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  • Review Article
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The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential

Key Points

  • PEDF is a member of the serpin superfamily that has many functions that often act in opposition to mechanisms that drive cancer progression.

  • Tumour progression is associated with reduced levels of PEDF in tumours. Exogenous administration of PEDF to bolster the declining intratumoural levels of PEDF during tumour progression results in the inhibition of tumour growth and prolonged organismal survival in various animal models.

  • PEDF can act directly on tumours to induce differentiation to a less-malignant phenotype, promote apoptotic tumour cell death and inhibit the proliferation of tumour cells.

  • Numerous studies in various models have shown the anti-angiogenic effects that PEDF has on tumours. PEDF is a potent inhibitor of angiogenesis through pro-apoptotic effects on endothelial cells. It can also inhibit endothelial cell migration, endothelial tube formation, vessel sprouting and intratumoural neovascularization, and can decrease the levels of pro-angiogenic factors.

  • Support for its anticancer role also comes from the findings that PEDF exhibits strong antimetastatic activity by suppressing tumour cell invasion and migration; these effects have been described in vitro and in several metastasis models in vivo.

  • The molecular mechanisms by which PEDF functions to regulate tumour and endothelial cell behaviour are based mostly on its interactions with different cell-surface receptors and their downstream signalling pathways.

  • PEDF abundance and activities are regulated both by extrinsic microenvironment-altering effectors (such as hormones, vitamins, oxygenation or extracellular matrix (ECM) composition), as well as by molecular drivers that alter its intrinsic properties (such as post-translational modifications).

  • Numerous reports have provided evidence in support of the use of PEDF as a prognostic factor in cancer management. PEDF-positive expression is described as an independent favourable prognostic factor for cancer.

Abstract

The potent actions of pigment epithelium-derived factor (PEDF) on tumour-associated cells, and its extracellular localization and secretion, stimulated research on this multifunctional serpin. Such studies have identified several PEDF receptors and downstream signalling pathways. Known cellular PEDF responses have expanded from the initial discovery that PEDF induces retinoblastoma cell differentiation to its anti-angiogenic, antitumorigenic and antimetastatic properties. Although the diversity of PEDF activities seems to be complex, they are consistent with the varied mechanisms that regulate this multimodal factor. If PEDF is to be used for cancer management, a deeper appreciation of its many functions and mechanisms of action is needed.

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Figure 1: PEDF in tumour cells.
Figure 2: Signalling events of PEDF in endothelial cells.
Figure 3: The effects of PEDF on tumour progression.

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Acknowledgements

This work was supported in part by the intramural research program of the US National Institutes of Health (NIH) (Project number 1ZIA-EY000306) to S.P.B. and by grant R01-CA134727 from the US National Cancer Institute (NCI) to V.N.

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Correspondence to S. Patricia Becerra.

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S.P.B. is an inventor of PEDF-related patents assigned by the US government.

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Stokes radius

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(IPM). This fills the part of the eye referred to by ophthalmologists as the subretinal space. It is located between the outer limiting membrane of the retina and the apical border of the retinal pigment epithelium, where it surrounds the photoreceptor inner and outer segments that project from the outer retinal surface.

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Neovascularization

In ophthalmology, choroidal, retinal or corneal neovascularization refers to the proliferation of blood vessels and the formation of a microvasculature within the innermost layer of the choroid of the eye, inner retina or cornea, respectively.

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An area of tissue in the eye that is located around the base of the cornea, near the ciliary body, and is responsible for draining the aqueous humour from the eye through the chamber at the front of the eye covered by the cornea.

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Becerra, S., Notario, V. The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential. Nat Rev Cancer 13, 258–271 (2013). https://doi.org/10.1038/nrc3484

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