Journal of Shanghai Jiao Tong University (Medical Science) >

2022 , Vol. 42 >Issue 9: 1225 - 1238

DOI: https://doi.org/10.3969/j.issn.1674-8115.2022.09.009

Innovative research team achievement column

Role of human pleiotrophin in the metastasis of malignant peripheral nerve sheath tumor

  • Xiwei CUI ,
  • Manhon CHUNG ,
  • Rehanguli AIMAIER ,
  • Zhichao WANG ,
  • Qingfeng LI
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  • Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
LI Qingfeng, E-mail: dr.liqingfeng@shsmu.edu.cn.

Received date: 2022-03-11

  Accepted date: 2022-07-27

  Online published: 2022-08-05

Supported by

National Natural Science Foundation of China(82172228);Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20210400);Biobank Project of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine(YBKA201901)

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Abstract

Objective ·To investigate the role of pleiotrophin (PTN) in the proliferation, migration and invasion of malignant peripheral nerve sheath tumor (MPNST). Methods ·The expression of PTN was verified by immunochemistry and bioinformatics analysis. By lentivirus transfection, the PTN-overexpressing and the PTN-knocked-down MPNST cell lines were established. To validate the role of PTN in MPNST migration and invasion, cell wound healing assay and Transwell migration/invasion assays were performed in boththe PTN-overexpressing MPNST cells and the PTN-knocked-down cells. By CCK8 assay, EdU assay and colony formation assay, the effects of PTN on the proliferation and the colony formation capabilities were evaluated. The pathway expression pattern regulated by PTN was validated by Western blotting and high-throughput transcriptome sequencing. To identify the biological function of PTN in vivo, an MPNST lung metastatic model in Balb/c nude mice was established. By mouse tail intravenous injection technique, PTN-knocked-down MPNST cells (experimental group) and negative control cells (control group) were injected into Balb/c nude mice, respectively. Results ·According to the immunochemistry staining results of the MPNST tissue samples from 49 patients and the normal nerve tissue samples from 3 non-MPNST people, PTN was significantly down-regulated in the MPNST tissues. In cell wound healing assay and Transwell migration/invasion assay, knocking down PTN significantly enhanced the migration and invasion capabilities of MPNST cells, while PTN overexpression inhibited them. The results of CCK8 assay, EdU assay and colony formation assay indicated that PTN overexpression hindered the proliferation of MPNST cells while colony formation was barely impacted; no significant differences in these assays were detected in the PTN-knocked-down cells. According to Western blotting assay, PTN overexpression activated mitogen activated protein kinase (MAPK) pathway while knocking down PTN showed mild influence. Transcriptome high-throughput sequencing showed that the expression levels of the genes related with programmed cell death pathway changed in the PTN-overexpressing cells. In the in vivo experiments, there was no significant difference in the tumor formation rate; however, the quantity and the volume of lung metastasis lesions were both larger in the experimental group. The most mice in the experimental group were diagnosed with severe pulmonary interstitial disease, and their growth rate of body mass also decreased. Conclusion ·PTN is down-regulated in the MPNST tissue and overexpressing PTN inhibites proliferation, migration and invasion of the MPNST cells in vitro. The ability of PTN-knocked-down MPNST cells to metastasize to the lungs in mice is enhanced.

Key words： malignant peripheral nerve sheath tumor (MPNST); pleiotrophin (PTN); tumor metastasis; neurofibromatosis type 1; plexiform neurofibroma

Cite this article

Xiwei CUI , Manhon CHUNG , Rehanguli AIMAIER , Zhichao WANG , Qingfeng LI . Role of human pleiotrophin in the metastasis of malignant peripheral nerve sheath tumor[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022 , 42(9) : 1225 -1238 . DOI: 10.3969/j.issn.1674-8115.2022.09.009

References

1 MOWERY A, CLAYBURGH D. Malignant peripheral nerve sheath tumors: analysis of the national cancer database[J]. Oral Oncol, 2019, 98: 13-19.
2 EVANS D G R, BASER M E, MCGAUGHRAN J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1[J]. J Med Genet, 2002, 39(5): 311-314.
3 FERNER R E, GUTMANN D H. International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis[J]. Cancer Res, 2002, 62(5): 1573-1577.
4 ZHOU H, COFFIN C M, PERKINS S L, et al. Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions[J]. Am J Surg Pathol, 2003, 27(10): 1337-1345.
5 KOCHAT V, RAMAN A T, LANDERS S M, et al. Enhancer reprogramming in PRC2-deficient malignant peripheral nerve sheath tumors induces a targetable de-differentiated state[J]. Acta Neuropathol, 2021, 142(3): 565-590.
6 PEACOCK J D, PRIDGEON M G, TOVAR E A, et al. Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors[J]. Cancer Res, 2018, 78(13): 3672-3687.
7 HIGHAM C S, DOMBI E, ROGIERS A, et al. The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors[J]. Neuro Oncol, 2018, 20(6): 818-825.
8 FARID M, DEMICCO E G, GARCIA R, et al. Malignant peripheral nerve sheath tumors[J]. Oncologist, 2014, 19(2): 193-201.
9 XU Y, XU G J, LIU Z, et al. Incidence and prognosis of distant metastasis in malignant peripheral nerve sheath tumors[J]. Acta Neurochir (Wien), 2021, 163(2): 521-529.
10 KOLBERG M, H?LAND M, AGESEN T H, et al. Survival meta-analyses for >1 800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1[J]. Neuro Oncol, 2013, 15(2): 135-147.
11 HIRBE A C, COSPER P F, DAHIYA S, et al. Neoadjuvant ifosfamide and epirubicin in the treatment of malignant peripheral nerve sheath tumors[J]. Sarcoma, 2017, 2017: 3761292.
12 PASQUALI S, GRONCHI A. Neoadjuvant chemotherapy in soft tissue sarcomas: latest evidence and clinical implications[J]. Ther Adv Med Oncol, 2017, 9(6): 415-429.
13 MURAMATSU T. Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis[J]. J Biochem, 2002, 132(3): 359-371.
14 BLONDET B, CARPENTIER G, LAFDIL F, et al. Pleiotrophin cellular localization in nerve regeneration after peripheral nerve injury[J]. J Histochem Cytochem, 2005, 53(8): 971-977.
15 BERTRAM S, ROLL L, REINHARD J, et al. Pleiotrophin increases neurite length and number of spiral ganglion neurons in vitro[J]. Exp Brain Res, 2019, 237(11): 2983-2993.
16 FERNáNDEZ-CALLE R, VICENTE-RODRíGUEZ M, GRAMAGE E, et al. Pleiotrophin regulates microglia-mediated neuroinflammation[J]. J Neuroinflammation, 2017, 14(1): 46.
17 GONZáLEZ-CASTILLO C, ORTU?O-SAHAGúN D, GUZMáN-BRAMBILA C, et al. Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus[J]. Front Cell Neurosci, 2015, 8: 443.
18 HERRADóN G, PéREZ-GARCíA C. Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: recent progress and perspectives[J]. Br J Pharmacol, 2014, 171(4): 837-848.
19 SHI Y, PING Y F, ZHOU W C, et al. Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth[J]. Nat Commun, 2017, 8: 15080.
20 WEI X, YANG S N, PU X, et al. Tumor-associated macrophages increase the proportion of cancer stem cells in lymphoma by secreting pleiotrophin[J]. Am J Transl Res, 2019, 11(10): 6393-6402.
21 ZHANG L, KUNDU S M, FEENSTRA T, et al. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas[J]. Sci Signal, 2015, 8(406): ra125.
22 YAO J, HU X F, FENG X S, et al. Pleiotrophin promotes perineural invasion in pancreatic cancer[J]. World J Gastroenterol, 2013, 19(39): 6555-6558.
23 ULBRICHT U, BROCKMANN M A, AIGNER A, et al. Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas[J]. J Neuropathol Exp Neurol, 2003, 62(12): 1265-1275.
24 CHEN H M, GORDON M S, CAMPBELL R A, et al. Pleiotrophin is highly expressed by myeloma cells and promotes myeloma tumor growth[J]. Blood, 2007, 110(1): 287-295.
25 CHOUDHURI R, ZHANG H T, DONNINI S, et al. An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis[J]. Cancer Res, 1997, 57(9): 1814-1819.
26 GRZELINSKI M, STEINBERG F, MARTENS T, et al. Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK[J]. Neoplasia, 2009, 11(2): 145-156.
27 LI F Q, TIAN F, WANG L, et al. Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN?γ/JAK/STAT1 signaling is critical for the expression of PTN in macrophages[J]. FASEB J, 2010, 24(3): 810-822.
28 FERNáNDEZ-CALLE R, VICENTE-RODRíGUEZ M, PASTOR M, et al. Pharmacological inhibition of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) modulates behavioral responses to ethanol[J]. Neuropharmacology, 2018, 137: 86-95.
29 HIMBURG H A, YAN X, DOAN P L, et al. Pleiotrophin mediates hematopoietic regeneration via activation of RAS[J]. J Clin Invest, 2014, 124(11): 4753-4758.
30 HERRADON G, RAMOS-ALVAREZ M P, GRAMAGE E. Connecting metainflammation and neuroinflammation through the PTN-MK-RPTPβ/ζ axis: relevance in therapeutic development[J]. Front Pharmacol, 2019, 10: 377.
31 WIDEMANN B C, ITALIANO A. Biology and management of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and malignant peripheral nerve sheath tumors: state of the art and perspectives[J]. J Clin Oncol, 2018, 36(2): 160-167.
32 KROEP J R, OUALI M, GELDERBLOM H, et al. First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: an EORTC soft tissue and bone sarcoma group study[J]. Ann Oncol, 2011, 22(1): 207-214.
33 MIAO R Y, WANG H T, JACOBSON A, et al. Radiation-induced and neurofibromatosis-associated malignant peripheral nerve sheath tumors (MPNST) have worse outcomes than sporadic MPNST[J]. Radiother Oncol, 2019, 137: 61-70.
34 KADOMATSU K, KISHIDA S, TSUBOTA S. The heparin-binding growth factor midkine: the biological activities and candidate receptors[J]. J Biochem, 2013, 153(6): 511-521.
35 MITSIADIS T A, SALMIVIRTA M, MURAMATSU T, et al. Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis[J]. Development, 1995, 121(1): 37-51.
36 MURAMATSU T. Structure and function of midkine as the basis of its pharmacological effects[J]. Br J Pharmacol, 2014, 171(4): 814-826.
37 MASHOUR G A, RATNER N, KHAN G A, et al. The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells[J]. Oncogene, 2001, 20(1): 97-105.
38 MASHOUR G A, WANG H L, CABAL-MANZANO R, et al. Aberrant cutaneous expression of the angiogenic factor midkine is associated with neurofibromatosis type-1[J]. J Invest Dermatol, 1999, 113(3): 398-402.
39 FRIEDRICH C, HOLTKAMP N, CINATL J, et al. Overexpression of midkine in malignant peripheral nerve sheath tumor cells inhibits apoptosis and increases angiogenic potency[J]. Int J Oncol, 2005, 27(5): 1433-1440.
40 LEMBERG K M, WANG J W, PRATILAS C A. From genes to-omics: the evolving molecular landscape of malignant peripheral nerve sheath tumor[J]. Genes, 2020, 11(6): 691.
41 MARTIN E, ACEM I, GRüNHAGEN D J, et al. Prognostic significance of immunohistochemical markers and genetic alterations in malignant peripheral nerve sheath tumors: a systematic review[J]. Front Oncol, 2020, 10: 594069.
42 WANG W P, CHEN J X, LIAO R, et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence[J]. Mol Cell Biol, 2002, 22(10): 3389-3403.
43 KYJACOVA L, SAUP R, R?NSCH K, et al. IER2-induced senescence drives melanoma invasion through osteopontin[J]. Oncogene, 2021, 40(47): 6494-6512.
44 FERBEYRE G, DE STANCHINA E, LIN A W, et al. Oncogenic ras and p53 cooperate to induce cellular senescence[J]. Mol Cell Biol, 2002, 22(10): 3497-3508.
45 ZHU J, WOODS D, MCMAHON M, et al. Senescence of human fibroblasts induced by oncogenic Raf[J]. Genes Dev, 1998, 12(19): 2997-3007.
46 REN J Y, GU Y H, CUI X W, et al. Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in malignant peripheral nerve sheath tumor via profilin 1-induced epithelial-mesenchymal transition[J]. Front Cell Dev Biol, 2020, 8: 582220.
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