The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma

Our plain-English summary of The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma, by T. Li, H. Li, Y. Wang, et al (The Journal of Pathology, 2011).

The study

• Authors: T. Li, H. Li, Y. Wang, C. Harvard, J.L. Tan, A. Au, Z. Xu, D.M. Jablons, L. You
• Journal: The Journal of Pathology
• Published: 2011;223(4):519-30
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, are involved in tumour progression, metastasis, and survival. We investigated the expression of CXCR4, CXCL12, and CXCR7 in malignant pleural mesothelioma to determine if they are possible biomarkers and potential therapeutic targets. Forty-one mesothelioma tumour tissues, ten normal human pleural tissues, and two mesothelioma cell lines were stained with anti-CXCR4, anti-CXCL12, anti-CXCR7, and anti-p-Akt antibodies. RT-PCR was performed to determine the expression of CXCR4, CXCL12, and CXCR7 in six human mesothelioma cell lines (H28, 211H, H2052, ms-1, H290, and H513) and one human normal mesothelial cell line, LP9. These seven cell lines were also stained with anti-CXCR7. We found that CXCR4 and CXCL12 were expressed in 97.6% and 78.0% mesothelioma tissue samples, concurrently with strong expression of p-Akt (R(2) = 0.739 and 0.620, respectively). In addition, CXCR7 expression was weaker than CXCR4 expression in mesothelioma tissues. Furthermore, RT-PCR showed that CXCR4 and CXCL12 were overexpressed in 5/6 mesothelioma cell lines (211H, H2052, ms-1, H290, and H513), whereas CXCR7 was overexpressed in only 2/6 (H513 and H2052). Moreover, we found that the CXCR4 antagonist AMD3100 inhibited the growth of all five mesothelioma cell lines that overexpress CXCR4 and CXCL12. Our results suggest that the Akt-mTOR pathway is involved during the interruption of the CXCL12/CXCR4 axis in these five mesothelioma cell lines. In conclusion, CXCR4 and CXCL12 are highly expressed in most mesothelioma cell lines and tumour tissues, suggesting that CXCR4 and CXCL12 may be used as biomarkers for patients with mesothelioma. The CXCL12-CXCR4 interaction may be a potential therapeutic target for mesothelioma.

Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In plain English

This laboratory study examined the signalling molecule CXCL12 and its receptors CXCR4 and CXCR7 in malignant pleural mesothelioma. It did not study asbestos exposure. The authors stained tumour tissue from 41 surgical patients and 10 normal pleura samples, and tested six mesothelioma cell lines and one normal line. CXCR4 was positive in 97.6% and CXCL12 in 78.0% of mesothelioma samples, versus 70% and 40% of normal samples. The discussion instead says CXCR4 and CXCL12 were overexpressed in 31/41 and 22/41 tumours, without relating these counts to the staining grades. Table counts show CXCR7 positive in 23 of 32 mesothelioma samples (71.9%) versus 1 of 9 normal samples (11.1%). Only 2 of 32 tumours stained strongly, the lowest share of any marker. CXCR4 and CXCL12 were overexpressed in five of the six mesothelioma cell lines. In those five, the CXCR4-blocking drug AMD3100 blocked CXCL12-driven growth and Akt–mTOR signalling, dose-dependently. It did not inhibit H28 or the normal line. The authors concluded that CXCR4 and CXCL12 may be usable as biomarkers and their interaction a potential treatment target, needing further investigation.

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 study: immunohistochemical staining of tumour and normal pleura tissue samples, plus experiments on cell lines (RT-PCR, staining, growth and viability assays, western blots)
• Who was studied: Tumour samples from 41 patients with malignant pleural mesothelioma undergoing surgical resection, with tissue use approved by the University of California, San Francisco review board. Normal pleura came from 7 of these patients and 3 other patients. Six human mesothelioma cell lines (H28, 211H, H2052, ms-1, H290, H513) and one normal mesothelial cell line (LP9) were also tested. No dates are given.
• Exposure: No asbestos or other exposure of patients was studied. The laboratory treatments were CXCL12 (100 ng/ml) applied to cells, with or without the CXCR4 inhibitor AMD3100 at a range of concentrations.
• Main results:
  • In the mesothelioma tissue samples, the overall positive ratios were 78.0% for CXCL12, 97.6% for CXCR4, 71.9% for CXCR7 and 84.8% for p-Akt.
  • In the normal pleura samples, the overall positive ratios were 40% for CXCL12, 70% for CXCR4, 11.1% for CXCR7 and 33.3% for p-Akt.
  • In its summary, the discussion states that CXCL12 and CXCR4 were overexpressed in 22/41 and 31/41 mesothelioma tissues, respectively. The article does not say how these 'overexpressed' counts relate to the staining grades or to the positive ratios.
  • CXCR7 in the mesothelioma samples (Table 2): 9 negative (28.1%), 15 weak (46.9%), 6 moderate (18.8%) and 2 strong (6.3%). These counts add up to 32 samples, of which 23 were positive.
  • CXCR7 in the normal pleura samples (Table 3): 8 negative (88.9%) and 1 weak (11.1%). These counts add up to 9 samples.
  • Among the mesothelioma samples, CXCR7 had the lowest strong-positive ratio and the highest negative ratio of the markers stained.
  • In the mesothelioma samples, CXCR4 staining correlated with CXCL12 (R2 = 0.794) and with p-Akt (R2 = 0.739). The authors reported a weaker correlation for CXCL12 with p-Akt (R2 = 0.620). They reported that CXCR4 was not correlated with CXCR7 (R2 = 0.408).
  • By RT-PCR, CXCR4 was overexpressed in mesothelioma cell lines H2052, ms-1, 211H, H513 and H290. It was weakly expressed in H28 and in the normal line LP9.
  • By RT-PCR, CXCL12 was overexpressed in the same five mesothelioma cell lines. It was weakly expressed in LP9 and was not detectable in H28.
  • By RT-PCR, CXCR7 was expressed in two mesothelioma cell lines, H2052 and H513.
  • AMD3100 blocked CXCL12-induced proliferation in a dose-dependent manner in mesothelioma cell lines H2052, ms-1, 211H, H513 and H290.
  • AMD3100 did not inhibit growth of mesothelioma cell line H28 or of the normal mesothelial cell line LP9.
  • CXCL12 increased phosphorylation of Akt, S6K and 4E-BP1, which are parts of the Akt–mTOR pathway. The increase peaked 5 and 10 minutes after stimulation.
  • This activation was blocked by AMD3100 in a dose-dependent manner.
• The authors' conclusion: The authors concluded that CXCR4 and CXCL12 may be used as biomarkers for patients with mesothelioma, and that the CXCL12–CXCR4 interaction may be a potential therapeutic target for mesothelioma.
• Limitations the authors state:
  • The authors stated that the relationship between CXCR7 and the Akt pathway in mesothelioma is still not clear.
  • The authors stated that two questions require further investigation: the role of CXCR7 in mesothelioma, and whether the CXCL12–CXCR4 interaction is a potential therapeutic target.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Metastasis, Biomarker, Mesothelioma, Mesothelial Cells.

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