The alpha folate receptor is highly activated in malignant pleural mesothelioma

Our plain-English summary of The alpha folate receptor is highly activated in malignant pleural mesothelioma, by R. Bueno, K. Appasani, H. Mercer, et al (The Journal of Thoracic and Cardiovascular Surgery, 2001).

The study

• Authors: R. Bueno, K. Appasani, H. Mercer, S. Lester, D. Sugarbaker
• Journal: The Journal of Thoracic and Cardiovascular Surgery
• Published: 2001;121(2):225-33
• Cited by: 126 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objective: To determine whether the folate receptor gene is overexpressed in malignant pleural mesothelioma.

Methods: Differential display analysis was performed with fresh frozen RNA obtained from normal lung, pleura, and mesothelioma. Sixty differentially expressed genes were identified and characterized. One gene that was over-expressed in mesothelioma versus normal tissue was the human alpha folate receptor. In situ hybridization with antisense probes designed on the basis of the sequence of the folate receptor was performed with frozen sections from 61 patients (33 epithelial and 28 mixed or sarcomatoid tumors) with malignant pleural mesothelioma. The controls included normal pleura, normal lung, other cancers, and sense controls for all of the tumors. Northern analysis with a folate receptor probe and immunohistochemical analysis with anti-alpha folate receptor antibodies were also performed.

Results: Forty-four (72%) of the 61 mesothelioma tumors were found to have between 2-fold and 4-fold higher mRNA expression of the folate receptor when compared with the control tissues. The histologic type of the tumor did not affect the rate of folate receptor activation. Northern analysis and immunohistochemical experiments confirmed these findings.

Conclusions: A majority of mesothelioma tumors examined overexpress the alpha folate receptor protein when compared with normal adjacent tissues. This finding may help explain the observations that antifolate drugs have activity in the treatment of mesothelioma. It also encourages further study of folate receptor-related treatment strategies in this malignancy.

In plain English

This was a laboratory study of tumor tissue, not a study of asbestos exposure. The authors used frozen specimens from the tumor bank at Brigham and Women's Hospital in Boston. They first compared gene activity in one patient's epithelial mesothelioma with normal lung and pleura. Among 60 genes that differed, they found a fragment closely matching the alpha folate receptor gene. They then scored receptor gene activity on a 1-to-5 scale in 61 malignant pleural mesothelioma tissues (33 epithelial, 25 mixed, 3 sarcomatoid). Normal lung and pleura controls scored 1 or 2. The article's text reports that 44 (72%) of the mesotheliomas scored 3 to 5, but its own table and discussion give different counts. Scores did not differ significantly between mixed and epithelial tumors. The authors found no survival difference by receptor level. Of 17 tumors tested for the receptor protein, 13 showed moderate to high levels. The authors concluded that most tumors they examined expressed the receptor gene and protein at higher levels than adjacent normal tissue.

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 of tumor tissue. Gene-expression screening (differential display) was followed by fluorescent in situ hybridization, Northern blot and immunohistochemistry.
• Who was studied: Frozen surgical tissue from the Thoracic Oncology Tumor Bank at Brigham and Women's Hospital, Boston, from patients undergoing extrapleural pneumonectomy or pleurectomy. Initial screening used one patient's epithelial tumor. In situ hybridization used 61 malignant pleural mesothelioma tissues (33 epithelial, 25 mixed, 3 sarcomatoid), with normal lung, normal pleura and other cancers as controls. Collection dates are not given.
• Exposure: No asbestos or fiber exposure was studied. The study measured alpha folate receptor gene and protein expression in mesothelioma tissue compared with normal lung and pleura.
• Main results:
  • In the initial screen, one gene fragment (cDNA tag #37) was highly expressed only in the mesothelioma. It had 92% homology to the human alpha folate receptor.
  • Normal lung and pleura controls scored 1 or 2 on the 1-to-5 in situ hybridization scale.
  • The Results text reports that 44 (72%) of the 61 mesothelioma tissues scored 3 to 5 and the rest scored 1 to 2. The Discussion and Table I give different counts (see text_problems).
  • Hybridization scores did not differ significantly between mixed and epithelial tumors (t = 0.2468, P = .8059).
  • Kaplan-Meier analysis found no survival difference between patients whose tumors had elevated folate receptor levels and those whose tumors did not.
  • Northern blots compared 5 mesotheliomas with their adjacent normal tissue. The normal controls showed a barely recognizable band, while all 5 tumors showed a band of about 1.3 kb, the expected size of the receptor transcript.
  • Of 17 mesothelioma specimens tested with antibodies, 13 showed the receptor protein at the cell membrane at moderate to high levels.
  • In 15 of the 17 specimens, antibody results fully matched the in situ hybridization results.
• The authors' conclusion: The authors concluded that the alpha folate receptor gene and protein were expressed in a majority of the mesothelioma tumors they examined, at higher levels than in adjacent normal tissues. They wrote that their findings were in keeping with the observed efficacy of antifolate drugs in mesothelioma.
• Limitations the authors state:
  • The authors stated that further work was needed to establish the importance of folate receptor overexpression in mesothelioma.
  • The authors noted that the in situ hybridization method was less sensitive than Northern blot analysis.

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, Pleura, Mesothelioma, Frozen Section, Sarcomatoid, Antifolate.

Related studies

• Despite some expression of folate receptor alpha in human mesothelioma cells, internalization of methotrexate is predominantly carrier mediated — N.Z. Khokhar, A.F. Lam, et al. (2002)
• Activated alveolar macrophages express the insulin-like growth factor-I receptor — W.N. Rom, P. Pääkkö (1991)
• Activated TNF-alpha/NF-kappaB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice — D.A. Altomare, C.W. Menges, et al. (2009)
• Expression of growth factor and growth factor receptor RNA in rat pleural mesothelial cells in culture — E. Bermudez, J. Everitt, et al. (1990)
• Asbestos upregulates expression of the urokinase-type plasminogen activator receptor on mesothelial cells — R.C. Perkins, V.C. Broaddus, et al. (1999)
• Expression and activity of urokinase and its receptor in endothelial and pulmonary epithelial cells exposed to asbestos — A. Barchowsky, R.R. Roussel, et al. (1998)

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