Journal of Molecular Medicine

, Volume 81, Issue 10, pp 600–612 | Cite as

Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis

Invited review

Abstract

Progranulin (Pgrn) is a pluripotent secreted growth factor that mediates cell cycle progression and cell motility. It activates the extracellular regulated kinases and phosphatidyl inositol-3 kinase signal cascades, among others, and increases expression of cyclins D and B. Structurally, it belongs to none of the well-established growth factor families. It regulates developmental events as diverse as the onset of cavitation in the preimplantation embryo and male-specific brain differentiation. During wound repair it promotes granulation and neovascularization. It regulates inflammation through a tripartite loop with secretory leukocyte protease inhibitor (SLPI) which protects pgrn from proteolysis, and elastase, which digests it to smaller peptides. Intact pgrn is anti-inflammatory through the inhibition of some of the actions of tumor necrosis factor, while the proteolytic peptides may stimulate the production of proinflammatory cytokines such as interleukin 8. Pgrn is highly expressed in aggressive cancer cell lines and clinical specimens including breast, ovarian, and renal cancers as well as gliomas. In experimental systems it confers an aggressive phenotype on poorly tumorigenic epithelial cancer cells. The malignancy of highly tumorigenic progranulin-expressing cell lines depends on the expression level of the pgrn gene since attenuating pgrn mRNA levels in pgrn-responsive cells greatly inhibits tumor progression. Given its actions in wound repair and tumorigenesis pgrn may prove a useful clinical target, both for prognosis and for therapy.

Keywords

Growth factor Tumorigenesis Wound repair Neovascularization Inflammation 

Abbreviations

EGF

Epidermal growth factor

FAK

Focal adhesion kinase

FGF

Fibroblast growth factor

grn/epi

Granulin-epithelin

IGF

Insulin-like growth factor

MAPK

Mitogen-activated protein kinase

MEF

Mouse embryo fibroblast

PDGF

Platelet-derived growth factor

Pgrn

Progranulin

PI-3K

Phosphatidylinositol-3 kinase

SLPI

Secretory leukocyte protease inhibitor

TGF-β

Transforming growth factor-β

TGFe

Epithelial transforming growth factor

TNF

Tumor necrosis factor

VEGF

Vascular endothelial growth factor

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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Vascular Cell Biology and Complications, Joslin Diabetes CenterHarvard Medical SchoolBostonUSA
  2. 2.Division of Experimental Medicine, McGill University, and Endocrine Research LaboratoryRoyal Victoria HospitalMontrealCanada

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