Top

Published in:

Open Access 01-10-2019 | Thyroid Cancer | Original paper

Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

Authors: Yvette J. E. Sloot, Katrin Rabold, Thomas Ulas, Dennis M. De Graaf, Bas Heinhuis, Kristian Händler, Joachim L. Schultze, Mihai G. Netea, Johannes W. A. Smit, Leo A. B. Joosten, Romana T. Netea-Maier

Published in: Cellular Oncology | Issue 5/2019

Abstract

Purpose

Interleukin 32 (IL-32) is a pro-inflammatory cytokine of which different isoforms have been identified. Recently, IL-32 has been shown to act as a potent inducer of cell migration in several types of cancer. Although previous research showed that IL-32 is expressed in differentiated thyroid cancer (TC) cells, the role of IL-32 in TC cell migration has not been investigated. Furthermore, tumour-associated macrophages (TAMs) may play a facilitating role in cancer cell migration. The aim of this study was to explore whether the interaction between TC cells and TAMs results in increased expression of IL-32 in TC cells and to investigate whether this affects TC cell migration.

Methods

TPC-1 cells were co-culture with TC-induced or naive macrophages. Next, transcriptome analysis on TPC-1 cells was performed and supernatants were used for stimulation of TPC-1 cells. IL-32β and IL-32γ were exogenously overexpressed in TPC-1 cells using transient transfection, after which an in vitro gap closure assay was performed to assess cell migration, and the expression of migratory factors was assessed using RT-qPCR.

Results

We found that TC-induced macrophages induced IL-32 expression in TC cells and that TAM-derived TNFα was the main inducer of IL-32β expression in TC cells. Overexpression of IL-32β and IL-32γ did not affect TC cell migration, but increased cell death. Finally, we found that IL-32β overexpression led to increased mRNA expression of the pro-survival cytokine IL-8, while the expression of other migratory factors was not affected.

Conclusions

From our data, we conclude that TAM-derived TNFα induces IL-32β in TC cells. Although IL-32β does not affect TC cell migration, alternative splicing of IL-32 towards the IL-32β isoform may be beneficial for TC cell survival through induction of the pro-survival cytokine IL-8.

Available only for authorised users

S.H. Kim, S.Y. Han, T. Azam, D.Y. Yoon, C.A. Dinarello, Interleukin-32: A cytokine and inducer of TNFalpha. Immunity 22, 131–142 (2005). https://doi.org/10.1016/j.immuni.2004.12.003 CrossRefPubMed

B. Heinhuis, M.I. Koenders, F.A. van de Loo, M.G. Netea, W.B. van den Berg, L.A. Joosten, Inflammation-dependent secretion and splicing of IL-32{gamma} in rheumatoid arthritis. Proc Natl Acad Sci U S A 108, 4962–4967 (2011). https://doi.org/10.1073/pnas.1016005108 CrossRefPubMedPubMedCentral

L.A. Joosten, B. Heinhuis, M.G. Netea, C.A. Dinarello, Novel insights into the biology of interleukin-32. Cell Mol Life Sci 70, 3883–3892 (2013). https://doi.org/10.1007/s00018-013-1301-9 CrossRefPubMed

B. Heinhuis, M.I. Koenders, P.L. van Riel, F.A. van de Loo, C.A. Dinarello, M.G. Netea, W.B. van den Berg, L.A. Joosten, Tumour necrosis factor alpha-driven IL-32 expression in rheumatoid arthritis synovial tissue amplifies an inflammatory cascade. Ann Rheum Dis 70, 660–667 (2011). https://doi.org/10.1136/ard.2010.139196 CrossRefPubMed

B. Heinhuis, C.D. Popa, B.L. van Tits, S.H. Kim, P.L. Zeeuwen, W.B. van den Berg, J.W. van der Meer, J.A. van der Vliet, A.F. Stalenhoef, C.A. Dinarello, M.G. Netea, L.A. Joosten, Towards a role of interleukin-32 in atherosclerosis. Cytokine 64, 433–440 (2013). https://doi.org/10.1016/j.cyto.2013.05.002 CrossRefPubMed

J.T. Hong, D.J. Son, C.K. Lee, D.Y. Yoon, D.H. Lee, M.H. Park, Interleukin 32, inflammation and cancer. Pharmacol Ther 174, 127–137 (2017). https://doi.org/10.1016/j.pharmthera.2017.02.025 CrossRefPubMed

A.M. Marcondes, A.J. Mhyre, D.L. Stirewalt, S.H. Kim, C.A. Dinarello, H.J. Deeg, Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. Proc Natl Acad Sci U S A 105, 2865–2870 (2008). https://doi.org/10.1073/pnas.0712391105 CrossRefPubMedPubMedCentral

C. Sorrentino, E. Di Carlo, Expression of IL-32 in human lung cancer is related to the histotype and metastatic phenotype. Am J Respir Crit Care Med 180, 769–779 (2009). https://doi.org/10.1164/rccm.200903-0400OC CrossRefPubMed

Y.J.E. Sloot, J.W. Smit, L.A.B. Joosten, R.T. Netea-Maier, Insights into the role of IL-32 in cancer. Semin Immunol 38, 24–32 (2018). https://doi.org/10.1016/j.smim.2018.03.004 CrossRefPubMed

10.

J.H. Oh, M.C. Cho, J.H. Kim, S.Y. Lee, H.J. Kim, E.S. Park, J.O. Ban, J.W. Kang, D.H. Lee, J.H. Shim, S.B. Han, D.C. Moon, Y.H. Park, D.Y. Yu, J.M. Kim, S.H. Kim, D.Y. Yoon, J.T. Hong, IL-32gamma inhibits cancer cell growth through inactivation of NF-kappaB and STAT3 signals. Oncogene 30, 3345–3359 (2011). https://doi.org/10.1038/onc.2011.52 CrossRefPubMedPubMedCentral

11.

E.S. Park, J.M. Yoo, H.S. Yoo, D.Y. Yoon, Y.P. Yun, J. Hong, IL-32gamma enhances TNF-alpha-induced cell death in colon cancer. Mol Carcinog 53(Suppl 1), E23–E35 (2014). https://doi.org/10.1002/mc.21990 CrossRefPubMed

12.

H.M. Yun, J.H. Oh, J.H. Shim, J.O. Ban, K.R. Park, J.H. Kim, D.H. Lee, J.W. Kang, Y.H. Park, D. Yu, Y. Kim, S.B. Han, D.Y. Yoon, J.T. Hong, Antitumor activity of IL-32beta through the activation of lymphocytes, and the inactivation of NF-kappaB and STAT3 signals. Cell Death Dis 4, e640 (2013). https://doi.org/10.1038/cddis.2013.166 CrossRefPubMedPubMedCentral

13.

J.S. Park, S.Y. Choi, J.H. Lee, M. Lee, E.S. Nam, A.L. Jeong, S. Lee, S. Han, M.S. Lee, J.S. Lim, D.Y. Yoon, Y. Kwon, Y. Yang, Interleukin-32beta stimulates migration of MDA-MB-231 and MCF-7cells via the VEGF-STAT3 signaling pathway. Cell Oncol 36, 493–503 (2013). https://doi.org/10.1007/s13402-013-0154-4 CrossRef

14.

C.Y. Tsai, C.S. Wang, M.M. Tsai, H.C. Chi, W.L. Cheng, Y.H. Tseng, C.Y. Chen, C.D. Lin, J.I. Wu, L.H. Wang, K.H. Lin, Interleukin-32 increases human gastric cancer cell invasion associated with tumor progression and metastasis. Clin Cancer Res 20, 2276–2288 (2014). https://doi.org/10.1158/1078-0432.ccr-13-1221 CrossRefPubMed

15.

Q. Zeng, S. Li, Y. Zhou, W. Ou, X. Cai, L. Zhang, W. Huang, L. Huang, Q. Wang, Interleukin-32 contributes to invasion and metastasis of primary lung adenocarcinoma via NF-kappaB induced matrix metalloproteinases 2 and 9 expression. Cytokine 65, 24–32 (2014). https://doi.org/10.1016/j.cyto.2013.09.017 CrossRefPubMed

16.

Y. Zhou, Z. Hu, N. Li, R. Jiang, Interleukin-32 stimulates osteosarcoma cell invasion and motility via AKT pathway-mediated MMP-13 expression. Int J Mol Med 35, 1729–1733 (2015). https://doi.org/10.3892/ijmm.2015.2159 CrossRefPubMed

17.

T.S. Plantinga, I. Costantini, B. Heinhuis, A. Huijbers, G. Semango, B. Kusters, M.G. Netea, A.R. Hermus, J.W. Smit, C.A. Dinarello, L.A. Joosten, R.T. Netea-Maier, A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma. Carcinogenesis 34, 1529–1535 (2013). https://doi.org/10.1093/carcin/bgt092 CrossRefPubMed

18.

B. Heinhuis, T.S. Plantinga, G. Semango, B. Kusters, M.G. Netea, C.A. Dinarello, J.W.A. Smit, R.T. Netea-Maier, L.A.B. Joosten, Alternatively spliced isoforms of IL-32 differentially influence cell death pathways in cancer cell lines. Carcinogenesis 37, 197–205 (2016). https://doi.org/10.1093/carcin/bgv172 CrossRefPubMed

19.

B. Caillou, M. Talbot, U. Weyemi, C. Pioche-Durieu, A. Al Ghuzlan, J.M. Bidart, S. Chouaib, M. Schlumberger, C. Dupuy, Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma. PLoS One 6, e22567 (2011). https://doi.org/10.1371/journal.pone.0022567 CrossRefPubMedPubMedCentral

20.

M. Ryder, R.A. Ghossein, J.C. Ricarte-Filho, J.A. Knauf, J.A. Fagin, Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer 15, 1069–1074 (2008). https://doi.org/10.1677/erc-08-0036 CrossRefPubMedPubMedCentral

21.

R.J.W. Arts, T.S. Plantinga, S. Tuit, T. Ulas, B. Heinhuis, M. Tesselaar, Y. Sloot, G.J. Adema, L.A.B. Joosten, J.W.A. Smit, M.G. Netea, J.L. Schultze, R.T. Netea-Maier, Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages. Oncoimmunology 5, e1229725 (2016). https://doi.org/10.1080/2162402X.2016.1229725

22.

R.E. Schweppe, J.P. Klopper, C. Korch, U. Pugazhenthi, M. Benezra, J.A. Knauf, J.A. Fagin, L.A. Marlow, J.A. Copland, R.C. Smallridge, B.R. Haugen, Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endocrinol Metab 93, 4331–4341 (2008). https://doi.org/10.1210/jc.2008-1102 CrossRefPubMedPubMedCentral

23.

J.T. Leek, W.E. Johnson, H.S. Parker, A.E. Jaffe, J.D. Storey, The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882–883 (2012). https://doi.org/10.1093/bioinformatics/bts034 CrossRefPubMedPubMedCentral

24.

M.E. Ritchie, B. Phipson, D. Wu, Y. Hu, C.W. Law, W. Shi, G.K. Smyth, Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43, e47 (2015). https://doi.org/10.1093/nar/gkv007 CrossRefPubMedPubMedCentral

25.

J.T. Robinson, H. Thorvaldsdóttir, W. Winckler, M. Guttman, E.S. Lander, G. Getz, J.P. Mesirov, Integrative genomics viewer. Nat Biotechnol 29, 24 (2011). https://doi.org/10.1038/nbt.1754 https://www.nature.com/articles/nbt.1754#supplementary-information CrossRefPubMedPubMedCentral

26.

M. Rotondi, F. Coperchini, F. Latrofa, L. Chiovato, Role of chemokines in thyroid Cancer microenvironment: Is CXCL8 the Main player? Front Endocrinol (Lausanne) 9(314) (2018). https://doi.org/10.3389/fendo.2018.00314

27.

F. Fagotto, B.M. Gumbiner, Cell contact-dependent signaling. Dev Biol 180, 445–454 (1996). https://doi.org/10.1006/dbio.1996.0318 CrossRefPubMed

28.

F. Vinals, J. Pouyssegur, Confluence of vascular endothelial cells induces cell cycle exit by inhibiting p42/p44 mitogen-activated protein kinase activity. Mol Cell Biol 19, 2763–2772 (1999)CrossRefPubMedPubMedCentral

29.

J. Landsberg, J. Kohlmeyer, M. Renn, T. Bald, M. Rogava, M. Cron, M. Fatho, V. Lennerz, T. Wolfel, M. Holzel, T. Tuting, Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012). https://doi.org/10.1038/nature11538 CrossRefPubMed

30.

A. Mehta, Y.J. Kim, L. Robert, J. Tsoi, B. Comin-Anduix, B. Berent-Maoz, A.J. Cochran, J.S. Economou, P.C. Tumeh, C. Puig-Saus, A. Ribas, Immunotherapy resistance by inflammation-induced dedifferentiation. Cancer Discov 8, 935–943 (2018). https://doi.org/10.1158/2159-8290.Cd-17-1178 CrossRefPubMedPubMedCentral

31.

S. Bhat, N. Gardi, S. Hake, N. Kotian, S. Sawant, S. Kannan, V. Parmar, S. Desai, A. Dutt, N.N. Joshi, Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients. J Cancer Res Clin Oncol 143, 1745–1756 (2017). https://doi.org/10.1007/s00432-017-2431-5 CrossRefPubMedPubMedCentral

32.

M.H. Park, M.J. Song, M.C. Cho, D.C. Moon, D.Y. Yoon, S.B. Han, J.T. Hong, Interleukin-32 enhances cytotoxic effect of natural killer cells to cancer cells via activation of death receptor 3. Immunology 135, 63–72 (2012). https://doi.org/10.1111/j.1365-2567.2011.03513.x CrossRefPubMedPubMedCentral

33.

K.Y. Jung, S.W. Cho, Y.A. Kim, D. Kim, B.C. Oh, D.J. Park, Y.J. Park, Cancers with higher density of tumor-associated macrophages were associated with poor survival rates. J Pathol Transl Med 49, 318–324 (2015). https://doi.org/10.4132/jptm.2015.06.01 CrossRefPubMedPubMedCentral

34.

Y.J.E. Sloot, K. Rabold, M.G. Netea, J.W.A. Smit, N. Hoogerbrugge, R.T. Netea-Maier, Effect of PTEN inactivating germline mutations on innate immune cell function and thyroid cancer-induced macrophages in patients with PTEN hamartoma tumor syndrome. Oncogene (2019). https://doi.org/10.1038/s41388-019-0685-x

Title: Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration
Authors: Yvette J. E. Sloot
Katrin Rabold
Thomas Ulas
Dennis M. De Graaf
Bas Heinhuis
Kristian Händler
Joachim L. Schultze
Mihai G. Netea
Johannes W. A. Smit
Leo A. B. Joosten
Romana T. Netea-Maier
Publication date: 01-10-2019
Publisher: Springer Netherlands
Keywords: Thyroid Cancer
Thyroid Cancer
Thyroid Cancer
Published in: Cellular Oncology / Issue 5/2019
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-019-00457-9

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

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2019

Tumor-associated macrophages: role in cancer development and therapeutic implications

Stromal organization as predictive biomarker for the treatment of colon cancer with adjuvant bevacizumab; a post-hoc analysis of the AVANT trial

Predictors of ribociclib-mediated antitumour effects in native and sorafenib-resistant human hepatocellular carcinoma cells

Clinical and biological impact of miR-18a expression in breast cancer after neoadjuvant chemotherapy

Apatinib inhibits glycolysis by suppressing the VEGFR2/AKT1/SOX5/GLUT4 signaling pathway in ovarian cancer cells

The role of TNF-α in chordoma progression and inflammatory pathways

Keynote webinar | Spotlight on antibody–drug conjugates in cancer