Possible reversibility between epithelioid and sarcomatoid types of mesothelioma is independent of ERC/mesothelin expression

Our plain-English summary of Possible reversibility between epithelioid and sarcomatoid types of mesothelioma is independent of ERC/mesothelin expression, by M. Kojima, K. Kajino, S. Momose, et al (Respiratory Research, 2020).

The study

• Authors: M. Kojima, K. Kajino, S. Momose, N. Wali, M.T. Hlaing, B. Han, L. Yue, M. Abe, T. Fujii, K. Ikeda, O. Hino
• Journal: Respiratory Research
• Published: 2020;21(1):187
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mesothelioma is histologically divided into three subgroups: epithelioid, sarcomatoid, and biphasic types. The epithelioid or sarcomatoid type is morphologically defined by polygonal or spindle-like forms of cells, respectively. The biphasic type consists of both components. It is not yet understood how histological differentiation of mesothelioma is regulated. ERC/mesothelin is expressed in most cases of the epithelioid type, but not in the sarcomatoid type of mesothelioma. Consequently, its expression is well correlated to the histological subtype. We hypothesized that ERC/mesothelin expression influences the histological differentiation of mesothelioma, and tested this hypothesis.

Methods: We performed studies using the overexpression or knockdown of ERC/mesothelin in mesothelioma cells to examine its effect on cellular morphology, growth kinetics, or migration/invasion activity, in vitro. We then transplanted ERC/mesothelin-overexpressing and control cells into the intraperitoneal space of mice. We examined the effect of ERC/mesothelin overexpression on mouse survival and tumor phenotype.

Results: In vitro cell culture manipulations of ERC/mesothelin expression did not affect cellular morphology or proliferation, although its overexpression enhanced cellular adhesion and the migration/invasion activity of mesothelioma cells. The survival rate of mice following intraperitoneal transplantation of ERC/mesothelin-overexpressing mesothelioma cells was significantly lower than that of mice with control cells. The histological evaluation of the tumors, however, did not show any morphological difference between two groups, and our hypothesis was not validated. Unexpectedly, both groups (ERC/mesothelin-overexpressing and control) of mesothelioma cells that were morphologically monophasic and spindle-like in vitro differentiated into a biphasic type consisting of polygonal and spindle-like components in the transplanted tumor, irrespective of ERC/mesothelin expression.

Conclusions: These results suggested that the histological transition of mesothelioma between epithelioid and sarcomatoid types may be reversible and regulated not by ERC/mesothelin, but by other unknown mechanisms.

In plain English

This laboratory study tested whether ERC/mesothelin expression determines whether mesothelioma takes an epithelioid (polygonal) or sarcomatoid (spindle) form. The authors overexpressed ERC/mesothelin in the human mesothelioma cell line H2452 (which lacks it) using a lentivirus vector, and knocked it down in H226 using siRNA, then injected ERC/mesothelin-overexpressing or control H2452 cells into the abdominal cavity of nude mice. Neither overexpression nor knockdown changed cell shape or proliferation, nor the EMT markers E-cadherin, vimentin, ZEB1 or Twist, but overexpression increased cell adhesion, migration/invasion and MMP-9 expression. In mice, all 8 given ERC/mesothelin-overexpressing cells died or were euthanized by day 40, while 3 of 8 control mice survived to day 70 without tumors; tumour-forming efficiency was 100% (8/8) versus 62.5% (5/8), and tumour size did not differ significantly. Tumours in both groups were biphasic, with polygonal cells at the invading front and spindle cells elsewhere. The authors concluded that the epithelioid-sarcomatoid transition may be reversible and may be regulated by other, unknown mechanisms rather than by ERC/mesothelin.

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: in vitro experiments with human mesothelioma cell lines plus intraperitoneal transplantation into nude mice
• Who was studied: Human mesothelioma cell lines NCI-H2452, NCI-H226 and ACC-MESO-4 studied in vitro; H2452 cells also transplanted into female BALB/c athymic nude mice, 8 per group (Japan)
• Exposure: Experimental manipulation of ERC/mesothelin (lentiviral overexpression in H2452, siRNA knockdown in H226); 2.5 x 10^6 cells injected into the intraperitoneal space of mice; no asbestos exposure studied
• Main results:
  • Overexpression in H2452 and knockdown in H226 did not change cell morphology
  • Overexpression of ERC/mesothelin increased adhesion and migration/invasion but not proliferation
  • Mice given ERC/mesothelin-overexpressing cells survived a significantly shorter time than control mice; all 8 died or were euthanized by day 40, while 3 of 8 control mice survived to day 70 with no tumours
  • Tumour-forming efficiency was 100% (8/8) with ERC/mesothelin-overexpressing cells versus 62.5% (5/8) with control cells
  • Tumour length did not differ significantly: 13.6 ± 2.9 mm in the eight ERC/mesothelin-overexpressing tumours versus 12.2 ± 4.4 mm in the five control tumours
  • Biphasic tumours were found in both the ERC/mesothelin-overexpressing and control groups
  • The polygonal (epithelioid) pattern appeared only at the invading front of the tumours in both groups
  • Ki-67 positivity in both groups was 20–30% in epithelioid areas and 60–80% in sarcomatoid areas
• The authors' conclusion: The authors suggested that histological differentiation between epithelioid and sarcomatoid mesothelioma may be reversible and may be regulated by mechanisms other than those for ERC/mesothelin or EMT/MET
• Limitations the authors state:
  • The authors state that the mechanisms are not yet known and that further studies of intrinsic and microenvironmental factors are required
  • The authors could not detect MMP-9 by immunohistochemistry in the transplanted tumours of either group
  • Some supporting results are reported only as 'data not shown'

Topics

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

Medical terms in this study, explained in our Lexicon: Epithelioid, Sarcomatoid, Mesothelioma, Mesothelin, Biphasic Mesothelioma, Histological Subtype.

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• Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma — K. Kadota, K. Suzuki, et al. (2011)
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• Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter — K. Tan, K. Kajino, et al. (2010)
• The recurrence of malignant pleural mesothelioma 14 years after extrapleural pneumonectomy: possible histological transformation — T. Kinoshita, G. Ishii, et al. (2012)

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