Microenvironment-Dependent Phenotypic Changes in a SCID Mouse Model for Malignant Mesothelioma

Our plain-English summary of Microenvironment-Dependent Phenotypic Changes in a SCID Mouse Model for Malignant Mesothelioma, by E. Darai-Ramqvist, G. Nilsonne, C. Flores-Staino, et al (Frontiers in Oncology, 2013).

The study

• Authors: E. Darai-Ramqvist, G. Nilsonne, C. Flores-Staino, A. Hjerpe, K. Dobra
• Journal: Frontiers in Oncology
• Published: 2013;3:203
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background And Aims: Malignant mesothelioma is an aggressive, therapy-resistant tumor. Mesothelioma cells may assume an epithelioid or a sarcomatoid phenotype, and presence of sarcomatoid cells predicts poor prognosis. In this study, we investigated differentiation of mesothelioma cells in a xenograft model, where mesothelioma cells of both phenotypes were induced to form tumors in severe combined immunodeficiency mice.

Methods: Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent in situ hybridization, and electron microscopy.

Results: Epithelioid and sarcomatoid cells gave rise to xenografts of similar epithelioid morphology. While sarcomatoid-derived xenografts had higher growth rates, the morphology and expression of differentiation-related markers was similar between xenografts derived from both phenotypes. aCGH showed a convergent genotype for both xenografts, resembling the original aggressive sarcomatoid cell sub-line.

Conclusion: Human mesothelioma xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state, and genetic analyses suggested that clonal selection in the mouse microenvironment was a major contributing factor. This thoroughly characterized animal model can be used for further studies of molecular events underlying tumor cell differentiation.

In plain English

This was an animal experiment in which two sub-lines of human malignant mesothelioma cells, derived from a single tumour and previously induced to stable epithelioid (STAV-AB) and sarcomatoid (STAV-FCS) phenotypes by serum composition, were inoculated into severe combined immunodeficiency (SCID) mice. One million cells were given subcutaneously or intraperitoneally to 6-week-old mice in three experiments using 19 mice in total; the first two experiments produced no tumours within 8 weeks. Tumour take after 15 weeks was 3/10 (two of five STAV-FCS, one of five STAV-AB), and 3/3 for STAV-FCS and 2/3 for STAV-AB in the second generation. Sarcomatoid-derived xenografts grew faster, but xenografts from both sub-lines converged on a similar epithelioid morphology and broadly similar marker expression; MIB-1 labelling was above 80% in STAV-AB xenografts and 40% in STAV-FCS xenografts. Chromosome 3 array CGH showed both xenografts resembled the sarcomatoid sub-line. The authors concluded that genetic analyses suggested clonal selection in the mouse microenvironment was a major contributing factor, while noting they could not rule out epigenetic changes or new (de novo) mutations.

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: animal experiment: human mesothelioma cell xenografts in SCID mice, with immunohistochemical, cytogenetic and ultrastructural characterisation
• Who was studied: Human mesothelioma cell sub-lines STAV-AB (epithelioid) and STAV-FCS (sarcomatoid), inoculated into 6-week-old SCID mice; three experiments with 19 mice in total (Karolinska Institutet, Sweden)
• Exposure: Not an exposure study; the manipulated variable was the phenotype of the inoculated mesothelioma cells (epithelioid STAV-AB versus sarcomatoid STAV-FCS), originally differentiated by serum composition
• Main results:
  • Tumour take after 15 weeks was 3/10 mice: two of five inoculated with sarcomatoid STAV-FCS and one of five with epithelioid STAV-AB; in the second generation take was 3/3 for STAV-FCS and 2/3 for STAV-AB
  • Sarcomatoid STAV-FCS tumours were detectable by palpation after 12 weeks
  • Epithelioid STAV-AB tumours required 14 weeks before they could be detected
  • At serial passage, STAV-FCS tumours were detected after 1 week, whereas STAV-AB xenografts were palpable only after 4 and 4.5 weeks and grew slower
  • Xenografts from both sub-lines showed a similar epithelioid-like morphology by light microscopy, irrespective of the inoculated phenotype
  • Proliferation marker MIB-1 was scored above 80% in STAV-AB xenografts and 40% in STAV-FCS xenografts (immunohistochemistry on one xenograft per cell sub-line)
  • Microvessel density (vessels per square millimetre) at 0 to 1.2 mm from the tumour margin was 14.3 plus or minus 1.7 for STAV-AB and 16.0 plus or minus 1.8 for STAV-FCS; at 1.2 to 4 mm it was 6.8 plus or minus 0.8 for STAV-AB and 3.2 plus or minus 0.5 for STAV-FCS
  • FISH showed heterogeneous subpopulations of about 10% in STAV-AB and about 20% in the FCS cell line, and non-dominant clones in 20% of cells in STAV-AB-derived and about 30% in STAV-FCS-derived xenografts
  • Chromosome 3 array CGH: both cell sub-lines shared a deletion at 3p14.3p21.3, and xenografts from both sub-lines showed a similar aberration pattern resembling the sarcomatoid STAV-FCS cells
  • Electron microscopy of both xenografts showed features of epithelioid mesothelioma (desmosomes, long slender microvilli, no glycocalyx), with lower microvillus density in the STAV-FCS-derived xenografts
• The authors' conclusion: The authors concluded that xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state and that genetic analyses suggested (not established) that clonal selection in the mouse microenvironment was a major contributing factor, with the model usable for further studies
• Limitations the authors state:
  • The authors stated they could not rule out contributions from epigenetic changes induced by the microenvironment or from de novo mutations
  • Greater variability in the array CGH data from xenografts, which the authors attributed to formaldehyde fixation of those specimens

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Epithelioid, Sarcomatoid, Prognosis, Clonal Selection.

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