Connective tissue growth factor produced by cancer‑associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma

Our plain-English summary of Connective tissue growth factor produced by cancer‑associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma, by Y. Ohara, A. Enomoto, Y. Tsuyuki, et al (Oncology Reports, 2020).

The study

• Authors: Y. Ohara, A. Enomoto, Y. Tsuyuki, K. Sato, T. Iida, H. Kobayashi, Y. Mizutani, Y. Miyai, A. Hara, S. Mii, J. Suzuki, K. Yamashita, F. Ito, Y. Motooka, N. Misawa, T. Fukui, K. Kawaguchi, K. Yokoi, S. Toyokuni
• Journal: Oncology Reports
• Published: 2020;44(3):838-848
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive neoplasm for which effective treatments are lacking. We often encounter mesothelioma cases with a profound desmoplastic reaction, suggesting the involvement of cancer‑associated fibroblasts (CAFs) in mesothelioma progression. While the roles of CAFs have been extensively studied in other tumors and have led to the view that the cancer stroma contains heterogeneous populations of CAFs, their roles in mesothelioma remain unknown. We previously showed that connective tissue growth factor (CTGF), a secreted protein, is produced by both mesothelioma cells and fibroblasts and promotes the invasion of mesothelioma cells in vitro. In this study, we examined the clinical relevance of CAFs in mesothelioma. Using surgical specimens of epithelioid malignant pleural mesothelioma, we evaluated the clinicopathological significance of the expression of α‑smooth muscle actin (αSMA), the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry and Elastica‑Masson staining. We also analyzed the expression of mesenchymal stromal cell‑ and fibroblast‑expressing Linx paralogue (Meflin; ISLR), a recently reported CAF marker that labels cancer‑restraining CAFs and differ from αSMA‑positive CAFs, by in situ hybridization. The extent of fibrosis and CTGF expression in mesothelioma cells did not correlate with patient prognosis. However, the expression of αSMA and CTGF, but not Meflin, in CAFs correlated with poor prognosis. The data suggest that CTGF+ CAFs are involved in mesothelioma progression and represent a potential molecular target for mesothelioma therapy.

In plain English

This was a laboratory study of tumor tissue removed during surgery from patients with epithelioid malignant pleural mesothelioma at Nagoya University Hospital in Japan between 2007 and 2016. Of 37 patients who had surgery, samples from 22 were analyzed. Patients with biphasic or sarcomatoid tumors were excluded because their tumor cells were hard to tell apart from cancer-associated fibroblasts (CAFs), the connective-tissue cells surrounding a tumor. The authors measured the amount of scar tissue (fibrosis) and three fibroblast markers (αSMA, CTGF and Meflin), then compared these with survival. The article does not report the patients' asbestos exposure. Neither the amount of fibrosis nor CTGF in the tumor cells themselves was significantly linked to survival. A higher αSMA area (P=0.0262) and higher CTGF in CAFs (P=0.0186) were linked to poorer prognosis. CTGF in CAFs also correlated with a marker of tumor cell growth, Ki-67 (r=0.533). Meflin was tested in only 15 patients and showed no significant link to survival. The authors stated that the small number of cases was a limitation. They concluded that CTGF-positive CAFs correlate with patient prognosis and may be a potential drug target.

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: Retrospective laboratory (pathology) study of stored surgical tumor specimens, using staining and in situ hybridization, with comparison to clinical features and overall survival
• Who was studied: Of 37 patients who had surgery for malignant pleural mesothelioma at Nagoya University Hospital, Japan, from January 2007 to December 2016, 22 with the epithelioid subtype were analyzed. Biphasic and sarcomatoid cases, patients with another cancer, patients with several surgeries, and patients with only cytoreductive surgery were excluded. Meflin was analyzed in 15 patients.
• Exposure: No asbestos exposure was measured or reported for these patients. The study examined tissue features: the extent of fibrosis and the expression of αSMA, CTGF, Meflin and Ki-67 in tumor tissue.
• Main results:
  • The extent of fibrosis (fibrotic area index) was not significantly associated with overall survival.
  • Overall survival differed significantly by αSMA area index (low under 20%, high 20% or more), P=0.0262. The authors report that αSMA expression in CAFs correlated with poor prognosis.
  • CTGF expression in the mesothelioma cells themselves was not significantly correlated with patient prognosis.
  • CTGF expression in CAFs correlated with poor prognosis. Survival differed significantly by modified CTGF score in CAFs (low under 30, high 30 or more), P=0.0186.
  • The CTGF score in CAFs correlated positively with the Ki-67 index of mesothelioma cells (r=0.533, P=0.0107) and with the αSMA area index (r=0.502, P=0.0172). The CTGF score in mesothelioma cells showed neither correlation.
  • In the tables, CTGF expression in neither mesothelioma cells nor CAFs correlated with pathological invasion, lymph node metastasis, stage or sensitivity to neoadjuvant chemotherapy.
  • Meflin expression in CAFs (15 patients) showed no significant association with patient prognosis or with clinicopathological features.
  • Non-tumorous mesothelial cells did not express CTGF. CTGF expression was seen in both mesothelioma cells and CAFs.
• The authors' conclusion: The authors concluded that CTGF-positive CAFs are important for mesothelioma growth, correlate with patient prognosis, and may be a potential drug target. They stated that whether the CTGF antibody FG-3019 has therapeutic effects in human mesothelioma patients warrants further investigation.
• Limitations the authors state:
  • The final number of cases was small, because surgical mesothelioma cases are rare at the hospital.
  • Meflin could be analyzed in only 15 patients, because the RNA test must be done on tissue less than five years old. The study did not settle whether Meflin correlates with survival.
  • The lack of correlation between CTGF and sensitivity to neoadjuvant chemotherapy may reflect the small number of cases.

Topics

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

Medical terms in this study, explained in our Lexicon: Fibroblast, Prognosis, Epithelioid, Pleural Mesothelioma, Mesothelioma, Neoplasm, Desmoplastic Mesothelioma, Fibrosis.

Related studies

• Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma — L. Jiang, Y. Yamashita, et al. (2014)
• BAG3 induces α-SMA expression in human fibroblasts and its over-expression correlates with poorer survival in fibrotic cancer patients — M. De Marco, N. Del Papa, et al. (2022)
• Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade — M. Fujii, H. Nakanishi, et al. (2012)
• BMP and activin membrane-bound inhibitor regulate connective tissue growth factor controlling mesothelioma cell proliferation — N.T.D. Hoang, G. Hassan, et al. (2022)
• Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model — Y. Ohara, S.H. Chew, et al. (2018)
• Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells — Y. Chrisochoidou, R. Roy, et al. (2023)

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