EGF-mediated EGFR/ERK Signaling Pathway Promotes Germinative Cell Proliferation in Echinococcus Multilocularis That Contributes to Larval Growth and Development

Overview

Journal PLoS Negl Trop Dis

Specialties Infectious Diseases
Tropical Medicine

Date 2017 Feb 28

PMID 28241017

Citations 30

Authors

Zhe Cheng

Fan Liu

Xiu Li

Mengya Dai

Jianjian Wu

Xinrui Guo

Huimin Tian

Zhijie Heng

Ying Lu

Xiaoli Chai

Yanhai Wang

Affiliations

Soon will be listed here.

Abstract

Background: Larvae of the tapeworm E. multilocularis cause alveolar echinococcosis (AE), one of the most lethal helminthic infections in humans. A population of stem cell-like cells, the germinative cells, is considered to drive the larval growth and development within the host. The molecular mechanisms controlling the behavior of germinative cells are largely unknown.

Methodology/principal Findings: Using in vitro cultivation systems we show here that the EGFR/ERK signaling in the parasite can promote germinative cell proliferation in response to addition of human EGF, resulting in stimulated growth and development of the metacestode larvae. Inhibition of the signaling by either the EGFR inhibitors CI-1033 and BIBW2992 or the MEK/ERK inhibitor U0126 impairs germinative cell proliferation and larval growth.

Conclusions/significance: These data demonstrate the contribution of EGF-mediated EGFR/ERK signaling to the regulation of germinative cells in E. multilocularis, and suggest the EGFR/ERK signaling as a potential therapeutic target for AE and perhaps other human cestodiasis.

Citing Articles

Investigation of the threonine metabolism of Echinococcus multilocularis: The threonine dehydrogenase as a potential drug target in alveolar echinococcosis.

Kaethner M, Zumstein P, Muller J, Preza M, Grossenbacher P, Bartetzko A Int J Parasitol Drugs Drug Resist. 2025; 27:100581.

PMID: 39847910 PMC: 11795093. DOI: 10.1016/j.ijpddr.2025.100581.

Purification and transcriptomic characterization of proliferative cells of selectively affected by irradiation.

Costabile A, Dominguez M, Guarnaschelli I, Preza M, Koziol U, Castillo E Front Parasitol. 2025; 3():1362199.

PMID: 39817174 PMC: 11732142. DOI: 10.3389/fpara.2024.1362199.

Ghrelin is involved in regulating the progression of Echinococcus Granulosus-infected liver lesions through suppression of immunoinflammation and fibrosis.

Zhu J, Zhao H, Aierken A, Zhou T, Menggen M, Gao H PLoS Negl Trop Dis. 2024; 18(10):e0012587.

PMID: 39436864 PMC: 11495594. DOI: 10.1371/journal.pntd.0012587.

Receptor Tyrosine Kinase Signaling Involves -Host Intercommunication: A Potential Therapeutic Target in Hepatic Echinococcosis.

Gao H, Bianba Z, Mo X, Hu W, Feng Z, Zhou F Trop Med Infect Dis. 2024; 9(8).

PMID: 39195613 PMC: 11360685. DOI: 10.3390/tropicalmed9080175.

HB-EGF activates EGFR to induce reactive neural stem cells in the mouse hippocampus after seizures.

Pastor-Alonso O, Dura I, Bernardo-Castro S, Varea E, Muro-Garcia T, Martin-Suarez S Life Sci Alliance. 2024; 7(9).

PMID: 38977310 PMC: 11231495. DOI: 10.26508/lsa.202201840.

References

Sun Y, Chen C, Fu J . Forcing stem cells to behave: a biophysical perspective of the cellular microenvironment. Annu Rev Biophys. 2012; 41:519-42. PMC: 4123632. DOI: 10.1146/annurev-biophys-042910-155306. View

Castanieto A, Johnston M, Nystul T . EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells. Elife. 2014; 3. PMC: 4298699. DOI: 10.7554/eLife.04437. View

Taylor C, Martin J, Rao R, Powell K, Abubucker S, Mitreva M . Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases. PLoS Pathog. 2013; 9(2):e1003149. PMC: 3573124. DOI: 10.1371/journal.ppat.1003149. View

Hemer S, Brehm K . In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae. Int J Antimicrob Agents. 2012; 40(5):458-62. DOI: 10.1016/j.ijantimicag.2012.07.007. View

Spiliotis M, Kroner A, Brehm K . Identification, molecular characterization and expression of the gene encoding the epidermal growth factor receptor orthologue from the fox-tapeworm Echinococcus multilocularis. Gene. 2003; 323:57-65. DOI: 10.1016/j.gene.2003.09.007. View

Eckert J, Deplazes P . Biological, epidemiological, and clinical aspects of echinococcosis, a zoonosis of increasing concern. Clin Microbiol Rev. 2004; 17(1):107-35. PMC: 321468. DOI: 10.1128/CMR.17.1.107-135.2004. View

Brehm K, Koziol U . On the importance of targeting parasite stem cells in anti-echinococcosis drug development. Parasite. 2014; 21:72. PMC: 4271656. DOI: 10.1051/parasite/2014070. View

Wagner D, Wang I, Reddien P . Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration. Science. 2011; 332(6031):811-6. PMC: 3338249. DOI: 10.1126/science.1203983. View

Rink J . Stem cell systems and regeneration in planaria. Dev Genes Evol. 2012; 223(1-2):67-84. PMC: 3552358. DOI: 10.1007/s00427-012-0426-4. View

10.

Ladurner P, Rieger R, Baguna J . Spatial distribution and differentiation potential of stem cells in hatchlings and adults in the marine platyhelminth macrostomum sp.: a bromodeoxyuridine analysis. Dev Biol. 2000; 226(2):231-41. DOI: 10.1006/dbio.2000.9867. View

11.

Brehm K . The role of evolutionarily conserved signalling systems in Echinococcus multilocularis development and host-parasite interaction. Med Microbiol Immunol. 2010; 199(3):247-59. DOI: 10.1007/s00430-010-0154-1. View

12.

Hemer S, Konrad C, Spiliotis M, Koziol U, Schaack D, Forster S . Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development. BMC Biol. 2014; 12:5. PMC: 3923246. DOI: 10.1186/1741-7007-12-5. View

13.

Pellettieri J, Sanchez Alvarado A . Cell turnover and adult tissue homeostasis: from humans to planarians. Annu Rev Genet. 2007; 41:83-105. DOI: 10.1146/annurev.genet.41.110306.130244. View

14.

Cheng Z, Liu F, Zhu S, Tian H, Wang L, Wang Y . A rapid and convenient method for fluorescence analysis of in vitro cultivated metacestode vesicles from Echinococcus multilocularis. PLoS One. 2015; 10(2):e0118215. PMC: 4337908. DOI: 10.1371/journal.pone.0118215. View

15.

Brehm K, Spiliotis M . Recent advances in the in vitro cultivation and genetic manipulation of Echinococcus multilocularis metacestodes and germinal cells. Exp Parasitol. 2008; 119(4):506-515. DOI: 10.1016/j.exppara.2008.03.007. View

16.

Sanchez Alvarado A, Newmark P, Robb S, Juste R . The Schmidtea mediterranea database as a molecular resource for studying platyhelminthes, stem cells and regeneration. Development. 2002; 129(24):5659-65. DOI: 10.1242/dev.00167. View

17.

Schubert A, Koziol U, Cailliau K, Vanderstraete M, Dissous C, Brehm K . Targeting Echinococcus multilocularis stem cells by inhibition of the Polo-like kinase EmPlk1. PLoS Negl Trop Dis. 2014; 8(6):e2870. PMC: 4046951. DOI: 10.1371/journal.pntd.0002870. View

18.

Morrison S, Spradling A . Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008; 132(4):598-611. PMC: 4505728. DOI: 10.1016/j.cell.2008.01.038. View

19.

Vicogne J, Cailliau K, Tulasne D, Browaeys E, Yan Y, Fafeur V . Conservation of epidermal growth factor receptor function in the human parasitic helminth Schistosoma mansoni. J Biol Chem. 2004; 279(36):37407-14. DOI: 10.1074/jbc.M313738200. View

20.

Hackett J, Surani M . Regulatory principles of pluripotency: from the ground state up. Cell Stem Cell. 2014; 15(4):416-430. DOI: 10.1016/j.stem.2014.09.015. View