Mitogen-activated protein kinase expression and activation does not differentiate benign from malignant mesothelial cells

Our plain-English summary of Mitogen-activated protein kinase expression and activation does not differentiate benign from malignant mesothelial cells, by L. Vintman, S. Nielsen, A. Berner, et al (Cancer, 2005).

The study

• Authors: L. Vintman, S. Nielsen, A. Berner, R. Reich, B. Davidson
• Journal: Cancer
• Published: 2005;103(11):2427-33
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: In vitro studies of malignant mesothelioma (MM) cells have suggested activation of mitogen-activated protein kinase (MAPK) in response to asbestos exposure. The objective of this study was to investigate protein expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), the c-Jun amino-terminal kinase (JNK), and the high-osmolarity glycerol response kinase (p38) in vivo through the analysis of fresh frozen reactive mesothelium (RM) and MM specimens.

Methods: MAPK levels were analyzed in 36 fresh-frozen MM specimens (32 effusions, 4 biopsies) and in 14 RM specimens (all effusions) using immunoblotting with antibodies detecting the total (pan-) and activated (phospho-) fraction (p-) of ERK, JNK, and p38. Values for pan-MAPK and p-MAPK expression and the p-MAPK/pan-MAPK ratio in MM and RM specimens were compared. Results were corroborated using immunocytochemistry for p-ERK, p-JNK, and p-38 in selected specimens.

Results: Pan-ERK, pan-JNK, and pan-p38 expression was found frequently in both MM specimens (35 of 36 specimens) and RM specimens (14 of 14 specimens) using immunoblotting, with comparable findings for activated p-p38 (34 of 36 MM specimens, 13 of 14 RM specimens). Activation of p-ERK (27 of 36 MM specimens, 10 of 14 RM specimens) and p-JNK (25 of 36 MM specimens, 10 of 14 RM specimens) was less frequent. Pan-ERK (P = 0.016), pan-JNK (P = 0.004), pan-p38 (P = 0.012), and p-ERK (P = 0.02) expression levels were higher in MM specimens from female patients. Pan-p38 expression levels also were higher in peritoneal MM specimens (P = 0.019). MM and RM showed similar MAPK expression, activation, and activation ratios (Mann-Whitney test; P > 0.05). Immunocytochemistry localized MAPK to MM and RM cells.

Conclusions: The current results provided the first evidence of in vivo activation of MAPK in clinical MM and RM. The similar values in these two cell types suggest that MAPK may not be involved in the transformation of benign to malignant mesothelium, thus bringing into question the validity of using MAPKs as molecular therapeutic targets in patients with MM.

In plain English

This laboratory study asked whether cell-signalling proteins called mitogen-activated protein kinases (ERK, JNK and p38) differ between malignant mesothelioma and benign, reactive mesothelial cells. The authors tested 36 mesothelioma specimens (32 fluid samples and 4 biopsies; 28 pleural and 8 peritoneal) from 36 patients and 14 reactive mesothelium fluid samples, all submitted to the pathology departments of The Norwegian Radium Hospital and Aalborg Hospital between 1998 and 2002. The article does not report patients' asbestos exposure. Total proteins were found in nearly all specimens. Activated p38 was nearly as common (34 of 36 mesothelioma, 13 of 14 reactive); activated ERK (27 of 36, 10 of 14) and activated JNK (25 of 36, 10 of 14) were less frequent. Levels did not differ significantly between mesothelioma and reactive specimens. Within mesothelioma, several levels were higher in specimens from the 6 women than the 30 men, and total p38 was higher in peritoneal than pleural tumors. The authors concluded that the similarity argued against a major role for the pathway in mesothelial cells becoming malignant, and questioned the proteins' value as treatment targets.

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 patient specimens comparing malignant mesothelioma with reactive (benign) mesothelium, using immunoblotting and immunocytochemistry
• Who was studied: 50 specimens submitted to the pathology departments of The Norwegian Radium Hospital and Aalborg Hospital from 1998 to 2002. Of these, 36 were malignant mesothelioma specimens (32 effusions, 4 biopsies; 28 pleural, 8 peritoneal) from 36 patients (30 males, 6 females, ages 39 to 91, mean age 67). The other 14 were reactive mesothelium specimens (all effusions) from patients with a previously diagnosed malignancy or a clinical suspicion of malignancy.
• Exposure: Not studied. The article does not report the patients' asbestos exposure; asbestos appears only in the background, where the authors describe laboratory (in vitro) studies by others. The study measured levels of total and activated (phosphorylated) ERK, JNK and p38 proteins in the specimens.
• Main results:
  • Total (pan-) MAPK proteins were found in nearly all specimens. Among the 36 mesothelioma specimens, all 36 showed pan-JNK and pan-p38, and 35 of 36 showed pan-ERK. All 14 reactive mesothelium specimens showed pan-ERK, pan-JNK and pan-p38.
  • In mesothelioma specimens, activated p38 was found in 34 of 36, nearly as often as the total proteins. Activated ERK (27 of 36) and activated JNK (25 of 36) were less frequent.
  • In reactive mesothelium specimens, activated p38 was found in 13 of 14. Activated ERK (10 of 14) and activated JNK (10 of 14) were less frequent.
  • Mesothelioma and reactive mesothelium specimens showed similar MAPK levels, activation and activation ratios. None of the differences was statistically significant (Mann–Whitney test). The P values listed in Table 1 ranged from 0.3 to 1.0.
  • Among mesothelioma specimens, four levels were higher in the 6 female patients than in the 30 male patients: pan-ERK (P = 0.016), pan-JNK (P = 0.004), pan-p38 (P = 0.012) and activated ERK (P = 0.02). Similar trends for activated JNK (P = 0.09) and activated p38 (P = 0.06) were not statistically significant.
  • Pan-p38 levels were higher in peritoneal mesothelioma than in pleural mesothelioma (P = 0.019). Women accounted for six of the eight peritoneal samples.
  • Immunocytochemistry was done on selected samples. All 8 mesothelioma specimens tested showed activated ERK and activated JNK in the cell nuclei, and 2 of 8 showed activated p38. All 5 reactive specimens tested showed activated ERK and activated JNK, and 4 of 5 showed activated p38.
• The authors' conclusion: The authors concluded that MAPK expression and activation are frequent in both malignant mesothelioma and reactive mesothelium. They said this argues against a major role for this pathway in the malignant transformation of mesothelial cells, and they questioned the value of these proteins as therapeutic targets.
• Limitations the authors state:
  • The authors noted that the infrequent activated-p38 staining in mesothelioma specimens on immunocytochemistry may reflect lower sensitivity of this antibody in paraffin-embedded material.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelial Cells, Malignant Mesothelioma, Asbestos Exposure, Mesothelium.

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