Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model

Our plain-English summary of Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model, by J.M. Hillegass, A. Shukla, S.A. Lathrop, et al (Annals of the New York Academy of Sciences, 2010).

The study

• Authors: J.M. Hillegass, A. Shukla, S.A. Lathrop, M.B. MacPherson, S.L. Beuschel, K.J. Butnor, J.R. Testa, H.I. Pass, M. Carbone, C. Steele, B.T. Mossman
• Journal: Annals of the New York Academy of Sciences
• Published: 2010;1203:7-14
• Cited by: 61 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived IL-6, IL-8, bFGF, and VEGF were observed in mice at 7 days postinjection of either MM line, and a striking neutrophilia was observed at all time points. Free-floating tumor spheroids developed in mice at 14 days, and both spheroids and adherent MM tumor masses occurred in all mice at 30 days. Results suggest that inflammation and cytokine production precede and may be critical to the development of MMs.

In plain English

This was a mouse experiment; no asbestos was used. The authors injected two human pleural malignant mesothelioma (MM) cell lines, Hmeso and PPM Mill, into the abdomens of male SCID mice, which lack working immune B and T cells. Three mice per group, including salt-water controls, were examined at 7, 14 and 30 days. Abdominal wash fluid was tested for immune cells and human and mouse signalling proteins (cytokines). No tumors were seen at 1 week. At 30 days all mice injected with MM cells had free-floating and attached tumors (epithelioid or biphasic MMs); control mice had none. Compared with controls, the share of abdominal-fluid cells that were neutrophils (white blood cells) was sixfold and 52-fold higher at 14 and 30 days after Hmeso cells, and up to 89-fold higher after PPM Mill cells. A twofold day-7 rise given in the text appears in the article's table as a lymphocyte change. Human cytokines including IL-6, IL-8, bFGF and VEGF were raised at 7 days with either cell line. The authors concluded that these changes came before tumor formation. They suggested that mesothelial cells may perpetuate chronic inflammation over mesothelioma's long latency.

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 (mouse xenograft model: human tumor cells grown in immunodeficient mice), with saline-injected control mice
• Who was studied: 6-week-old male Fox Chase SCID mice, 3 mice per group per time point, examined at 7, 14 and 30 days after injection
• Exposure: No asbestos exposure in this study. Mice were injected in the peritoneal cavity with 5 million cells of one of two human pleural MM cell lines: Hmeso (epithelioid in the lab dish) or PPM Mill (fibrosarcomatoid in the lab dish). Control mice were injected with saline.
• Main results:
  • No tumors were seen in mice examined at 1 week after injection of MM cells.
  • At 30 days, all MM-injected mice had free-floating spheroid tumors and masses attached to the mesentery. The tables list 0% spheroid and 0% mesenteric tumors in control mice and 100% of each in MM-injected mice at 30 days.
  • Both cell lines formed epithelioid or biphasic MMs in the mice, judged by histopathology.
  • The tables report fold changes in the percentages of lavage cells, not absolute counts.
  • In Hmeso-injected mice, the Results text gives neutrophils as twofold, sixfold and 52-fold higher than in saline-injected mice at 7, 14 and 30 days. Table 1 lists the sixfold (day 14) and 52-fold (day 30) neutrophil changes, but assigns the day-7 twofold change to lymphocytes and lists no day-7 neutrophil change.
  • In PPM Mill-injected mice, neutrophils rose progressively, up to 89-fold higher than in saline-injected mice.
  • With either cell line, human cytokines including IL-6, IL-8, bFGF and VEGF were increased in abdominal wash fluid at 7 days.
  • The mouse cytokine KC, a neutrophil attractant, was increased at all time points with both cell lines.
• The authors' conclusion: The authors concluded that cytokines related to inflammation, cell growth and blood-vessel formation were produced before tumors formed. Because MM cells can secrete these factors themselves, and several of the same cytokines are produced in response to asbestos fibers, they suggested that chronic inflammation may be perpetuated by mesothelial cells.

Topics

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

Medical terms in this study, explained in our Lexicon: Inflammation, Malignant Mesothelioma, Chronic Inflammation, Cytokine.

Related studies

• Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma — M.J. Lathrop, E.K. Sage, et al. (2015)
• Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts — S.L. Macura, J.L. Steinbacher, et al. (2013)
• ERK2 is essential for the growth of human epithelioid malignant mesotheliomas — A. Shukla, J.M. Hillegass, et al. (2011)
• Decreased asbestos-induced lung inflammation and fibrosis after radiation and bone marrow transplant — J. Levis, R. Loi, et al. (2008)
• Restored expression of the MYO18B gene suppresses orthotopic growth and the production of bloody pleural effusion by human malignant pleural mesothelioma cells in SCID mice — N. Edakuni, K. Ikuta, et al. (2006)
• Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model — A.S. Abu Lila, C. Kato, et al. (2016)

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