune response by pro-angiogenic factors. Front Oncol 4:70. https://doi.org/10.3389/fonc.2014.00070CrossRefPubMedPubMedCentral

45.

Nissinen L, Kähäri VM (2014) Matrix metalloproteinases in inflammation. Biochim Biophys Acta 1840(8):2571–2580. https://doi.org/10.1016/j.bbagen.2014.03.007CrossRefPubMed

46.

Chimal-Ramírez GK, Espinoza-Sánchez NA, Fuentes-Pananá EM (2015) A role for the inflammatory mediators Cox-2 and metalloproteinases in cancer stemness. Anticancer Agents Med Chem 15(7):837–855CrossRefPubMed

47.

Anastasov A, Vlaykova T (2011) Matrix metalloproteinases in tumor biology—a special attention on their role in HNSCC. Trakia J Sci 9(3):74–81

48.

Novitskiy SV, Forrester E, Pickup MW, Gorska AE, Chytil A, Aakre M, Polosukhina D, Owens P, Yusupova DR, Zhao Z, Ye F, Shyr Y, Moses HL (2014) Attenuated transforming growth factor beta signaling promotes metastasis in a model of HER2 mammary carcinogenesis. Breast Cancer Res 16(5):425. https://doi.org/10.1186/s13058-014-0425-7CrossRefPubMedPubMedCentral

49.

Huang S, Peng L, Tang Y, Zhang L, Guo W, Zou X, Peng X (2013) Hypoxia of PC-3 prostate cancer cells enhances migration and vasculogenesis in vitro of bone marrow-derived endothelial progenitor cells by secretion of cytokines. Oncol Rep 29(6):2369–2377. https://doi.org/10.3892/or.2013.2363CrossRefPubMed

50.

Zhang Y, Choksi S, Chen K, Pobezinskaya Y, Linnoila I, Liu ZG (2013) ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. Cell Res 23(7):898–914. https://doi.org/10.1038/cr.2013.75CrossRefPubMedPubMedCentral

51.

Osinsky S, Zavelevich M, Vaupel P (2009) Tumor hypoxia and malignant progression. Exp Oncol 31(2):80–86PubMed

52.

Jain M, Rivera S, Monclus EA, Synenki L, Zirk A, Eisenbart J, Feghali-Bostwick C, Mutlu GM, Budinger GR, Chandel NS (2013) Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling. J Biol Chem 288(2):770–777. https://doi.org/10.1074/jbc.M112.431973CrossRefPubMed

53.

Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, Gulati M, Homer RJ, Russell T, van Rooijen N, Elias JA, Hogaboam CM, Herzog EL (2011) TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol 43(1):154–162. https://doi.org/10.1016/j.biocel.2010.10.013CrossRefPubMed

54.

Arsenijevic M, Milovanovic M, Jovanovic S, Arsenijevic N, Markovic BS, Gazdic M, Volarevic V (2017) In vitro and in vivo anti-tumor effects of selected platinum(IV) and dinuclear platinum(II) complexes against lung cancer cells. J Biol Inorg Chem 22(6):807–817. https://doi.org/10.1007/s00775-017-1459-yCrossRefPubMed

55.

Petersson M, Charo J, Salazar-Onfray F, Noffz G, Mohaupt M, Qin Z, Klein G, Blankenstein T, Kiessling R (1996) Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1. J Immunol 161(5):2099–2105

56.

Ayalon O, Hughes EA, Cresswell P, Lee J, O’Donnell L, Pardi R, Bender JR (1998) Induction of transporter associated with antigen processing by interferon gamma confers endothelial cell cytoprotection against natural killer-mediated lysis. Proc Natl Acad Sci USA 95(5):2435–2440CrossRefPubMedPubMedCentral

57.

Xu X, Rao GS, Groh V, Spies T, Gattuso P, Kaufman HL, Plate J, Prinz RA (2011) Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: role of uric acid accumulation in gemcitabine-induced MICA/B expression. BMC Cancer 11:194. https://doi.org/10.1186/1471-2407-11-194CrossRefPubMedPubMedCentral

58.

Anguille S, Van Acker HH, Van den Bergh J, Willemen Y, Goossens H, Van Tendeloo VF, Smits EL, Berneman ZN, Lion E (2015) Interleukin-15 dendritic cells harness NK cell cytotoxic effector function in a contact- and IL-15-dependent manner. PLoS One 10(5):e0123340. https://doi.org/10.1371/journal.pone.0123340CrossRefPubMedPubMedCentral

59.

Ferlazzo G, Morandi B (2014) Cross-talks between natural killer cells and distinct subsets of dendritic cells. Front Immunol 5:159. https://doi.org/10.3389/fimmu.2014.00159CrossRefPubMedPubMedCentral

60.

Yewdall AW, Drutman SB, Jinwala F, Bahjat KS, Bhardwaj N (2010) CD8+ T cell priming by dendritic cell vaccines requires antigen transfer to endogenous antigen presenting cells. PLoS One 5(6):e11144. https://doi.org/10.1371/journal.pone.0011144CrossRefPubMedPubMedCentral

Title: Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells
Authors: Olexandr Fedorchuk
Yaroslav Susak
Mariia Rudyk
Nataliia Senchylo
Nataliia Khranovska
Oksana Skachkova
Larysa Skivka
Publication date: 01-02-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3503-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2018

A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study)

A pilot study of daunorubicin-augmented hyper-CVAD induction chemotherapy for adults with acute lymphoblastic leukemia

Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors

The impact of skeletal muscle on the pharmacokinetics and toxicity of 5-fluorouracil in colorectal cancer

Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients

Correction to: Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer