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Open AccessReview

Nephronectin as a Matrix Effector in Cancer

1
Department of Medical Biology, Faculty of Health Sciences, UiT—The Arctic University of Norway, 9037 Tromsø, Norway
2
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway
3
Cancer Clinic, St. Olavs Hospital HF, 7006 Trondheim, Norway
4
The Public Dental Health Service Competence Center of Northern Norway, 9271 Tromsø, Norway
*
Author to whom correspondence should be addressed.
Academic Editors: Nikos Karamanos and Zoi Piperigkou
Cancers 2021, 13(5), 959; https://doi.org/10.3390/cancers13050959
Received: 31 January 2021 / Revised: 21 February 2021 / Accepted: 22 February 2021 / Published: 25 February 2021
(This article belongs to the Special Issue Matrix Effectors and Cancer)
The extracellular matrix provides an important scaffold for cells and tissues of multicellular organisms. The scaffold not only provides a secure anchorage point, but also functions as a reservoir for signalling molecules, sequestered and released when necessary. A dysregulated extracellular matrix may therefore modulate cellular behaviour, as seen during cancer progression. The extracellular matrix protein nephronectin was discovered two decades ago and found to regulate important embryonic developmental processes. Loss of either nephronectin or its receptor, integrin α8β1, leads to underdeveloped kidneys. Recent findings show that nephronectin is also dysregulated in breast cancer and plays a role in promoting metastasis. To enable therapeutic intervention, it is important to fully understand the role of nephronectin and its receptors in cancer progression. In this review, we summarise the literature on nephronectin, analyse the structure and domain-related functions of nephronectin and link these functions to potential roles in cancer progression.
The extracellular matrix protein nephronectin plays an important regulatory role during embryonic development, controlling renal organogenesis through integrin α8β1 association. Nephronectin has three main domains: five N-terminal epidermal growth factor-like domains, a linker region harbouring two integrin-binding motifs (RGD and LFEIFEIER), and a C-terminal MAM domain. In this review, we look into the domain-related functions of nephronectin, and tissue distribution and expression. During the last two decades it has become evident that nephronectin also plays a role during cancer progression and in particular metastasis. Nephronectin is overexpressed in both human and mouse breast cancer compared to normal breast tissue where the protein is absent. Cancer cells expressing elevated levels of nephronectin acquire increased ability to colonise distant organs. In particular, the enhancer-motif (LFEIFEIER) which is specific to the integrin α8β1 association induces viability via p38 MAPK and plays a role in colonization. Integrins have long been desired as therapeutic targets, where low efficiency and receptor redundancy have been major issues. Based on the summarised publications, the enhancer-motif of nephronectin could present a novel therapeutic target. View Full-Text
Keywords: nephronectin; cancer; breast cancer; extracellular matrix; metastasis; cancer progression nephronectin; cancer; breast cancer; extracellular matrix; metastasis; cancer progression
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MDPI and ACS Style

Magnussen, S.N.; Toraskar, J.; Hadler-Olsen, E.; Steigedal, T.S.; Svineng, G. Nephronectin as a Matrix Effector in Cancer. Cancers 2021, 13, 959. https://doi.org/10.3390/cancers13050959

AMA Style

Magnussen SN, Toraskar J, Hadler-Olsen E, Steigedal TS, Svineng G. Nephronectin as a Matrix Effector in Cancer. Cancers. 2021; 13(5):959. https://doi.org/10.3390/cancers13050959

Chicago/Turabian Style

Magnussen, Synnøve N.; Toraskar, Jimita; Hadler-Olsen, Elin; Steigedal, Tonje S.; Svineng, Gunbjørg. 2021. "Nephronectin as a Matrix Effector in Cancer" Cancers 13, no. 5: 959. https://doi.org/10.3390/cancers13050959

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