Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration

Our plain-English summary of Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration, by A. Crowe, C. Jackaman, K.M. Beddoes, et al (PloS One, 2013).

The study

• Authors: A. Crowe, C. Jackaman, K.M. Beddoes, B. Ricciardo, D.J. Nelson
• Journal: PloS One
• Published: 2013;8(8):e73684
• Cited by: 51 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4(+) T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.

In plain English

This was a laboratory study in mice, with some experiments on cells grown in dishes. The authors implanted a mouse mesothelioma cell line called AE17 under the skin of female C57BL/6J mice in Perth, Western Australia. The cell line had originally been made by injecting asbestos fibres into the abdomens of mice; the fibre type is not named. The authors measured copper in the growing tumors and tested three drugs that lower available copper: penicillamine, trientine and tetrathiomolybdate (TM). Tumors held the most copper at early stages, at concentrations over 5 times those in livers and kidneys. When started after tumors were established, all three drugs slowed tumor growth, significantly so for trientine and TM (4 or 5 mice per group). TM worked about as well as the chemotherapy drug cisplatin. However, mice given TM or trientine all eventually succumbed to their tumors. In dishes, the drugs did not significantly affect tumor cell growth. In small groups of 2 treated mice per drug, copper lowering was linked to changes in tumor blood vessels. With penicillamine and trientine it was also linked to more CD4+ T cells in the tumors. The authors concluded that copper lowering is a potentially useful strategy that could allow other treatments to be added.

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 tumor model), with supporting in vitro cell experiments
• Who was studied: Female C57BL/6J mice aged 6 to 8 weeks, housed at Curtin University, Perth, Western Australia, given subcutaneous implants of the AE17 mouse mesothelioma cell line; group sizes ranged from 2 to 10 mice depending on the experiment
• Exposure: The tumor cells came from a cell line derived in mice after intraperitoneal injection of asbestos fibres (fibre type not stated). The treatments tested were three copper-lowering drugs: TM 500 µg, trientine 700 µg and penicillamine 2000 µg per dose per mouse. These were compared with cisplatin and with an anti-VEGF receptor antibody (DC101).
• Main results:
  • Mesothelioma tumors had their highest copper concentrations at early stages, over 5 times those found in livers and kidneys; levels then dropped as tumors grew
  • Treatment started after tumors reached 20-25 mm2: all three copper-lowering drugs slowed tumor growth, and tumors in trientine- and TM-treated mice were significantly smaller than in controls (n = 4 or 5 mice per group)
  • In a separate experiment (n = 6 mice per group), TM and cisplatin were equally effective and each significantly slowed tumor growth
  • TM and trientine did not give long-term survival; all treated mice eventually succumbed to tumors
  • In cell culture, none of the three drugs had a significant effect on AE17 tumor cell proliferation
  • Copper lowering begun two weeks before tumor implantation delayed tumor growth only temporarily; after day 35 tumors in all treated groups had caught up with or overtaken controls
  • In TM- and trientine-treated mice, tumor vessel diameter decreased and vessel length increased; penicillamine appeared to increase vessel diameter (2 mice per treated group, 4 controls)
  • Trientine and TM significantly increased the proportion of normal CD31+CD34+ endothelial cells, which showed lower proliferation (Ki67) and lower ICAM/CD54 expression
  • CD4+ T cells in tumors increased significantly with penicillamine and trientine; the increase with TM was not statistically significant; CD8+ T cells did not change (2 mice per group)
  • Adding copper to drinking water after tumors had started growing unexpectedly slowed tumor growth
• The authors' conclusion: The authors proposed that copper lowering is a potentially useful and relatively non-toxic anti-mesothelioma strategy. In their view, it slows tumor growth enough to provide a window for adding other treatments.
• Limitations the authors state:
  • The mouse food still contained copper; future studies will use a copper-depleted diet
  • The authors did not measure copper accumulation in tumors growing in an environment depleted of copper, nor release tumors from copper depletion
  • The copper-loading results were described as difficult to interpret
  • The reasons for the selective increase in CD4+ T cells are unclear

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cisplatin, Chemotherapy.

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