Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma

Our plain-English summary of Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma, by L. Jiang, Y. Yamashita, S.H. Chew, et al (The Journal of Pathology, 2014).

The study

• Authors: L. Jiang, Y. Yamashita, S.H. Chew, S. Akatsuka, S. Ukai, S. Wang, H. Nagai, Y. Okazaki, T. Takahashi, S. Toyokuni
• Journal: The Journal of Pathology
• Published: 2014;233(4):402-14
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Due to the formerly widespread use of asbestos, malignant mesothelioma (MM) is increasingly frequent worldwide. MM is classified into epithelioid (EM), sarcomatoid (SM), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM, and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM, we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor (Ctgf), whose expression was significantly increased in SM compared with EM; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM, Ctgf was a major regulator of MM proliferation and invasion through activation of the β-catenin-TCF-LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial-mesenchymal transition in MM. Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6-GSK3β-β-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target.

Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In plain English

This was a laboratory and animal study from Nagoya University, Japan. The authors used a rat model in which injected asbestos, described as UICC standard asbestos with no fiber type named in this article, produced peritoneal malignant mesothelioma. They compared gene activity in 24 rat tumours (13 sarcomatoid, eight epithelioid, three biphasic) with normal mesothelial cells. A gene called connective tissue growth factor (Ctgf) was the top gene differing between sarcomatoid and epithelioid tumours. It was also raised in epithelioid tumours compared with normal cells. In cell experiments, reducing Ctgf slowed tumour cell growth and invasion, and it reduced tumour formation in mice. Ctgf appeared to act through a receptor called LRP6 and a signalling pathway involving beta-catenin. Blood was taken 420 days after asbestos injection. At that point, rats that later developed mesothelioma had mean serum Ctgf of 37.52 ng/ml (31 rats), compared with 2.97 ng/ml in 7 control rats. Higher Ctgf was associated with shorter survival. The authors concluded from these preclinical studies that Ctgf and its associated molecules are crucial in maintaining the malignant potential of 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 and animal experiment: comparison of gene activity in asbestos-induced rat mesotheliomas, cell-line experiments, a nude-mouse tumour test, and serum measurements in asbestos-injected rats followed over time (the authors call this part a prospective study)
• Who was studied: F1 hybrid rats (female Fischer 344 crossed with male Norway Brown) with asbestos-induced peritoneal mesothelioma. The gene-activity screen used 24 tumours (13 sarcomatoid, 8 epithelioid, 3 biphasic) and 4 samples of normal mesothelial cells (2 pleural, 2 peritoneal). Cell lines were grown from rat ascites. Serum came from 33 asbestos-injected rats and 7 controls. Nude mice (n = 6) were used for tumour-formation tests.
• Exposure: UICC standard asbestos suspended in saline and injected into rats. The fiber type and dose are not stated in this article, which refers to the authors' earlier work.
• Main results:
  • Ctgf was the top gene with differing expression between sarcomatoid and epithelioid rat mesothelioma, with higher expression in sarcomatoid tumours
  • Ctgf was also over-expressed in epithelioid mesothelioma compared with normal mesothelial cells
  • In sarcomatoid and epithelioid cell lines, reducing Ctgf suppressed cell proliferation
  • In sarcomatoid and epithelioid cell lines, reducing Ctgf inhibited cell invasion in laboratory assays
  • In nude mice, sarcomatoid and epithelioid cells with reduced Ctgf formed tumours less readily than control cells
  • When LRP6 was knocked down, added Ctgf did not reactivate the beta-catenin signalling pathway. The authors took this to suggest that LRP6 is a major receptor for Ctgf.
  • In epithelioid cells, adding Ctgf lowered an epithelial marker (E-cadherin) and raised mesenchymal-type markers. The authors describe this as an epithelial-mesenchymal transition-like change.
  • At day 420 after asbestos injection, rats that later developed mesothelioma had serum Ctgf of 37.52 plus or minus 4.83 ng/ml (mean plus or minus SEM, n = 31). Control rats had 2.97 plus or minus 0.56 ng/ml (n = 7).
  • At day 420, rats that later developed mesothelioma had serum mesothelin of 96.06 plus or minus 10.10 ng/ml (n = 31). Control rats had 31.53 plus or minus 0.44 ng/ml (n = 7).
  • Two asbestos-injected rats that did not develop mesothelioma had low serum Ctgf at day 420 (2.15 and 2.87 ng/ml)
  • The 15 rats later found to have sarcomatoid mesothelioma had significantly higher serum Ctgf than rats with epithelioid mesothelioma
  • Serum Ctgf at day 420 was inversely associated with survival (r = minus 0.84; p less than 0.0001). The text reports r = minus 0.89 for sarcomatoid cases only.
  • Serum mesothelin was not associated with survival (r = minus 0.34, not significant)
• The authors' conclusion: The authors concluded that their preclinical results show Ctgf and its associated molecules are crucial in maintaining the malignant potential of mesothelioma. They pointed to these molecules as targets for diagnosis and treatment.

Topics

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

Medical terms in this study, explained in our Lexicon: Sarcomatoid, Mesothelioma, Malignant Mesothelioma, Epithelioid, Biphasic Mesothelioma, Prognosis, Mesothelium, Biomarker.

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