nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

15.02.2019 | Original Article – Cancer Research

CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis

verfasst von: Zilong Yan, Kenoki Ohuchida, Biao Zheng, Takashi Okumura, Shin Takesue, Hiromichi Nakayama, Chika Iwamoto, Koji Shindo, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Takao Ohtsuka, Kazuhiro Mizumoto, Yoshinao Oda, Makoto Hashizume, Masafumi Nakamura

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 5/2019

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 186:1947–1955CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

Hitchcock IS, Kaushansky K (2014) Thrombopoietin from beginning to end. Br J Haematol 165:259–268. https://doi.org/10.1111/bjh.12772 CrossRefPubMed

Kaushansky K (2005) The molecular mechanisms that control thrombopoiesis. J Clin Invest 115:3339–3347. https://doi.org/10.1172/JCI26674 CrossRefPubMedPubMedCentral

Kaushansky K (2006) Lineage-specific hematopoietic growth factors. N Engl J Med 354:2034–2045. https://doi.org/10.1056/NEJMra052706 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRef

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

Qian BZ et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225. https://doi.org/10.1038/nature10138 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 94:1273PubMed

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 17:4991–5000CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

Sato N, Maehara N, Goggins M (2004) Gene expression profiling of tumor–stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 64:6950CrossRefPubMed

Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR (2000) Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14:2501–2514CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904. https://doi.org/10.1038/nm1469 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRef

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

Titel: CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis
verfasst von: Zilong Yan
Kenoki Ohuchida
Biao Zheng
Takashi Okumura
Shin Takesue
Hiromichi Nakayama
Chika Iwamoto
Koji Shindo
Taiki Moriyama
Kohei Nakata
Yoshihiro Miyasaka
Takao Ohtsuka
Kazuhiro Mizumoto
Yoshinao Oda
Makoto Hashizume
Masafumi Nakamura
Publikationsdatum: 15.02.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 5/2019
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-02860-z

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis