Relationship Between Pregnancy-Associated Plasma Protein-A and Lung Cancer

Bulut, İsmet; Coşkun, Abdurrahman; Çiftçi, Abdullah; Çetınkaya, Erdoğan; Altıay, Gündeniz; Tunçay, Çağlar; Gülcan, Erim

doi:10.1097/maj.0b013e31818967a3

Cited by 49 publications

(46 citation statements)

References 24 publications

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“…Recently, the level of circulating PAPP-A was found to be increased in patients with lung cancer [29]. We therefore screened a panel of human lung cancer derived cells (Table 1), and picked the adenocarcinoma cell line, A549, as a model for PAPP-A-mediated stimulation of the IGF receptor based on its high level of PAPP-A secretion.…”

Section: Resultsmentioning

confidence: 99%

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Indirect targeting of IGF receptor signalingin vivoby substrate-selective inhibition of PAPP-A proteolytic activity

Mikkelsen

Resch

Kalra³

et al. 2014

Oncotarget

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The insulin-like growth factor (IGF) signaling pathway is involved in certain human cancers, and the feasibility of directly targeting the IGF receptor has been actively investigated. However, recent evidence from clinical trials suggests that this approach can be problematic. We have developed an alternative strategy to indirectly inhibit the IGF signaling by targeting the metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). PAPP-A associated with the cell surface cleaves IGF binding protein-4 (IGFBP-4), when IGF is bound to IGFBP-4, and thereby increases IGF bioavailability for receptor activation in an autocrine/paracrine manner. We hypothesized that inhibition of PAPP-A would suppress excessive local IGF signaling in tissues where this is caused by increased PAPP-A proteolytic activity. To test this hypothesis, we developed an inhibitory monoclonal antibody, mAb 1/41, which targets a unique substrate-binding exosite of PAPP-A. This inhibitor selectively and specifically inhibits proteolytic cleavage of IGFBP-4 with an inhibitory constant (Ki) of 135 pM. In addition, it inhibited intracellular signaling of the IGF receptor (AKT phosphorylation) in monolayers of A549 cells, an IGF-responsive lung cancer-derived cell line found to express high levels of PAPP-A. We further showed that mAb 1/41 is effective towards PAPP-A bound to cell surfaces, and that it is capable of inhibiting PAPP-A activity in vivo. Using a murine xenograft model of A549 cells, we demonstrated that mAb 1/41 administered intraperitoneally significantly inhibited tumor growth. Analysis of xenograft tumor tissue recovered from treated mice showed penetration of mAb 1/41, reduced IGFBP-4 proteolysis, and reduced AKT phosphorylation. Our study provides proof of concept that IGF signaling can be selectively reduced by targeting a regulatory proteinase that functions extracellularly, upstream of the IGF receptor. PAPP-A targeting thus represents an alternative therapeutic strategy for inhibiting IGF receptor signaling.

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Section: Resultsmentioning

confidence: 99%

“…These include ovarian cancer, renal cancer, mammary cancer, gastric cancer, lung cancer, and pleural mesothelioma [29, 32-41]. Furthermore, studies in mice have shown that PAPP-A transcription is activated by mutant p53 [42], and, of particular interest, PAPP-A null mice have a markedly reduced incidence of spontaneous cancers of age [43].…”

Section: Discussionmentioning

confidence: 99%

Indirect targeting of IGF receptor signalingin vivoby substrate-selective inhibition of PAPP-A proteolytic activity

Mikkelsen

Resch

Kalra³

et al. 2014

Oncotarget

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“…Our results indicate that the individual prognostic validity of PAPP-A levels in ACS can be verified not earlier than 12 h after UFH application (Table II), if the ACT control levels are in the normal range and if other clinical complications, including tumours, are excluded [12]. It is necessary to consider also individual variation in pharmacogenetic inactivation of UFH/LMWH.…”

Section: Discussionmentioning

confidence: 95%

Influence of concomitant heparin administration on pregnancy-associated plasma protein-A levels in acute coronary syndrome with ST segment elevation

Hájek

Maçek²,

Lashkevich³

et al. 2011

aoms

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IntroductionThe time course of pregnancy-associated plasma protein-A (PAPP-A) levels was studied at admission, immediately after percutaneous coronary intervention (PCI) and 1, 2, 4, 6, 12, 24 and 48 h after PCI in acute coronary syndrome with ST segment elevation (ACS-STE) to determine the impact of PCI, concomitant clinical complications and heparin administration.Material and methodsPregnancy-associated plasma protein-A serum levels, examined by the KryptorTM system, were studied in 30 heparinized PCI ACS-STE patients, in 10 elective PCIs and 12 coronary angiographies with heparin, and in 5 patients with normal coronary angiogram without heparin.ResultsHeparin caused a high PAPP-A increase in ACS-STE patients, in all patients with heparin without ACS and angiographic signs of significant atherosclerosis. This increase was directly associated with heparin dosage and activated clotting time (ACT) (r = 0.71, p = 0.0001) and inversely with the interval between heparin applications and time of serum sampling. It was followed by a rapid decrease within 1 to 2 h and return to normal levels in 10 to 12 h. In ACS-STE patients the decrease was significantly slower than in heparinized elective PCI and angiography patients. The PAPP-A increase was not significantly dependent on the length of PCI. Persistent increase after 24 h was associated in 4/7 patients with concomitant clinical complications.ConclusionsThe diagnostic validity of PAPP-A can be verified only within the 1st h after clinical onset of ACS before heparin administration, the prognostic value in heparinized patients not earlier than 12 h after the last heparin application, if ACT is normal and serious clinical concomitant complications are eliminated.

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“…However, very little is known about PAPP-A expression in cancer. PAPP-A was found to be elevated in subsets of patients with lung and ovarian cancer [4,5], and overexpression of PAPP-A by a human ovarian cancer cell line was shown to have increased tumor aggressiveness in vivo [6]. Down-regulation of PAPP-A expression decreased lung and ovarian cancer growth in vivo [7,8].…”

Section: Introductionmentioning

confidence: 99%

Pregnancy-associated plasma protein-A expression in human breast cancer

Mansfield

Visscher

Hart³

et al. 2014

Growth Hormone & IGF Research

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Objective Pregnancy-associated plasma protein-A (PAPP-A) is a zinc metalloproteinase in the insulin-like growth factor system that is expressed by tissues outside of pregnancy and involved in normal and dysregulated growth. PAPP-A has been implicated in several cancers. However, studies of PAPP-A expression in breast cancer are limited. In this study, we assessed PAPP-A expression in different subtypes of human malignant breast cancer. Design Formalin-fixed paraffin-embedded tumor samples from 46 female patients with invasive breast cancer were divided into five defined groups [using markers for HER2, estrogen receptor, progesterone receptor, proliferation] that roughly correlate with molecularly defined subtypes (luminal A, luminal B, luminal/HER2+, HER2+, triple negative). These samples were analyzed for PAPP-A expression by immunohistochemistry. Results PAPP-A staining in tumor tissue was detected in 45 of 46 specimens. There was significantly greater extent and intensity of PAPP-A expression in luminal B specimens with high proliferation index than luminal A specimens (P = 0.01). However, there were no differences between specimens positive or negative for HER2 (P = 0.14) or positive and negative for estrogen receptor (P = 0.31). Conclusion PAPP-A was detected in almost all breast cancer specimens and a more intense and greater extent of its expression was associated with luminal B specimens compared to luminal A specimens. The role of PAPP-A in breast cancer prognosis, and possibly therapeutics, warrants further investigation.

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Relationship Between Pregnancy-Associated Plasma Protein-A and Lung Cancer

Cited by 49 publications

References 24 publications

Indirect targeting of IGF receptor signalingin vivoby substrate-selective inhibition of PAPP-A proteolytic activity

Indirect targeting of IGF receptor signalingin vivoby substrate-selective inhibition of PAPP-A proteolytic activity

Influence of concomitant heparin administration on pregnancy-associated plasma protein-A levels in acute coronary syndrome with ST segment elevation

Pregnancy-associated plasma protein-A expression in human breast cancer

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