Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma

Our plain-English summary of Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma, by J.S. Nader, J. Abadie, S. Deshayes, et al (Oncotarget, 2018).

The study

• Authors: J.S. Nader, J. Abadie, S. Deshayes, A. Boissard, S. Blandin, C. Blanquart, N. Boisgerault, O. Coqueret, C. Guette, M. Grégoire, D.L. Pouliquen
• Journal: Oncotarget
• Published: 2018;9(23):16311-16329
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Sarcomatoid mesothelioma (SM) is a devastating cancer associated with one of the poorest outcome. Therefore, representative preclinical models reproducing different tumor microenvironments (TME) observed in patients would open up new prospects for the identification of markers and evaluation of innovative therapies. Histological analyses of four original models of rat SM revealed their increasing infiltrative and metastatic potential were associated with differences in Ki67 index, blood-vessel density, and T-lymphocyte and macrophage infiltration. In comparison with the noninvasive tumor M5-T2, proteomic analysis demonstrated the three invasive tumors F4-T2, F5-T1 and M5-T1 shared in common a very significant increase in the abundance of the multifunctional proteins galectin-3, prohibitin and annexin A5, and a decrease in proteins involved in cell adhesion, tumor suppression, or epithelial differentiation. The increased metastatic potential of the F5-T1 tumor, relative to F4-T2, was associated with an increased macrophage vs T-cell infiltrate, changes in the levels of expression of a panel of cytokine genes, an increased content of proteins involved in chromatin organization, ribosome structure, splicing, or presenting anti-adhesive properties, and a decreased content of proteins involved in protection against oxidative stress, normoxia and intracellular trafficking. The most invasive tumor, M5-T1, was characterized by a pattern of specific phenotypic and molecular features affecting the presentation of MHC class I-mediated antigens and immune cell infiltration, or involved in the reorganization of the cytoskeleton and composition of the extracellular matrix. These four preclinical models and data represent a new resource available to the cancer research community to catalyze further investigations on invasiveness.

In plain English

This was a laboratory study in rats. The authors injected four rat mesothelioma cell lines, named M5-T2, F4-T2, F5-T1 and M5-T1, into the abdominal cavity of 12-week-old male Fischer F344 rats and compared the tumors that grew. The study did not test asbestos or any other fiber exposure. The tumors were mostly of the sarcomatoid type. M5-T2 tumors stayed on the surface lining and did not invade. F4-T2 and F5-T1 showed an intermediate level of invasion. M5-T1 invaded abdominal organs deeply and spread to multiple organs and nearby lymph nodes. F4-T2 and F5-T1 tumors were heavily infiltrated by macrophages and T lymphocytes, while M5-T1 tumors had few of these immune cells. Protein analysis found 137 proteins that changed in all three invasive tumors compared with M5-T2; the largest change was in galectin-3. M5-T1 showed lower levels of several proteins linked to immune recognition, the lowest expression of most cytokine genes tested, and the highest expression of the growth-factor genes Vegfa and Fgf2. The authors concluded that the four models are new tools for basic research.

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: rat mesothelioma cell lines were injected into the peritoneal cavity of rats, and the resulting tumors were compared by histology, immunohistochemistry, proteomics (SWATH-MS) and cytokine gene expression (RT-qPCR)
• Who was studied: 12-week-old male Fischer F344 rats (France) injected with four rat mesothelioma cell lines (M5-T2, F4-T2, F5-T1, M5-T1). The lines came from a biocollection of 27 preneoplastic and neoplastic F344 rat cell lines established in 2011. The number of rats is not stated.
• Exposure: No asbestos or fiber exposure was studied. Rats received intraperitoneal injections of mesothelioma cells: 5 million cells for M5-T2 and F4-T2, and 3 million cells for F5-T1 and M5-T1.
• Main results:
  • M5-T2 tumors were noninvasive: growth was restricted to the serosal surface, and the mean Ki67 index was 6 per high-power field
  • M5-T1 tumors showed deep infiltration of abdominal organs and multiple visceral and regional nodal metastases, with high blood-vessel density and low T-lymphocyte and macrophage infiltration
  • F4-T2 and F5-T1 tumors had an intermediate invasive phenotype, with stroma heavily infiltrated by macrophages and a significant T-lymphocyte infiltrate; infiltration was greater with F4-T2 than with F5-T1
  • Compared with noninvasive M5-T2, 137 proteins were changed in all three invasive tumors; the largest change was in galectin-3
  • In M5-T1, four immune-related proteins (including an RT1 class I histocompatibility antigen and antigen peptide transporter 2) were specifically reduced
  • M5-T1 had the lowest expression of most cytokine genes but the highest expression of the growth-factor genes Vegfa and Fgf2; F5-T1 had the highest level of seven cytokines
• The authors' conclusion: The authors concluded that the four rat mesothelioma models, with their specific cellular and molecular features, are new tools for basic research in oncoimmunology and oncoproteomics

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Sarcomatoid, Tumor Microenvironment, Macrophage, Cytokine, Oxidative Stress.

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