Long-term exposure of mesothelial cells to SV40 and asbestos leads to malignant transformation and chemotherapy resistance

Our plain-English summary of Long-term exposure of mesothelial cells to SV40 and asbestos leads to malignant transformation and chemotherapy resistance, by A.L. Cleaver, K. Bhamidipaty, B. Wylie, et al (Carcinogenesis, 2014).

The study

• Authors: A.L. Cleaver, K. Bhamidipaty, B. Wylie, T. Connor, C. Robinson, B.W. Robinson, S.E. Mutsaers, R.A. Lake
• Journal: Carcinogenesis
• Published: 2014;35(2):407-14
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Simian virus 40 (SV40) has been implicated in the development of several cancers including malignant mesothelioma. A definitive role for the virus in human mesothelioma has not been unequivocally demonstrated but has been rigorously debated. The virus clearly has oncogenic potential: the TAg is one of the most potent transforming proteins known and acts synergistically with crocidolite asbestos to transform mesothelial cells. In this study, we show that SV40 oncogenes alone can cause malignant transformation and that asbestos-induced DNA damage and apoptosis occurs principally in cycling cells. After long-term exposure (up to 100 days) to both SV40 and asbestos, cells become resistant to stress-induced senescence. Significantly, these cells demonstrate resistance to chemotherapy-induced apoptosis. This finding has implications for the development of effective treatment options for patients with mesothelioma.

In plain English

This laboratory study used mouse cells, not people. The authors put two cancer-related genes from simian virus 40 (SV40) into mouse peritoneal mesothelial cells, creating a cell line called 20–2. They compared it with normal mouse mesothelial cells and an asbestos-induced mouse mesothelioma line, then exposed 20–2 and normal cells to crocidolite for 24 hours or up to 100 days. The 20–2 cells grew faster than normal cells and grew in soft agarose. They formed slow tumours (over 70 days) in mice engineered to carry the SV40 gene, but not in congenic mice. At one asbestos dose, 20–2 cells lost more activity than normal cells. After 100 days with crocidolite, 20–2 cells formed more colonies than unexposed 20–2 cells and did not senesce (stop dividing) with cisplatin. They also resisted chemotherapy-induced cell death more than unexposed 20–2 cells. Normal cells cultured long term had gained the ability to grow in soft agarose; those given asbestos became more sensitive to these drugs than those without. The authors suggested that patients with SV40 infection may be more resistant to such chemotherapies.

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: Laboratory (in vitro) study using a mouse cell model, with an additional experiment growing cells as tumours in mice
• Who was studied: Primary peritoneal mouse mesothelial cells (MTM), an SV40 large/small tumour antigen-expressing line made from them (20–2), and the mouse mesothelioma cell line AE17. Cells were also injected into C57Bl/6 or SV40 TAg transgenic mice.
• Exposure: Crocidolite asbestos (International Union against Cancer reference sample of Wittenoom Gorge), given to MTM and 20–2 cells. Doses were 0 to 10 µg/cm2 for 24 hours, or 5 µg/cm2 for up to 100 days. The 20–2 cells also expressed SV40 TAg/tAg oncogenes, which were introduced with a plasmid.
• Main results:
  • The SV40 oncogene-expressing 20–2 cells proliferated significantly faster than normal MTM cells (P < 0.0001).
  • Both 20–2 and AE17 cells formed colonies in soft agarose, and 20–2 did so at a higher frequency (P < 0.05). Normal MTM cells did not.
  • 20–2 cells did not form tumours in congenic mice but did form tumours in SV40 TAg transgenic mice. These tumours were slow to form (more than 70 days).
  • With 24 hours of crocidolite, metabolic activity fell with dose in both 20–2 and MTM cells. The fall was significantly greater in 20–2 cells at 7.5 µg/cm2 (P < 0.01).
  • Short-term asbestos exposure did not significantly change colony frequency or size for 20–2 cells.
  • MTM cells cultured long term had acquired anchorage independence and formed colonies in soft agarose.
  • After long-term asbestos exposure, 20–2 cells formed significantly more colonies than 20–2 cells cultured long-term without asbestos (P < 0.05).
  • Long-term cultured 20–2 cells, with or without asbestos, had no senescing cells, and cisplatin did not induce senescence in them.
  • Compared with long-term 20–2 cells without asbestos, long-term asbestos-exposed 20–2 cells showed increased resistance to apoptotic killing by low-concentration hydrogen peroxide, gemcitabine and cisplatin. The text gives no numbers for this.
  • Long-term MTM cultures given asbestos were more susceptible to apoptosis than long-term MTM cultures without asbestos.
• The authors' conclusion: The authors concluded that SV40 oncogene expression combined with long-term asbestos exposure led to resistance to apoptosis-inducing chemotherapy in these cells. They suggested that mesothelioma patients with SV40 infection may be more resistant to such chemotherapies.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Wittenoom, Western Australia

All asbestos mines

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelial Cells, SV40, Malignant Transformation, Chemotherapy, Mesothelioma, Crocidolite, Apoptosis.

Related studies

• Spontaneously immortalized mouse mesothelial cells display characteristics of malignant transformation — A.L. Sherwood, S.E. Mutsaers, et al. (2008)
• Crocidolite induces cell transformation and p53 gene mutation in BALB/c-3T3 cells — F. Lin, Y. Liu, et al. (2000)
• SV40-induced expression of calretinin protects mesothelial cells from asbestos cytotoxicity and may be a key factor contributing to mesothelioma pathogenesis — T. Henzi, W.V. Blum, et al. (2009)
• Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma — O.D. Røe, A. Szulkin, et al. (2012)
• Resistance to platinum-based chemotherapy in lung cancer cell lines — J. Chen, N. Emara, et al. (2010)
• Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma — F. Ishiguro, H. Murakami, et al. (2012)

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