Antitumor efficacy of Kisspeptin in human malignant mesothelioma cells

Our plain-English summary of Antitumor efficacy of Kisspeptin in human malignant mesothelioma cells, by V. Ciaramella, C.M. Della Corte, C. Di Mauro, et al (Oncotarget, 2018).

The study

• Authors: V. Ciaramella, C.M. Della Corte, C. Di Mauro, S. Tomassi, S. Di Maro, T. Troiani, E. Martinelli, R. Bianco, S. Cosconati, R. Pierantoni, R. Meccariello, R. Chianese, F. Ciardiello, F. Morgillo
• Journal: Oncotarget
• Published: 2018;9(27):19273-19282
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Kisspeptin signaling, via its receptors GPR54, could be an essential players in the inhibition of mesothelioma progression, invasion and metastasis formation. The loss of KiSS1 by tumor cells has been associated with a metastatic phenotype but the mechanistic insights of this process are still unknown.

Experimental Design: The blockade of the metastatic process at early stage is a hot topic in cancer research. We studied the role of KiSS1 on proliferation, invasiveness, migration abilities of mesothelioma cell lines focusing on the effect on epithelial-to-mesenchymal transition (EMT).

Results: Treatment with the KiSS1 peptide or with a synthesis peptide with longer half-life, the FTM080, significantly inhibited cell proliferation, migration and invasion of mesothelioma cell lines; the same treatment reduced the activity of MMP-2 and MMP-9 determining consequently a marked reduction in the invasiveness of primary tumors and metastases. Thespecificexpression of EMT markers, as E-caderin, Vimentin, Slug and Snail, suggested the inhibition of EMT after treatment with KiSS1 as well as the preservation of epithelial components.

Conclusion: Our results support anti-proliferative effect of KiSS1 in cancer cells and suggest that targeting the KiSS1/GPR54 system may represent a novel therapeutic approach for mesothelioma.

In plain English

This was a laboratory study using cells and mice. It did not study people or asbestos exposure. The authors tested Kisspeptin-10 (Kp-10), a natural peptide, and FTM080, a longer-lasting synthetic version, on three human pleural mesothelioma cell lines: H2452 (epithelial), H28 (sarcomatoid) and MSTO (biphasic). All three lines made Kisspeptin and its receptor, GPR54, with lower levels in MSTO. Kp-10 reduced cell viability in a dose-dependent way and strongly reduced invasion. At 0.1 nM, migration decreased to about 50% in H2452 cells and to about 60% in H28 and MSTO cells, compared with untreated cells. FTM080 had a stronger effect on proliferation, invasion and colony formation. In H28 and H2452 cells, Kp-10 raised epithelial markers, lowered mesenchymal markers, and reduced MMP-2 and MMP-9. In an artificial metastasis test, H2452 cells were injected into mouse tail veins, six mice per group. No mouse showed visible lesions, but untreated mice had about 5 times more human DNA in their lungs than FTM080-treated mice. The authors concluded that their work opens the possibility of using Kisspeptin as therapy in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiments on human mesothelioma cell lines, plus an animal experiment: an artificial metastasis assay in nude mice, with cells injected into the tail vein
• Who was studied: Three human pleural mesothelioma cell lines: H2452 (epithelial), H28 (sarcomatoid) and MSTO (biphasic). The animal experiment used athymic (Balb/c) nude mice injected in the tail vein with H2452 cells, six mice per control group and six per treatment group.
• Exposure: No asbestos exposure was studied. Cells were treated with Kisspeptin-10 (Kp-10) or the synthetic Kisspeptin receptor agonist FTM080 at a range of doses. Mice received FTM080 at 10 mg/kg by mouth, four days a week for three weeks.
• Main results:
  • KiSS1 and GPR54 were present in all three cell lines, with higher expression in H2452 and H28 than in MSTO.
  • In all three cell lines, Kp-10 reduced cell viability in a dose-dependent way. The concentration that halved viability (IC50) was between 10 to the power minus 9 and 10 to the power minus 7 molar.
  • Kp-10 strongly reduced cell invasion compared with untreated control cells. The authors describe this as a reduction 'to the > 80%'.
  • With 0.1 nM Kp-10, migration decreased to about 50% in H2452 cells and to about 60% in H28 and MSTO cells, compared with untreated controls.
  • Compared with Kp-10, FTM080 had a stronger effect in inhibiting proliferation, invasion and colony formation.
  • After Kp-10 treatment, the epithelial marker Ep-Cam increased by 27% in H28 cells and by 15% in H2452 cells, compared with control cells.
  • In H28 and H2452 cells treated with 0.1 nM Kp-10, MMP-2 and MMP-9 were considerably reduced on gelatin zymography.
  • In H28 and H2452 cells, Kp-10 raised E-cadherin and reduced the mesenchymal markers Vimentin, Snail and Slug. Survivin expression increased.
  • In the mice, no animal in either the control or the treatment group showed visible lesions in the lungs, liver or spleen.
  • Untreated mice had about 5 times more human DNA (Alu sequences) in their lungs than FTM080-treated mice. The authors used this as a measure of micrometastasis.
• The authors' conclusion: The authors concluded that the KiSS1/GPR54 system may have a 'protective' function by inhibiting the change of epithelial cells into more aggressive mesenchymal cells. They said their work opens the possibility of using Kisspeptin as therapy in tumors with poor survival, such as mesothelioma.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Metastasis.

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