40 YEARS OF IGF1: PAPP-A and cancer

Conover, Cheryl A.; Oxvig, Claus

doi:10.1530/jme-17-0236

Cited by 47 publications

(30 citation statements)

References 74 publications

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“…PAPP-A plays an important role in various biological processes such as the normal healing response and healthy ovarian follicular development, and regulates prenatal or postnatal growth and skeletal muscle formation (39)(40)(41)(42). PAPP-A is also involved in pathogenesis of several disease and is a therapeutic target in diseases such as atherosclerosis and cancer, as well as age-related diseases (43)(44)(45)(46)(47)(48). Plasma PAPP-A has also been shown to correlate with renal function, been present at higher levels in patients on dialysis, and serve as an independent predictor of mortality of patients on hemodialysis (49)(50)(51).…”

Section: Papp-a Levels Increase With the Progression Of Cystic Diseasementioning

confidence: 99%

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Kashyap¹,

Hein²,

Chini³

et al. 2020

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Section: Papp-a Levels Increase With the Progression Of Cystic Diseasementioning

confidence: 99%

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Kashyap¹,

Hein²,

Chini³

et al. 2020

JCI Insight

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“…Papp-a2 knockout mice showed a modest decrease in body size (Christians et al, 2006;. These findings have led to the proposal that PAPP-A and PAPP-A2 promote somatic growth by increasing bioavailable IGFs (Oxvig, 2015;Fujimoto et al, 2017;Conover and Oxvig, 2018). This notion is further supported by recent clinical studies showing that human patients carrying inactivating mutations in the PAPP-A2 gene showed progressive growth failure (Dauber et al, 2016;Fujimoto et al, 2017).…”

Section: Introductionmentioning

confidence: 94%

“…Pregnancy-associated plasma protein-a (PAPP-A) and PAPP-A2 belong to the conserved pappalysin protein family Oxvig, 2015;Conover and Oxvig, 2018). PAPP-A was first discovered in the plasma of pregnant women in the 1970s.…”

Section: Introductionmentioning

confidence: 99%

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The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

Liu

Noer

et al. 2019

Preprint

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Human patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca 2+ ]dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca 2+transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca 2+ ] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Pappaa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca 2+ ]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.

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“…A number of genes were more highly expressed in the stroma of ILC, but not that of IDC or normal breast. These genes included PAPPA encoding pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) when IGF-1 is bound to IGFBP-4 [13]. This results in a local increase in IGF-1 bioavailability and subsequent downstream signaling.…”

Section: Introductionmentioning

confidence: 99%

Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A

Gómez-Cuadrado

Zhao

Souleimanova

et al. 2020

Preprint

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Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer and exhibits a number of clinico-pathological characteristics that are distinct from the more common invasive ductal carcinoma (IDC). Despite these differences, ILC is treated in the same way as IDC. We set out to identify alterations in the tumor microenvironment (TME) of ILC with potential clinical significance. Methods:We used laser-capture microdissection (LCM) to separate tumor epithelium from stroma in 23 ER+ ILC samples. Gene expression analysis was used to identify genes that are enriched in the stroma of ILC, but not IDC or normal breast.Results: 45 genes involved in regulation of the extracellular matrix (ECM) were enriched in the stroma of ILC, but not stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets. PAPPA was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. PAPPA encodes pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves insulin-like binding protein-4 (IGFBP-4) increasing IGF-1 bioavailability and subsequent downstream signaling. Analysis of PAPPA and IGF1 associated genes identified a paracrine signaling pathway and active PAPP-A was shown to be secreted from primary CAFs. Comprehensive survival analysis across 3000 breast cancers identified PAPPA as a potential ILC-specific prognostic marker.Conclusions: This is the first study to demonstrate molecular differences in the TME between ILC and IDC and identifies PAPP-A, a CAF-derived proteinase, as a potential prognostic marker.

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40 YEARS OF IGF1: PAPP-A and cancer

Cited by 47 publications

References 74 publications

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

Identification of stromal genes differentially expressed in lobular breast cancer highlights role for pregnancy-associated-plasma protein-A

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