Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade

Our plain-English summary of Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade, by M. Fujii, H. Nakanishi, T. Toyoda, et al (Cell Cycle, 2012).

The study

• Authors: M. Fujii, H. Nakanishi, T. Toyoda, I. Tanaka, Y. Kondo, H. Osada, Y. Sekido
• Journal: Cell Cycle
• Published: 2012;11(18):3373-9
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a neoplasm that arises from serosal surfaces of the pleural, peritoneal and pericardial cavities with worldwide incidence, much of which is caused by asbestos exposure. Patients suffer from pain and dyspnea due to direct invasion of the chest wall, lungs and vertebral or intercostal nerves by masses of thick fibrotic tumors. Although there has been recent progress in the clinical treatment, current therapeutic approaches do not provide satisfactory results. Therefore, development of a molecularly targeted therapy for MM is urgently required. Our recent studies suggest that normal mesothelial and MM cell growth is promoted by TGFβ, and that TGFβ signaling together with intrinsic disturbances in neurofibromatosis type 2 (NF2) and Hippo signaling cascades in MM cells converges upon further expression of connective tissue growth factor (CTGF). The formation of a YAP-TEAD4-Smad3-p300 complex on the specific CTGF promoter site with an adjacent TEAD and Smad binding motif is a critical and synergistic event caused by the dysregulation of these two distinct cascades. Furthermore, we demonstrated the functional importance of CTGF through the mouse studies and human histological analyses, which may elucidate the clinical features of MM with severe fibrosis in the thoracic cavity.

In plain English

This "extra view" article summarized and discussed the authors' own recent laboratory research on malignant mesothelioma (MM) cell growth. Most findings came from the authors' earlier paper. Asbestos appeared only as background. The article did not study asbestos exposure. The work used MeT-5A, a normal human pleural mesothelial cell line that had been transformed by SV40 early region DNA, along with MM cell lines, patient tissue specimens and nude mice. A drug blocking the TGFβ type I receptor suppressed growth of both cell types. Given by mouth, it prolonged survival of mice with MM cells implanted in the chest. In MM cells, the growth factor CTGF was induced by TGFβ but reduced when the protein YAP was knocked down. CTGF was mainly overexpressed in sarcomatoid and biphasic tumor cells, with little in epithelioid tissue. Mice implanted with CTGF-knockdown MM cells survived longer than control mice, and fewer were emaciated at death. The authors concluded that CTGF is a strong candidate for targeted MM therapy. They noted that their gene-silencing method may not apply to patients. Their tissue findings suggested that other, unknown mechanisms may also regulate CTGF.

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: Extra view (commentary and review) article. The authors summarized and discussed their own recent laboratory, mouse and human tissue research, largely published in an earlier paper, with some mouse observations described here.
• Who was studied: MeT-5A, described as a normal human pleural mesothelial cell line transformed by SV40 early region DNA. Also MM cell lines; NCI-H290 MM cells implanted into the right chest cavity of female athymic nude mice (KSN strain, 7 to 8 weeks old); and tissue specimens from MM patients (24 in the p-Smad2 staining analysis). The work was done at the Aichi Cancer Center Research Institute, Japan.
• Exposure: No asbestos exposure was studied. The experiments examined TGFβ stimulation, a TGFβ type I receptor (TβRI) kinase inhibitor, knockdown of YAP, and knockdown of CTGF using short hairpin RNA (shCTGF) lentivirus vectors.
• Main results:
  • In both MeT-5A mesothelial cells and MM cell lines, treatment with a TβRI kinase inhibitor suppressed cell growth.
  • In mice with MM cells implanted in the chest, the TβRI kinase inhibitor given by oral gavage prolonged survival.
  • In MM cells, CTGF expression was induced by TGFβ but reduced by YAP knockdown. Most other TGFβ-activated genes tested were not affected by YAP depletion.
  • Smad3 bound more readily to TEAD than to YAP. The authors described a YAP-TEAD4-Smad3-p300 complex acting on the CTGF promoter.
  • In tissue from MM patients, p-Smad2 staining was seen in all 24 specimens. CTGF staining differed clearly between epithelioid and sarcomatoid tissue, and CTGF was mainly overexpressed in sarcomatoid and biphasic tumor cells.
  • Nude mice implanted in the chest with CTGF-knockdown NCI-H290 MM cells survived longer than mice implanted with control NCI-H290 cells.
  • Emaciation at the time of death was seen in 7/8 mice with control cells, 3/8 with shCTGF #1 cells and 1/8 with shCTGF #2 cells (p less than 0.05 versus control).
• The authors' conclusion: The authors concluded that TGFβ signaling and disturbances in the Hippo signaling pathway together promote MM cell growth. They concluded that CTGF is a strong candidate for molecularly targeted therapy for MM patients.
• Limitations the authors state:
  • The authors stated that it is uncertain whether the shRNA system used in the mouse studies is applicable in actual clinical treatment.
  • CTGF overexpression in NCI-H290 cells did not cause histological change in mice (data not shown). The authors said this may reflect insufficient CTGF expression or unique characteristics of the cell line used.
  • The authors stated that it is unknown whether CTGF expression induces deposition of extracellular matrix proteins or the reverse, and that this needs further study.
  • In human MM tissues, TGFβ signaling and Hippo defects were not perfectly linked to CTGF expression. The authors suggested that additional unknown mechanisms may regulate CTGF.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Neoplasm, Serosal Surface, Pericardial, Asbestos Exposure, Dyspnea, Targeted Therapy, Fibrosis.

Related studies

• TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth — M. Fujii, T. Toyoda, et al. (2012)
• LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade — I. Tanaka, H. Osada, et al. (2015)
• Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma — L. Jiang, Y. Yamashita, et al. (2014)
• BMP and activin membrane-bound inhibitor regulate connective tissue growth factor controlling mesothelioma cell proliferation — N.T.D. Hoang, G. Hassan, et al. (2022)
• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)

Browse return to medical research.