Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells

Our plain-English summary of Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells, by R. Mezzapelle, E. Rrapaj, E. Gatti, et al (Scientific Reports, 2016).

The study

• Authors: R. Mezzapelle, E. Rrapaj, E. Gatti, C. Ceriotti, F.D. Marchis, A. Preti, A.E. Spinelli, L. Perani, M. Venturini, S. Valtorta, R.M. Moresco, L. Pecciarini, C. Doglioni, M. Frenquelli, L. Crippa, C. Recordati, E. Scanziani, H. de Vries, A. Berns, R. Frapolli, R. Boldorini, M. D'Incalci, M.E. Bianchi, M.P. Crippa
• Journal: Scientific Reports
• Published: 2016;6:22850
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment.

In plain English

This laboratory study characterized three murine malignant mesothelioma cell lines (AB1, AB12, AB22), originally derived from tumors in female BALB/c mice injected intraperitoneally with asbestos fibers, and the tumors they produced when injected into immunocompetent BALB/c mice. In culture the cells showed sarcomatoid (AB1), biphasic (AB12) and stellate/epithelioid (AB22) morphology and surface microvilli. Karyotyping showed AB1-B/c and AB22-B/c were hyper-triploid (61-76 and 64-75 chromosomes, with two AB1-B/c nuclei containing 131 and 133 chromosomes) and AB12-B/c nearly tetraploid (73-80 chromosomes). HMGB1 mRNA was about twofold higher in AB lines than primary mesothelial cells, and secreted HMGB1 measured by ELISA was 20-30 fold higher. HMGB1 at 30 ng/ml attracted all AB lines and increased invasion of AB1- and AB12-B/c-LUC but not AB22-B/c-LUC cells. Intraperitoneal injection of the AB cells produced sizable tumor masses in 2-3 weeks; tumors grown from AB1 cells were studied by bioluminescence, ultrasound and 18F-FDG PET and showed vascularization without necrosis. In mice bearing AB1-B/c-LUC tumors (ten per group), cisplatin extended survival and gemcitabine delayed disease onset, while pemetrexed did not significantly affect survival. The authors advocated this syngeneic system for studying mesothelioma development and treatment.

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: Experimental laboratory and animal study: molecular, cellular, histological and imaging characterization of murine mesothelioma cell lines and of syngeneic tumors in immunocompetent mice, with a drug-treatment survival experiment
• Who was studied: Murine mesothelioma cell lines AB1, AB12 and AB22 (obtained from Cell Bank Australia) and their re-isolated and luciferase-expressing derivatives, plus immunocompetent BALB/c mice injected intraperitoneally with these cells; the drug experiment used 7-week-old female BALB/c mice, ten per group; work done at Italian institutes, published 2016
• Exposure: Not an exposure study in people: the cell lines originated from mesotheliomas arising in BALB/c mice injected intraperitoneally with asbestos fibers; experimental exposures were HMGB1 (30 ng/ml) and the drugs cisplatin (DDP) 5 mg/kg q7dx3, gemcitabine 100 mg/kg q4dx5 and pemetrexed 200 mg/kg q4dx4
• Main results:
  • The three cell lines showed sarcomatoid (AB1), biphasic (AB12) and stellate/epithelioid (AB22) morphology, with microvilli seen by transmission electron microscopy
  • Karyotypes: AB1-B/c and AB22-B/c hyper-triploid (61-76 and 64-75 chromosomes, with two AB1-B/c nuclei containing 131 and 133 chromosomes); AB12-B/c nearly tetraploid (73-80 chromosomes)
  • HMGB1 mRNA was about twofold higher in the AB mesothelioma lines than in primary mesothelial cells
  • Secreted HMGB1 measured by ELISA was 20-30 fold higher in the culture medium of the murine mesothelioma cells than of primary mesothelial cells
  • HMGB1 (30 ng/ml) acted as a chemoattractant for all AB lines and increased invasion of AB1-B/c-LUC and AB12-B/c-LUC cells but not AB22-B/c-LUC cells (p less than 0.0001)
  • Intraperitoneal injection of AB cells into BALB/c mice produced sizable tumor masses in 2-3 weeks
  • In explanted tumors generated by injection of AB1 cells there was no evidence of necrosis, and anti-CD31 staining showed capillaries inside the masses
  • On immunohistochemistry only vimentin was positive in all cells and tumors; few AB1 cells stained for wide spectrum cytokeratin and AB22 cells for WT1; E-cadherin, beta-catenin and smooth muscle actin also gave signals
  • In mice bearing AB1-B/c-LUC tumors, cisplatin (DDP) and gemcitabine extended survival relative to the control group
  • In the same AB1-B/c-LUC tumor-bearing mice, pemetrexed did not significantly extend survival
• The authors' conclusion: The authors concluded that AB cells show phenotypical and functional features of mesothelioma in vitro and in vivo, produce tumors similar to human mesothelioma and respond to drugs qualitatively as human mesothelioma does, and they advocated use of immunocompetent mice injected with AB cells (particularly AB1) as a preclinical system
• Limitations the authors state:
  • The authors noted the genome sequencing of the three original cell lines was done at low coverage
  • The combined cisplatin (carboplatin)-pemetrexed regimen used in patients was not tested in this study
  • The authors noted discrepancies between cultured cells and the tumors derived from them in expression of surface markers
  • At early stages of tumor development growth could be followed only by bioluminescence signal, because ultrasound could not distinguish tumor masses from structures such as lymph nodes

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, High Mobility Group Box 1 (HMGB1).

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