Abstract
Purpose
This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer.
Methods
We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin–CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model.
Results
CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK–MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model.
Conclusions
CD110 promotes pancreatic cancer progression and it may serve as a predictive factor for liver metastasis.
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References
Anderberg C et al (2013) Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210:563–579. https://doi.org/10.1084/jem.20120662
Bartley TD et al (1994) Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor. MpI Cell 77:1117–1124. https://doi.org/10.1016/0092-8674(94)90450-2
Besancenot R et al (2010) A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation PLoS Biol. https://doi.org/10.1371/journal.pbio.1000476
Besancenot R et al (2014) JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation. Blood 124:2104–2115. https://doi.org/10.1182/blood-2014-03-559815
Chabottaux V et al (2009) Membrane-type 4 matrix metalloproteinase (MT4-MMP) induces lung metastasis by alteration of primary breast tumour vascular architecture. J Cell Mol Med 13:4002–4013. https://doi.org/10.1111/j.1582-4934.2009.00764.x
Chanprasert S, Geddis AE, Barroga C, Fox NE, Kaushansky K (2006) Thrombopoietin (TPO) induces c-myc expression through a PI3K- and MAPK-dependent pathway that is not mediated by Akt, PKCzeta or mTOR in TPO-dependent cell lines and primary megakaryocytes. Cell Signal 18:1212–1218. https://doi.org/10.1016/j.cellsig.2005.09.010
Chijiiwa Y et al (2016) Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL. Int J Oncol 48:1688–1700. https://doi.org/10.3892/ijo.2016.3389
Choi C, Helfman DM (2014) The Ras-ERK pathway modulates cytoskeleton organization, cell motility and lung metastasis signature genes in MDA-MB-231. LM2 Oncogene 33:3668–3676. https://doi.org/10.1038/onc.2013.341
Dong-Feng Z, Ting L, Yong Z, Cheng C, Xi Z, Pei-Yan K (2014) The TPO/c-MPL pathway in the bone marrow may protect leukemia cells from chemotherapy in AML Patients. Pathol Oncol Res 20:309–317. https://doi.org/10.1007/s12253-013-9696-z
Dorsch M, Fan P-D, Danial NN, Rothman PB, Goff SP (1997) The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. J Exp Med 186:1947–1955
Elf S et al (2016) Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov 6:368–381. https://doi.org/10.1158/2159-8290.CD-15-1434
Engl T et al (2006) CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 8:290–301. https://doi.org/10.1593/neo.05694
Gao W, Chen L, Ma Z, Du Z, Zhao Z, Hu Z, Li Q (2013) Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential. Gastroenterology 145:636–646 e635. https://doi.org/10.1053/j.gastro.2013.05.049
Gleisner AL et al (2007) Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer 110:2484–2492. https://doi.org/10.1002/cncr.23074
Goetz JG et al (2011) Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146:148–163. https://doi.org/10.1016/j.cell.2011.05.040
Hayes TK et al (2016) Long-term ERK Inhibition in KRAS-mutant pancreatic cancer is associated with myc degradation and senescence-like growth suppression. Cancer Cell 29:75–89. https://doi.org/10.1016/j.ccell.2015.11.011
Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, Abbruzzese JL (2006) Metastatic patterns in adenocarcinoma. Cancer 106:1624–1633. https://doi.org/10.1002/cncr.21778
Hitchcock IS, Kaushansky K (2014) Thrombopoietin from beginning to end. Br J Haematol 165:259–268. https://doi.org/10.1111/bjh.12772
Kaushansky K (2005) The molecular mechanisms that control thrombopoiesis. J Clin Invest 115:3339–3347. https://doi.org/10.1172/JCI26674
Kaushansky K (2006) Lineage-specific hematopoietic growth factors. N Engl J Med 354:2034–2045. https://doi.org/10.1056/NEJMra052706
Kukreja P, Abdel-Mageed AB, Mondal D, Liu K, Agrawal KC (2005) Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. Cancer Res 65:9891–9898. https://doi.org/10.1158/0008-5472.CAN-05-1293
Lin WC et al (2013) Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer Res 73:1821–1830. https://doi.org/10.1158/0008-5472.CAN-12-2067
Lok S et al (1994) Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 369:565. https://doi.org/10.1038/369565a0
Moriyama T, Ohuchida K, Mizumoto K, Cui L, Ikenaga N, Sato N, Tanaka M (2010) Enhanced cell migration and invasion of CD133 + pancreatic cancer cells cocultured with pancreatic stromal cells. Cancer 116:3357–3368. https://doi.org/10.1002/cncr.25121
Morris EJ et al (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 3:742–750. https://doi.org/10.1158/2159-8290.CD-13-0070
Neyaz A et al (2018) Investigation of targetable predictive and prognostic markers in gallbladder carcinoma. J Gastrointest Oncol 9:111–125. https://doi.org/10.21037/jgo.2017.10.02
Noone AM, Cronin KA, Altekruse SF, Howlader N, Lewis DR, Petkov VI, Penberthy L (2017) Cancer incidence and survival trends by subtype using data from the surveillance epidemiology and end results program, 1992–2013. Cancer Epidemiol Biomark Prev 26:632–641. https://doi.org/10.1158/1055-9965.EPI-16-0520
Palomero T et al (2006) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 103:18261–18266. https://doi.org/10.1073/pnas.0606108103
Pikman Y et al (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3:e270. https://doi.org/10.1371/journal.pmed.0030270
Principe DR et al (2017) TGFbeta engages MEK/ERK to differentially regulate benign and malignant pancreas cell function. Oncogene 36:4336–4348. https://doi.org/10.1038/onc.2016.500
Qian BZ et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225. https://doi.org/10.1038/nature10138
Reymond N et al (2012) Cdc42 promotes transendothelial migration of cancer cells through beta1 integrin. J Cell Biol 199:653–668. https://doi.org/10.1083/jcb.201205169
Reymond N, d’Água BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870. https://doi.org/10.1038/nrc3628
Rojnuckarin P, Drachman JG, Kaushansky K (1999) Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood 94:1273
Rouyez MC, Boucheron C, Gisselbrecht S, Dusanter-Fourt I, Porteu F (1997) Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol 17:4991–5000
Roy LD et al (2011) MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30:1449–1459. https://doi.org/10.1038/onc.2010.526
Sakamoto A et al (2016) Live-cell single-molecule imaging of the cytokine receptor MPL for analysis of dynamic dimerization. J Mol Cell Biol 8:553–555. https://doi.org/10.1093/jmcb/mjw027
Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS (2014) The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood 124:3956–3963. https://doi.org/10.1182/blood-2014-07-587238
Sato N, Maehara N, Goggins M (2004) Gene expression profiling of tumor–stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 64:6950
Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR (2000) Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14:2501–2514
Sheng W et al (2017) Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway. Cell Death Dis 8:e3147. https://doi.org/10.1038/cddis.2017.547
Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904. https://doi.org/10.1038/nm1469
Stewart BW, Wild C, International Agency for Research on Cancer, World Health Organization (2014) World cancer report 2014. International Agency for Research on Cancer
Talmadge JE, Fidler IJ (2010) AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 70:5649–5669. https://doi.org/10.1158/0008-5472.CAN-10-1040
Tichet M et al (2015) Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nat Commun 6:6993. https://doi.org/10.1038/ncomms7993
Tsai WB, Aiba I, Long Y, Lin HK, Feun L, Savaraj N, Kuo MT (2012) Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. Cancer Res 72:2622–2633. https://doi.org/10.1158/0008-5472.CAN-11-3605
Vaseva AV et al (2018) KRAS suppression-induced degradation of MYC Is antagonized by a MEK5-ERK5 compensatory. Mech Cancer Cell 34:807–807+. https://doi.org/10.1016/j.ccell.2018.10.001
Wang X, Cunningham M, Zhang X, Tokarz S, Laraway B, Troxell M, Sears RC (2011) Phosphorylation regulates c-Myc’s oncogenic activity in the mammary gland. Cancer Res 71:925–936. https://doi.org/10.1158/0008-5472.CAN-10-1032
Wendel C, Hemping-Bovenkerk A, Krasnyanska J, Mees ST, Kochetkova M, Stoeppeler S, Haier J (2012) CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model. PLoS One 7:e30046. https://doi.org/10.1371/journal.pone.0030046
Weng AP et al (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20:2096–2109. https://doi.org/10.1101/gad.1450406
Wu Z et al (2015) TPO-induced metabolic reprogramming drives liver metastasis of colorectal cancer CD110 + tumor-initiating cells. Cell Stem Cell 17:47–59. https://doi.org/10.1016/j.stem.2015.05.016
Yamazaki H, Nishida H, Iwata S, Dang NH, Morimoto C (2009) CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells. Biochem Biophys Res Commun 383:172–177. https://doi.org/10.1016/j.bbrc.2009.03.127
Zabel BA et al (2009) Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol 183:3204–3211. https://doi.org/10.4049/jimmunol.0900269
Zheng B et al (2016) CD146 attenuation in cancer-associated fibroblasts promotes pancreatic cancer progression. Mol Carcinog 55:1560–1572. https://doi.org/10.1002/mc.22409
Acknowledgements
We are grateful to Emiko Manabe and Shoko Sadatomi (Department of Surgery and Oncology, Kyushu University) for skillful technical assistance. Zilong Yan is the recipient of Rotary Yoneyama Memorial Foundation scholarship [http://www.rotary-yoneyama.or.jp]. We thank Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript. This work was supported by JSPS KAKENHI (Grant number: 26108010, 26293305, 15K10185, 25713050, 16K15621, 16K10601, 16K10600, 16H05417, 15K15498, 15H04933, 16H05418, 17H04284, 17K19602 and 17K19605).
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Yan, Z., Ohuchida, K., Zheng, B. et al. CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis. J Cancer Res Clin Oncol 145, 1147–1164 (2019). https://doi.org/10.1007/s00432-019-02860-z
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DOI: https://doi.org/10.1007/s00432-019-02860-z