Integrin-linked kinase, phosphorylated AKT and the prognosis of malignant pleural mesothelioma

Our plain-English summary of Integrin-linked kinase, phosphorylated AKT and the prognosis of malignant pleural mesothelioma, by S.B. Watzka, U. Setinek, E.B. Stubenberger, et al (European Journal of Cardio-thoracic Surgery, 2011).

The study

• Authors: S.B. Watzka, U. Setinek, E.B. Stubenberger, M. Tötsch, G. Dekan, M. Marcher, T. Fleck, M.R. Müller
• Journal: European Journal of Cardio-thoracic Surgery
• Published: 2011;39(2):180-4
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objective: Integrin-linked kinase (ILK) is a cell membrane-bound molecule implicated in the metastatic progression of many tumour types. It phosphorylates the downstream target AKT (phosphorylated AKT, pAKT), and, by doing this, it activates anti-apoptotic pathways. We have recently shown ILK expression in malignant pleural mesothelioma (MPM). To determine whether ILK expression in MPM is connected with pAKT expression, and whether ILK and pAKT expression have any influence on the patient's prognosis, we correlated ILK and pAKT expression, as assessed by immunohistochemistry, with disease-related survival in a retrospective cohort of 80 MPM patients.

Material And Methods: The paraffin specimens of 80 MPM cases treated from 1990 to 2006 (52 surgical cases, 28 conservative cases) have been retrieved from the archive. The median (range) patients' age was 62 (28-83 years) years; the male-to-female ratio was 3:1. Fifty percent of the patients had an epitheloid subtype. The samples have been stained with anti-ILK as well as with anti-pAKT and scored by two independent pathologists. Intensity of ILK and pAKT expression has been correlated with disease-related survival.

Results: In total, 73 of 80 (91%) MPM samples expressed ILK; 65 of 74 (88%) MPM samples expressed pAKT. Comparing the 5-year disease-related survival according to ILK or pAKT expression, no statistically significant difference could be found between ILK and pAKT expressing or non-expressing patients. However, in the subgroup of conservatively treated MPM patients, those with strong ILK expression had a longer 5-year disease-related survival (p < 0.0001). In total, the only prognostic factor across all ILK, pAKT and therapy subgroups was the histological subtype (p = 0.01). The prognostic significance of the histological subtype has been confirmed in multivariate analysis (p = 0.005).

Conclusion: The expression of ILK in MPM is connected with the expression of the downstream target pAKT, but neither ILK nor pAKT expression has a measurable influence on the patient's prognosis, except for certain subgroups of MPM. However, to shed light on the true prognostic impact of ILK and pAKT expression in MPM, prospective trials are needed.

Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

In plain English

This retrospective study examined stored tumour samples from 80 patients with malignant pleural mesothelioma. The authors stained the samples for integrin-linked kinase (ILK) and phosphorylated AKT (pAKT) and compared staining with disease-related survival. The article does not report a systematic assessment of asbestos exposure. ILK was found in 73 of 80 samples (91%) and pAKT in 65 of 74 (88%). Overall, 5-year disease-related survival did not differ significantly by expression of either protein. Among the 28 patients treated without surgery, the few with strong ILK expression had a 5-year disease-related survival of 50% plus or minus 25% (p less than 0.0001). The authors cautioned that this subgroup was small. Across all ILK, pAKT and therapy subgroups, tumour type was the only significant prognostic factor. Five-year disease-related survival was 20% plus or minus 7% for epitheloid tumours and 9% plus or minus 6% for biphasic tumours. Biphasic tumours had a hazard ratio of 2.4 (95% confidence interval 1.3 to 4.3) compared with epitheloid tumours. The authors concluded that neither protein had a measurable influence on prognosis, except in certain subgroups.

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 clinico-pathological study (immunohistochemistry on archived tumour samples, correlated with survival)
• Who was studied: 80 patients with malignant pleural mesothelioma whose surgical specimens were retrieved from the archive of the Division of Pathology. The methods give the treatment period as 1990 to 2000; the abstract gives 1990 to 2006. Median age was 62 (range 28 to 83). There were 60 men and 20 women. By tumour type: 38 epitheloid, 39 biphasic, 1 sarcomatoid and 2 not conclusive. 52 patients had surgery and 28 had conservative therapy. Median follow-up was 1 year (range 0 to 9 years).
• Exposure: Not an asbestos exposure study. The factors studied were tumour expression of integrin-linked kinase (ILK) and phosphorylated AKT (pAKT), measured by immunohistochemistry and scored as absent, weak, medium or strong. The article does not report a systematic assessment of asbestos exposure. A table footnote records proven asbestos exposure in two patients whose histology was not conclusive.
• Main results:
  • 73 of 80 samples (91%) expressed ILK. Of the 73 positive samples, 46 (63%) had medium or strong expression.
  • 65 of 74 samples (88%) expressed pAKT. Only 25 of 65 (39%) pAKT-positive samples had medium or strong expression. The difference in expression between ILK and pAKT was statistically significant (p = 0.002).
  • ILK and pAKT expression were not correlated with age, gender or histological subtype.
  • Across all patients, 5-year disease-related survival showed no statistically significant difference between patients who expressed ILK or pAKT and patients who did not.
  • In surgically treated patients (n = 52), the intensity of ILK expression did not affect survival.
  • In conservatively treated patients (n = 28), the few with strong ILK expression had a 5-year disease-related survival of 50% plus or minus 25%. The p value of less than 0.0001 refers to the comparison by ILK expression within this subgroup.
  • pAKT expression did not influence disease-related survival in either therapy subgroup.
  • Across all ILK, pAKT and therapy subgroups, histological subtype was the only significant prognostic factor. Five-year disease-related survival was 20% plus or minus 7% for patients with epitheloid tumours and 9% plus or minus 6% for patients with biphasic tumours (p = 0.01).
  • In multivariate analysis, biphasic histology had a hazard ratio of 2.4 (95% CI 1.3 to 4.3, p = 0.005) compared with epitheloid histology. Gender, therapy, ILK and pAKT had no significant effect in this model.
• The authors' conclusion: The authors concluded that ILK expression in this tumour is connected to pAKT expression. They also concluded that neither ILK nor pAKT expression has a measurable influence on prognosis, except in certain subgroups. They suggested that a prospective cohort of patients given standardised treatment could give more conclusive data.
• Limitations the authors state:
  • Disease-related survival is an ambiguous end point, because only a minority of deaths from this tumour undergo a thorough post-mortem examination.
  • Treatment in this cohort was very heterogeneous, so the true influence of therapy on survival could not be assessed with certainty.
  • The finding in conservatively treated patients must be interpreted with caution because that subgroup was small.

Topics

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

Medical terms in this study, explained in our Lexicon: Prognosis, Pleural Mesothelioma, Immunohistochemistry, Histological Subtype, Multivariate Analysis.

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• Serum concentration of integrin-linked kinase in malignant pleural mesothelioma and after asbestos exposure — S.B. Watzka, F. Posch, et al. (2013)
• beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line — A. Berken, J. Abel, et al. (2003)
• DCLK1 is correlated with MET and ERK5 expression, and associated with prognosis in malignant pleural mesothelioma — H. Wang, Y.Y. Dai, et al. (2017)
• Antiproliferative effect of Aurora kinase targeting in mesothelioma — S. Crispi, C. Fagliarone, et al. (2010)
• Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways — C.W. Menges, E. Sementino, et al. (2012)

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