Kinetics of host cell recruitment during dissemination of diffuse malignant peritoneal mesothelioma

Our plain-English summary of Kinetics of host cell recruitment during dissemination of diffuse malignant peritoneal mesothelioma, by N.R. Miselis, B.W. Lau, Z. Wu, et al (Cancer Microenvironment, 2010).

The study

• Authors: N.R. Miselis, B.W. Lau, Z. Wu, A.B. Kane
• Journal: Cancer Microenvironment
• Published: 2010;4(1):39-50
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Diffuse malignant mesothelioma is an aggressive tumor which displays a median survival of 11.2 months and a 5-year survival of less than 5% emphasizing the need for more effective treatments. This study uses an orthotopic model of malignant mesothelioma established in syngeneic, immunocompetent C57Bl/6 mice which produce malignant ascites and solid tumors that accurately replicate the histopathology of the human disease. Host stromal and immune cell accumulation within malignant ascites and solid tumors was determined using immunofluorescent labeling with confocal microscopy and fluorescence-activated cell sorting. An expression profile of cytokines and chemokines was produced using quantitative real-time PCR arrays. Tumor spheroids and solid tumors show progressive growth and infiltration with host stromal and immune cells including macrophages, endothelial cells, CD4(+) and CD8(+) lymphocytes, and a novel cell type, myeloid derived suppressor cells (MDSCs). The kinetics of host cell accumulation and inflammatory mediator expression within the tumor ascites divides tumor progression into two distinct phases. The first phase is characterized by progressive macrophage and T lymphocyte recruitment, with a cytokine profile consistent with regulatory T lymphocytes differentiation and suppression of T cell function. The second phase is characterized by decreased expression of macrophage chemotactic and T-cell regulating factors, an increase in MDSCs, and increased expression of several cytokines which stimulate differentiation of MDSCs. This cellular and expression profile suggests a mechanism by which host immune cells promote diffuse malignant mesothelioma progression.

Electronic Supplementary Material: The online version of this article (doi:10.1007/s12307-010-0048-1) contains supplementary material, which is available to authorized users.

In plain English

In this laboratory experiment, the authors injected cells from a mouse mesothelioma line, derived from an asbestos-induced mesothelioma, into the abdominal cavity of male C57Bl/6 mice. This produced malignant abdominal fluid (ascites), floating tumor-cell clusters (spheroids) and solid tumors. Clusters from a non-tumor comparison cell line disappeared after 14 days. Over 28 days the authors tracked tumor growth and the host cells entering the tumors. They measured signaling-gene activity in abdominal fluid cells before injection and at days 7, 14 and 21. Total tumor area rose from 2.1 to 5.4 square millimeters between days 7 and 14, then to 43.9 by day 21. At day 21, macrophages were the main host cell type (45.5% of ascitic cells, 27% of spheroid cells). Myeloid-derived suppressor cells made up 45% of ascitic cells at day 7 and reached 47% of spheroid cells at day 28. Of 64 gene transcripts, 42 changed in the same direction as in a published human pleural mesothelioma profile. In each species, changes were measured against laboratory-grown mesothelioma cells. The authors concluded that these profiles suggest a mechanism by which host immune cells promote mesothelioma progression.

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: orthotopic (tumor cells placed in the same body lining where the disease arises) model of peritoneal malignant mesothelioma in immunocompetent mice
• Who was studied: Male C57Bl/6 wild-type mice and C57Bl/6 mice carrying a green fluorescent protein (eGFP) marker, purchased from Jackson Laboratories. Tissues and ascites were harvested on days 7, 14, 21 and 28 after injection. RNA from abdominal fluid cells was collected before injection and at days 7, 14 and 21.
• Exposure: Intraperitoneal injection of cells from mouse mesothelioma cell line 40 L, which was derived from cell line 40, an asbestos-induced mesothelioma. The asbestos fiber type is not named in this text. The comparison was a non-tumorigenic immortalized mesothelial cell line, D9.
• Main results:
  • In mice injected with mesothelioma cells, total tumor area (tumor burden) increased from 2.1 mm2 to 5.4 mm2 between days 7 and 14
  • In mice injected with mesothelioma cells, tumor burden increased from 5.4 mm2 to 43.9 mm2 between days 14 and 21
  • In mice injected with the non-tumorigenic mesothelial cells, only very small cell aggregates formed, and they disappeared after 14 days
  • At 21 days, macrophages were the predominant host cell type: 45.5% of cells in ascitic fluid and 27% in spheroids (flow cytometry, at least 2 mice per group)
  • Myeloid-derived suppressor cells made up 45% of ascitic cells at 7 days but were not found in spheroids until 14 days
  • The proportion of myeloid-derived suppressor cells in spheroids rose to a maximum of 47% at 28 days
  • Host cell build-up and inflammatory signal gene expression in the ascites divided tumor progression into two phases
  • 42 of 64 transcripts (66%) in the mouse mesotheliomas showed changes similar to those in a published expression profile of human epithelial diffuse malignant pleural mesotheliomas. In each species, changes were measured relative to mesothelioma cell lines of that species grown in vitro.
• The authors' conclusion: The authors concluded that the cell and gene-expression profile suggests a mechanism by which host immune cells promote diffuse malignant mesothelioma progression

Topics

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Mesothelioma, Median Overall Survival, Ascites, Histopathology, Cytokine, Macrophage.

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