Proceedings of the National Academy of Sciences of the United States of America

Our medical research library holds 35 studies published in Proceedings of the National Academy of Sciences of the United States of America (1985–2024). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 33 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 2 studies PubMed has no abstract for, we give the abstract printed in the article or, where there is none, a summary we wrote from it, each labeled as such.

About the journal

• Publisher: National Academy of Sciences
• Published: 1915 to the present, United States
• Language: English
• ISSN: 0027-8424 (print), 1091-6490 (electronic)
• Its record in the NLM Catalog

2020s

• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling. F. Novelli, Y. Yoshikawa, V.A.M. Vitto, et al. 2024;121(29):e2405231121. PubMed · Publisher · Free full text

  Abstract

  We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.

• Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting a juxtamembrane epitope. X.F. Liu, M. Onda, J. Schlomer, et al. 2024;121(4):e2317283121. PubMed · Publisher · Free full text

  Abstract

  Despite many clinical trials, CAR-T cells are not yet approved for human solid tumor therapy. One popular target is mesothelin (MSLN) which is highly expressed on the surface of about 30% of cancers including mesothelioma and cancers of the ovary, pancreas, and lung. MSLN is shed by proteases that cleave near the C terminus, leaving a short peptide attached to the cell. Most anti-MSLN antibodies bind to shed MSLN, which can prevent their binding to target cells. To overcome this limitation, we developed an antibody (15B6) that binds next to the membrane at the protease-sensitive region, does not bind to shed MSLN, and makes CAR-T cells that have much higher anti-tumor activity than a CAR-T that binds to shed MSLN. We have now humanized the Fv (h15B6), so the CAR-T can be used to treat patients and show that h15B6 CAR-T produces complete regressions in a hard-to-treat pancreatic cancer patient derived xenograft model, whereas CAR-T targeting a shed epitope (SS1) have no anti-tumor activity. In these pancreatic cancers, the h15B6 CAR-T replicates and replaces the cancer cells, whereas there are no CAR-T cells in the tumors receiving SS1 CAR-T. To determine the mechanism accounting for high activity, we used an OVCAR-8 intraperitoneal model to show that poorly active SS1-CAR-T cells are bound to shed MSLN, whereas highly active h15B6 CAR-T do not contain bound MSLN enabling them to bind to and kill cancer cells.

• BAP1 is a novel regulator of HIF-1α. A. Bononi, Q. Wang, A.A. Zolondick, et al. 2023;120(4):e2217840120. PubMed · Publisher · Free full text

  Abstract

  BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.

• Defining and targeting tumor-associated macrophages in malignant mesothelioma. L. Wu, M. Kohno, J. Murakami, et al. 2023;120(9):e2210836120. PubMed · Publisher · Free full text

  Abstract

  Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal/pleural macrophages (SPM), and the tissue-resident large peritoneal/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D-/-) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in vivo and in vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial-mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-α/NFkB signaling pathways, LPM activated the IFN-γ response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes, TREM2, STAB1, LAIR1, GPNMB, and MARCO, could potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM.

• HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma. J.S. Suarez, F. Novelli, K. Goto, et al. 2023;120(39):e2307999120. PubMed · Publisher · Free full text

  Abstract

  Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.

• Anti-mesothelin immunotoxin induces mesothelioma eradication, anti-tumor immunity, and the development of tertiary lymphoid structures. W. Liu, C.H. Tai, X. Liu, et al. 2022;119(48):e2214928119. PubMed · Publisher · Free full text

  Abstract

  LMB-100 is a recombinant immunotoxin composed of a Fab linked to a toxin. It kills cells expressing human mesothelin (hMSLN), which is highly expressed on the surface of mesothelioma and many other cancer cells. Clinically, we observed some patients had delayed responses to an anti-hMSLN immunotoxin treatment, suggesting the induction of anti-tumor immunity. We aimed to develop a mouse model to investigate whether immunotoxin alone can induce anti-tumor immunity and to study the mechanism of this immunity. An immunocompetent transgenic mouse was used to grow mouse mesothelioma AB1 cells expressing hMSLN in the peritoneal cavity. Mice were treated with LMB-100, and mice with complete responses (CRs) were rechallenged with tumor cells to determine whether anti-tumor immunity developed. Changes in gene expression profiles were evaluated by Nanostring, and changes in cytokines and chemokines were checked by protein arrays. The distribution of various immune cells was assessed by immunohistochemistry. Our results show that the mice with tumor reached CRs and developed anti-tumor immunity after LMB-100 treatment alone. The primary response requires CD8+ T cells, CD4+ T cells, and B cells. Transcriptional profiling shows that LMB-100 treatment reshapes the tumor immune microenvironment by upregulating chemotaxis signals. LMB-100 treatment upregulates genes associated with tertiary lymphoid structures (TLS) development and induces TLS formation in tumors. In sum, immunotoxin-mediated cell death induces anti-tumor immunity and the development of TLS, which provides insights into how immunotoxins cause tumor regressions.

• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos. F. Novelli, A. Bononi, Q. Wang, et al. 2021;118(48). PubMed · Publisher · Free full text

  Abstract

  Carriers of heterozygous germline BAP1 mutations (BAP1+/-) are affected by the "BAP1 cancer syndrome." Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1+/- cells secrete increased amounts of HMGB1, and that BAP1+/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.

• Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis. S. Watanabe, N.S. Markov, Z. Lu, et al. 2021;118(20). PubMed · Publisher · Free full text

  Abstract

  Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

  Copyright © 2021 the Author(s). Published by PNAS.

• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy. J. Xue, S. Patergnani, C. Giorgi, et al. 2020;117(41):25543-25552. PubMed · Publisher · Free full text

  Abstract

  Asbestos causes malignant transformation of primary human mesothelial cells (HM), leading to mesothelioma. The mechanisms of asbestos carcinogenesis remain enigmatic, as exposure to asbestos induces HM death. However, some asbestos-exposed HM escape cell death, accumulate DNA damage, and may become transformed. We previously demonstrated that, upon asbestos exposure, HM and reactive macrophages releases the high mobility group box 1 (HMGB1) protein that becomes detectable in the tissues near asbestos deposits where HMGB1 triggers chronic inflammation. HMGB1 is also detectable in the sera of asbestos-exposed individuals and mice. Searching for additional biomarkers, we found higher levels of the autophagy marker ATG5 in sera from asbestos-exposed individuals compared to unexposed controls. As we investigated the mechanisms underlying this finding, we discovered that the release of HMGB1 upon asbestos exposure promoted autophagy, allowing a higher fraction of HM to survive asbestos exposure. HMGB1 silencing inhibited autophagy and increased asbestos-induced HM death, thereby decreasing asbestos-induced HM transformation. We demonstrate that autophagy was induced by the cytoplasmic and extracellular fractions of HMGB1 via the engagement of the RAGE receptor and Beclin 1 pathway, while nuclear HMGB1 did not participate in this process. We validated our findings in a novel unique mesothelial conditional HMGB1-knockout (HMGB1-cKO) mouse model. Compared to HMGB1 wild-type mice, mesothelial cells from HMGB1-cKO mice showed significantly reduced autophagy and increased cell death. Autophagy inhibitors chloroquine and desmethylclomipramine increased cell death and reduced asbestos-driven foci formation. In summary, HMGB1 released upon asbestos exposure induces autophagy, promoting HM survival and malignant transformation.

• Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma. A. Bononi, K. Goto, G. Ak, et al. 2020;117(52):33466-33473. PubMed · Publisher · Free full text

  Abstract

  Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM+/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM+/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm+/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm+/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm+/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM+/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

  Copyright © 2020 the Author(s). Published by PNAS.

2010s

• Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma. T. Villanova, I. Gesmundo, V. Audrito, et al. 2019;116(6):2226-2231. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

  Copyright © 2019 the Author(s). Published by PNAS.

• Mantle wedge infiltrated with saline fluids from dehydration and decarbonation of subducting slab. T. Kawamoto, M. Yoshikawa, Y. Kumagai, et al. 2013;110(24):9663-8. PubMed · Publisher · Free full text

  Abstract

  Slab-derived fluids play an important role in heat and material transfer in subduction zones. Dehydration and decarbonation reactions of minerals in the subducting slab have been investigated using phase equilibria and modeling of fluid flow. Nevertheless, direct observations of the fluid chemistry and pressure-temperature conditions of fluids are few. This report describes CO2-bearing saline fluid inclusions in spinel-harzburgite xenoliths collected from the 1991 Pinatubo pumice deposits. The fluid inclusions are filled with saline solutions with 5.1 ± 1.0% (wt) NaCl-equivalent magnesite crystals, CO2-bearing vapor bubbles, and a talc and/or chrysotile layer on the walls. The xenoliths contain tremolite amphibole, which is stable in temperatures lower than 830 °C at the uppermost mantle. The Pinatubo volcano is located at the volcanic front of the Luzon arc associated with subduction of warm oceanic plate. The present observation suggests hydration of forearc mantle and the uppermost mantle by slab-derived CO2-bearing saline fluids. Dehydration and decarbonation take place, and seawater-like saline fluids migrate from the subducting slab to the mantle wedge. The presence of saline fluids is important because they can dissolve more metals than pure H2O and affect the chemical evolution of the mantle wedge.

• Microbial diversity in The Cedars, an ultrabasic, ultrareducing, and low salinity serpentinizing ecosystem. S. Suzuki, S. Ishii, A. Wu, et al. 2013;110(38):15336-41. PubMed · Publisher · Free full text

  Abstract

  The Cedars, in coastal northern California, is an active site of peridotite serpentinization. The spring waters that emerge from this system feature very high pH, low redox potential, and low ionic concentrations, making it an exceptionally challenging environment for life. We report a multiyear, culture-independent geomicrobiological study of three springs at The Cedars that differ with respect to the nature of the groundwater feeding them. Within each spring, both geochemical properties and microbial diversity in all three domains of life remained stable over a 3-y period, with multiple samples each year. Between the three springs, however, the microbial communities showed considerable differences that were strongly correlated with the source of the serpentinizing groundwater. In the spring fed solely by deep groundwater, phylum Chloroflexi, class Clostridia, and candidate division OD1 were the major taxa with one phylotype in Euryarchaeota. Less-abundant phylotypes include several minor members from other candidate divisions and one phylotype that was an outlier of candidate division OP3. In the springs fed by the mixture of deep and shallow groundwater, organisms close to the Hydrogenophaga within Betaproteobacteria dominated and coexisted with the deep groundwater community members. The shallow groundwater community thus appears to be similar to those described in other terrestrial serpentinizing sites, whereas the deep community is distinctly different from any other previously described terrestrial serpentinizing community. These unique communities have the potential to yield important insights into the development and survival of life in these early-earth analog environments.

• High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma. E. Mazzoni, A. Corallini, A. Cristaudo, et al. 2012;109(44):18066-71. PubMed · Publisher · Free full text

  Abstract

  Human malignant pleural mesothelioma (MPM) is considered a rare tumor, but recent estimations indicate that one-quarter million people will die of this neoplasm in Europe in the next three decades. The mineral asbestos is considered the main causative agent of this neoplasm. MPM is largely unresponsive to conventional chemotherapy/radiotherapy. In addition to asbestos exposure, genetic predisposition to asbestos carcinogenesis and to simian virus (SV)40 infection has also been suggested. SV40 is a DNA tumor virus found in some studies to be associated at high prevalence with MPM. SV40 sequences have also been detected, although at a lower prevalence than in MPM, in blood specimens from healthy donors. However, some studies have failed to reveal SV40 footprints in MPM and its association with this neoplasm. These conflicting results indicate the need for further investigations with new approaches. We report on the presence of antibodies in serum samples from patients affected by MPM that specifically react with two different SV40 mimotopes. The two SV40 peptides used in indirect ELISAs correspond to viral capsid proteins. ELISA with the two SV40 mimotopes gave overlapping results. Our data indicate that in serum samples from MPM-affected patients (n = 97), the prevalence of antibodies against SV40 viral capsid protein antigens is significantly higher (26%, P = 0.043) than in the control group (15%) represented by healthy subjects (n = 168) with the same median age (66 y) and sex. Our results suggest that SV40 is associated with a subset of MPM and circulates in humans.

• Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. H. Nagai, Y. Okazaki, S.H. Chew, et al. 2011;108(49):E1330-8. PubMed · Publisher · Free full text

  Abstract

  Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter ∼ 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammogenicity and mesotheliomagenicity in vivo. In contrast, thick (diameter ∼ 150 nm) or tangled (diameter ∼ 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.

• Erionite exposure in North Dakota and Turkish villages with mesothelioma. M. Carbone, Y.I. Baris, P. Bertino, et al. 2011;108(33):13618-23. PubMed · Publisher · Free full text

  Abstract

  Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted.

• Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β. A.S. Yazdi, G. Guarda, N. Riteau, et al. 2010;107(45):19449-54. PubMed · Publisher · Free full text

  Abstract

  Nanoparticles are increasingly used in various fields, including biomedicine and electronics. One application utilizes the opacifying effect of nano-TiO(2), which is frequently used as pigment in cosmetics. Although TiO(2) is believed to be biologically inert, an emerging literature reports increased incidence of respiratory diseases in people exposed to TiO(2). Here, we show that nano-TiO(2) and nano-SiO(2), but not nano-ZnO, activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome, leading to IL-1β release and in addition, induce the regulated release of IL-1α. Unlike other particulate Nlrp3 agonists, nano-TiO(2)-dependent-Nlrp3 activity does not require cytoskeleton-dependent phagocytosis and induces IL-1α/β secretion in nonphagocytic keratinocytes. Inhalation of nano-TiO(2) provokes lung inflammation which is strongly suppressed in IL-1R- and IL-1α-deficient mice. Thus, the inflammation caused by nano-TiO(2) in vivo is largely caused by the biological effect of IL-1α. The current use of nano-TiO(2) may present a health hazard due to its capacity to induce IL-1R signaling, a situation reminiscent of inflammation provoked by asbestos exposure.

• Noachian and more recent phyllosilicates in impact craters on Mars. A.G. Fairén, V. Chevrier, O. Abramov, et al. 2010;107(27):12095-100. PubMed · Publisher · Free full text

  Abstract

  Hundreds of impact craters on Mars contain diverse phyllosilicates, interpreted as excavation products of preexisting subsurface deposits following impact and crater formation. This has been used to argue that the conditions conducive to phyllosilicate synthesis, which require the presence of abundant and long-lasting liquid water, were only met early in the history of the planet, during the Noachian period (> 3.6 Gy ago), and that aqueous environments were widespread then. Here we test this hypothesis by examining the excavation process of hydrated minerals by impact events on Mars and analyzing the stability of phyllosilicates against the impact-induced thermal shock. To do so, we first compare the infrared spectra of thermally altered phyllosilicates with those of hydrated minerals known to occur in craters on Mars and then analyze the postshock temperatures reached during impact crater excavation. Our results show that phyllosilicates can resist the postshock temperatures almost everywhere in the crater, except under particular conditions in a central area in and near the point of impact. We conclude that most phyllosilicates detected inside impact craters on Mars are consistent with excavated preexisting sediments, supporting the hypothesis of a primeval and long-lasting global aqueous environment. When our analyses are applied to specific impact craters on Mars, we are able to identify both pre- and postimpact phyllosilicates, therefore extending the time of local phyllosilicate synthesis to post-Noachian times.

• Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. H. Yang, Z. Rivera, S. Jube, et al. 2010;107(28):12611-6. PubMed · Publisher · Free full text

  Abstract

  Asbestos carcinogenesis has been linked to the release of cytokines and mutagenic reactive oxygen species (ROS) from inflammatory cells. Asbestos is cytotoxic to human mesothelial cells (HM), which appears counterintuitive for a carcinogen. We show that asbestos-induced HM cell death is a regulated form of necrosis that links to carcinogenesis. Asbestos-exposed HM activate poly(ADP-ribose) polymerase, secrete H(2)O(2), deplete ATP, and translocate high-mobility group box 1 protein (HMGB1) from the nucleus to the cytoplasm, and into the extracellular space. The release of HMGB1 induces macrophages to secrete TNF-alpha, which protects HM from asbestos-induced cell death and triggers a chronic inflammatory response; both favor HM transformation. In both mice and hamsters injected with asbestos, HMGB1 was specifically detected in the nuclei, cytoplasm, and extracellular space of mesothelial and inflammatory cells around asbestos deposits. TNF-alpha was coexpressed in the same areas. HMGB1 levels in asbestos-exposed individuals were significantly higher than in nonexposed controls (P < 0.0001). Our findings identify the release of HMGB1 as a critical initial step in the pathogenesis of asbestos-related disease, and provide mechanistic links between asbestos-induced cell death, chronic inflammation, and carcinogenesis. Chemopreventive approaches aimed at inhibiting the chronic inflammatory response, and especially blocking HMGB1, may decrease the risk of malignant mesothelioma among asbestos-exposed cohorts.

2000s

• Activated TNF-alpha/NF-kappaB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice. D.A. Altomare, C.W. Menges, J. Pei, et al. 2009;106(9):3420-5. PubMed · Publisher · Free full text

  Abstract

  The human CDKN2A locus encodes 2 distinct proteins, p16(INK4A) and p14(ARF) [mouse p19(Arf)], designated INK4A (inhibitor of cyclin dependent kinase 4) and ARF (alternative reading frame) here, that are translated from alternatively spliced mRNAs. Human ARF is implicated as a tumor suppressor gene, mainly in association with the simultaneous deletion of INK4A. However, questions remain as to whether loss of ARF alone is sufficient to drive tumorigenesis. Here, we report that mice deficient for Arf are susceptible to accelerated asbestos-induced malignant mesothelioma (MM). MMs arising in Arf (+/-) mice consistently exhibit biallelic inactivation of Arf, but, unexpectedly, do not acquire additional recurrent genetic alterations that we previously identified in asbestos-induced MMs arising in Nf2 (+/-) mice. Array CGH analysis was used to detect a recurrent deletion at chromosome 4C6 in MMs from Arf (+/-) mice. A candidate gene in this region, Faf1 (FAS-associated factor 1), was further explored, because it encodes a protein implicated in tumor cell survival and in the pathogenesis of some human tumor types. We confirmed hemizygous loss of Faf1 and down-regulation of Faf1 protein in a series of MMs from Arf (+/-) mice, and we then showed that Faf1 regulates TNF-alpha-mediated NF-kappaB signaling, a pathway previously implicated in asbestos-induced oncogenesis of human mesothelial cells. Collectively, these data indicate that Arf inactivation has a significant role in driving MM pathogenesis, and implicate Faf1 as a key component in the TNF-alpha/NF-kappaB signaling node that has now been independently implicated in asbestos-induced oncogenesis.

• The Nalp3 inflammasome is essential for the development of silicosis. S.L. Cassel, S.C. Eisenbarth, S.S. Iyer, et al. 2008;105(26):9035-40. PubMed · Publisher · Free full text

  Abstract

  Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1beta and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.

• The Sackler Colloquium on promises and perils in nanotechnology for medicine. R.H. Austin, S.F. Lim. 2008;105(45):17217-21. PubMed · Publisher · Free full text

  Abstract

  The Sackler Colloquium entitled "Nanomaterials in Biology and Medicine: Promises and Perils" was held on April 10-11, 2007. We have been able to assemble a representative sampling of 17 of the invited talks ranging over the topics presented. Any new technology carries with it both a promise of transforming the way we do things and the possibility that there are unforeseen consequences. The papers collected here represent a cross-section of these issues. As an example, we present our own work on nano-upconversion phosphors as an example of this new class of nanomaterials with potential use in medicine and biology.

• Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters. B. Kroczynska, R. Cutrone, M. Bocchetta, et al. 2006;103(38):14128-33. PubMed · Publisher · Free full text

  Abstract

  Only a fraction of subjects exposed to asbestos develop malignant mesothelioma (MM), suggesting that additional factors may render some individuals more susceptible. We tested the hypothesis that asbestos and Simian virus (SV40) are cocarcinogens. Asbestos and SV40 in combination had a costimulatory effect in inducing ERK1/2 phosphorylation and activator protein-1 (AP-1) activity in both primary Syrian hamster mesothelial cells (SHM) and primary human mesothelial cells (HM). Ap-1 activity caused the expression and activation of matrix metalloprotease (MMP)-1 and MMP-9, which in turn led to cell invasion. Experiments using siRNA and chemical inhibitors confirmed the specificity of these results. The same effects were observed in HM and SHM. Experiments in hamsters showed strong cocarcinogenesis between asbestos and SV40: SV40 did not cause MM, asbestos caused MM in 20% of hamsters, and asbestos and SV40 together caused MM in 90% of hamsters. Significantly lower amounts of asbestos were sufficient to cause MM in animals infected with SV40. Our results indicate that mineral fibers and viruses can be cocarcinogens and suggest that lower amounts of asbestos may be sufficient to cause MM in individuals infected with SV40.

• TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. H. Yang, M. Bocchetta, B. Kroczynska, et al. 2006;103(27):10397-10402. PubMed · Publisher · Free full text

  Abstract

  Asbestos is the main cause of human malignant mesothelioma (MM). In vivo, macrophages phagocytize asbestos and, in response, release TNF-alpha and other cytokines that contribute to carcinogenesis through unknown mechanisms. In vitro, asbestos does not induce transformation of primary human mesothelial cells (HM); instead, asbestos is very cytotoxic to HM, causing extensive cell death. This finding raised an apparent paradox: How can asbestos cause MM if HM exposed to asbestos die? We found that asbestos induced the secretion of TNF-alpha and the expression of TNF-alpha receptor I in HM. Treatment of HM with TNF-alpha significantly reduced asbestos cytotoxicity. Through numerous technical approaches, including chemical inhibitors and small interfering RNA strategies, we demonstrate that, in HM, TNF-alpha activates NF-kappaB and that NF-kappaB activation leads to HM survival and resistance to the cytotoxic effects of asbestos. Our data show a critical role for TNF-alpha and NF-kappaB signaling in mediating HM responses to asbestos. TNF-alpha signaling through NF-kappaB-dependent mechanisms increases the percent of HM that survives asbestos exposure, thus increasing the pool of asbestos-damaged HM that are susceptible to malignant transformation. Cytogenetics supported this hypothesis, showing only rare, aberrant metaphases in HM exposed to asbestos and an increased mitotic rate with fewer irregular metaphases in HM exposed to both TNF-alpha and asbestos. Our findings provide a mechanistic rationale for the paradoxical inability of asbestos to transform HM in vitro, elucidate and underscore the role of TNF-alpha in asbestos pathogenesis in humans, and identify potential molecular targets for anti-MM prevention and therapy.

• H2-rich fluids from serpentinization: geochemical and biotic implications. N.H. Sleep, A. Meibom, T. Fridriksson, et al. 2004;101(35):12818-23. PubMed · Publisher · Free full text

  Abstract

  Metamorphic hydration and oxidation of ultramafic rocks produces serpentinites, composed of serpentine group minerals and varying amounts of brucite, magnetite, and/or FeNi alloys. These minerals buffer metamorphic fluids to extremely reducing conditions that are capable of producing hydrogen gas. Awaruite, FeNi3, forms early in this process when the serpentinite minerals are Fe-rich. Olivine with the current mantle Fe/Mg ratio was oxidized during serpentinization after the Moon-forming impact. This process formed some of the ferric iron in the Earth's mantle. For the rest of Earth's history, serpentinites covered only a small fraction of the Earth's surface but were an important prebiotic and biotic environment. Extant methanogens react H2 with CO2 to form methane. This is a likely habitable environment on large silicate planets. The catalytic properties of FeNi3 allow complex organic compounds to form within serpentinite and, when mixed with atmospherically produced complex organic matter and waters that circulated through basalts, constitutes an attractive prebiotic substrate. Conversely, inorganic catalysis of methane by FeNi3 competes with nascent and extant life.

  Copyright 2004 The National Academy of Sciencs of the USA

• Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity. M. Bocchetta, I. Di Resta, A. Powers, et al. 2000;97(18):10214-9. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma, a malignancy associated with asbestos, has been recently linked to simian virus 40 (SV40). We found that infection of human mesothelial cells by SV40 is very different from the semipermissive infection thought to be characteristic of human cells. Mesothelial cells are uniformly infected but not lysed by SV40, a mechanism related to p53, and undergo cell transformation at an extremely high rate. Exposure of mesothelial cells to asbestos complemented SV40 mutants in transformation. Our data provide a mechanistic explanation for the ability of SV40 to transform mesothelial cells preferentially and indicate that asbestos and SV40 may be cocarcinogens.

• Simian virus 40 and the human mesothelium. G. Klein. 2000;97(18):9830-1. Comment PubMed · Publisher · Free full text

  Summary

  This commentary discussed a companion study by Bocchetta et al., published in the same issue of PNAS, on how simian virus 40 (SV40) interacts with human mesothelial cells. The author described how DNA tumor viruses can cause tumors and noted that the SV40 large T protein inactivates both the retinoblastoma and p53 pathways. He summarized the companion findings. SV40 infection of human mesothelial cells was nonlytic, T-antigen was made in 100% of the cells, and transformed foci appeared at more than 1,000-fold higher efficiency than in human fibroblasts infected in parallel. Most mesothelial foci contained immortalized cells. Bocchetta et al. attributed this to the higher p53 level in mesothelial cells, a view supported by antisense p53 experiments. The author noted that SV40 DNA has frequently been reported in about two-thirds of malignant mesotheliomas. In the companion study, crocidolite asbestos caused only a moderate increase in focus formation with one SV40 plasmid. It rescued focus formation with another plasmid that induced no foci on its own. Its high toxicity to mesothelial cells was counteracted by transforming SV40 plasmids. The author judged these asbestos effects too minor to account for mesothelioma in vivo. He discussed possible roles for asbestos through immunosuppression, oxygen radicals from macrophages, or genetic changes. He concluded that the findings were consistent with, but did not prove, a role for SV40 in some human mesotheliomas, and that how SV40 reaches the human mesothelium remained to be clarified.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

1990s

• A risk assessment for exposure to grunerite asbestos (amosite) in an iron ore mine. R.P. Nolan, A.M. Langer, R. Wilson. 1999;96(7):3412-9. PubMed · Publisher · Free full text

  Abstract

  The potential for health risks to humans exposed to the asbestos minerals continues to be a public health concern. Although the production and use of the commercial amphibole asbestos minerals-grunerite (amosite) and riebeckite (crocidolite)-have been almost completely eliminated from world commerce, special opportunities for potentially significant exposures remain. Commercially viable deposits of grunerite asbestos are very rare, but it can occur as a gangue mineral in a limited part of a mine otherwise thought asbestos-free. This report describes such a situation, in which a very localized seam of grunerite asbestos was identified in an iron ore mine. The geological occurrence of the seam in the ore body is described, as well as the mineralogical character of the grunerite asbestos. The most relevant epidemiological studies of workers exposed to grunerite asbestos are used to gauge the hazards associated with the inhalation of this fibrous mineral. Both analytical transmission electron microscopy and phase-contrast optical microscopy were used to quantify the fibers present in the air during mining in the area with outcroppings of grunerite asbestos. Analytical transmission electron microscopy and continuous-scan x-ray diffraction were used to determine the type of asbestos fiber present. Knowing the level of the miner's exposures, we carried out a risk assessment by using a model developed for the Environmental Protection Agency.

• Asbestos and mesothelioma: genetic lessons from a tragedy. A. Knudson. 1995;92(24):10819-20. Comment · Review PubMed · Publisher · Free full text

  Summary

  In this commentary, the author discussed what malignant mesothelioma, an uncommon tumor of the pleural and peritoneal surfaces associated in the vast majority of cases with asbestos fibers, revealed about the genetics of cancer. He noted that smoking produced a synergistically high incidence of lung cancer among asbestos-exposed people but not a significantly higher incidence of mesothelioma. He reviewed reported genetic changes in mesothelioma. These were loss of chromosome 9p with loss or mutation of the CDKN2 (p16) gene, TP53 mutations in some tumors, mutations of the Wilms tumor gene WT1, and monosomy 22, which removes the neurofibromatosis type 2 (NF2) tumor suppressor gene. He discussed a report in the same issue by Bianchi et al., which found NF2 mutations in 8 of 15 cell lines and in 6 matching tumors, all predicting truncation of the protein. He described the 40% incidence as clearly significant. He asked why mesothelioma is not a feature of hereditary NF2. He suggested that in renewal tissues such as mesothelium some pathological condition must stimulate stem cell proliferation, and that asbestos fibers seemed to provide this stimulus. Citing a rat model in which asbestos acted like a tumor promoter, he proposed that asbestos may act epigenetically and may cause chromosome missegregation, with mutations accumulating over many years. He concluded that studying this asbestos-linked tumor was teaching lessons about carcinogenesis.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells. Y.M. Janssen, A. Barchowsky, M. Treadwell, et al. 1995;92(18):8458-62. PubMed · Publisher · Free full text

  Abstract

  Nuclear factor kappa B (NF-kappa B) is a transcription factor regulating expression of genes intrinsic to inflammation and cell proliferation--features of asbestos-associated diseases. In studies here, crocidolite asbestos caused protracted and dose-responsive increases in proteins binding to nuclear NF-kappa B-binding DNA elements in hamster tracheal epithelial (HTE) cells. This binding was modulated by cellular glutathione levels. Antibodies recognizing p65 and p50 protein members of the NF-kappa B family revealed these proteins in two of the DNA complexes. Transient transfection assays with a construct containing six NF-kappa B-binding DNA consensus sites linked to a luciferase reporter gene indicated that asbestos induced transcriptional activation of NF-kappa B-dependent genes, an observation that was confirmed by northern blot analyses for c-myc mRNA levels in HTE cells. Studies suggest that NF-kappa B induction by asbestos is a key event in regulation of multiple genes involved in the pathogenesis of asbestos-related lung cancers.

• High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. A.B. Bianchi, S.I. Mitsunaga, J.Q. Cheng, et al. 1995;92(24):10854-8. PubMed · Publisher · Free full text

  Abstract

  Malignant mesotheliomas (MMs) are aggressive tumors that develop most frequently in the pleura of patients exposed to asbestos. In contrast to many other cancers, relatively few molecular alterations have been described in MMs. The most frequent numerical cytogenetic abnormality in MMs is loss of chromosome 22. The neurofibromatosis type 2 gene (NF2) is a tumor suppressor gene assigned to chromosome 22q which plays an important role in the development of familial and spontaneous tumors of neuroectodermal origin. Although MMs have a different histogenic derivation, the frequent abnormalities of chromosome 22 warranted an investigation of the NF2 gene in these tumors. Both cDNAs from 15 MM cell lines and genomic DNAs from 7 matched primary tumors were analyzed for mutations within the NF2 coding region. NF2 mutations predicting either interstitial in-frame deletions or truncation of the NF2-encoded protein (merlin) were detected in eight cell lines (53%), six of which were confirmed in primary tumor DNAs. In two samples that showed NF2 gene transcript alterations, no genomic DNA mutations were detected, suggesting that aberrant splicing may constitute an additional mechanism for merlin inactivation. These findings implicate NF2 in the oncogenesis of primary MMs and provide evidence that this gene can be involved in the development of tumors other than nervous system neoplasms characteristic of the NF2 disorder. In addition, unlike NF2-related tumors, MM derives from the mesoderm; malignancies of this origin have not previously been associated with frequent alterations of the NF2 gene.

• Persistent induction of c-fos and c-jun expression by asbestos. N.H. Heintz, Y.M. Janssen, B.T. Mossman. 1993;90(8):3299-303. PubMed · Publisher · Free full text

  Abstract

  To investigate the mechanisms of asbestos-induced carcinogenesis, expression of c-fos and c-jun protooncogenes was examined in rat pleural mesothelial cells and hamster tracheal epithelial cells after exposure to crocidolite or chrysotile asbestos. In contrast to phorbol 12-myristate 13-acetate, which induces rapid and transient increases in c-fos and c-jun mRNA, asbestos causes 2- to 5-fold increases in c-fos and c-jun mRNA that persist for at least 24 hr in mesothelial cells. The induction of c-fos and c-jun mRNA by asbestos in mesothelial cells is dose-dependent and is most pronounced with crocidolite, the type of asbestos most pathogenic in the causation of pleural mesothelioma. Induction of c-jun gene expression by asbestos occurs in tracheal epithelial cells but is not accompanied by a corresponding induction of c-fos gene expression. In both cell types, asbestos induces increases in protein factors that bind specifically to the DNA sites that mediate gene expression by the AP-1 family of transcription factors. The persistent induction of AP-1 transcription factors by asbestos suggests a model of asbestos-induced carcinogenesis involving chronic stimulation of cell proliferation through activation of the early response gene pathway that includes c-jun and/or c-fos.

• Hydrolysis of inositol phospholipids precedes cellular proliferation in asbestos-stimulated tracheobronchial epithelial cells. A. Sesko, M. Cabot, B. Mossman. 1990;87(19):7385-9. PubMed · Publisher · Free full text

  Abstract

  Metabolism of inositol phospholipids and phosphatidylcholine was investigated in tracheobronchial epithelial cells exposed to mitogenic concentrations of crocidolite asbestos. Alterations in levels of diacylglycerol, the endogenous activator of protein kinase C, and inositol polyphosphates, presumed mobilizers of intracellular calcium, were examined. Cultures labeled with [3H]glycerol and exposed to proliferative concentrations of crocidolite asbestos demonstrated significant elevations in [3H]diacylglycerol. In contrast, crocidolite-exposed cells labeled with [3H]myristic acid or [3H]choline did not display elevated production of [3H]diacylglycerol or release of [3H]choline metabolites--i.e., evidence of phosphatidylcholine hydrolysis. The soluble tumor promoter phorbol 12-myristate 13-acetate catalyzed both of these changes. myo-[3H]Inositol-labeled cells exposed as briefly as 10 min to mitogenic concentrations of crocidolite demonstrated elevations in [3H]inositol mono-, tris-, and terakisphosphates, phenomena indicating turnover of inositol phospholipids. The detection of diacylglycerol and inositol phosphates in crocidolite asbestos-exposed cells suggests that this fibrous tumor promoter activates phospholipase C as it stimulates cellular proliferation.

1980s

• Asbestos fibers mediate transformation of monkey cells by exogenous plasmid DNA. J.D. Appel, T.M. Fasy, D.S. Kohtz, et al. 1988;85(20):7670-4. PubMed · Publisher · Free full text

  Abstract

  We have tested the ability of chrysotile asbestos fibers to introduce plasmid DNA into monkey COS-7 cells and the ability of this DNA to function in both replication and gene expression. Chrysotile fibers are at least as effective as calcium phosphate in standard transfection assays at optimal ratios of asbestos to DNA. After transfection with chrysotile, a minor percentage of introduced plasmid DNA bearing a simian virus 40 origin of replication replicates after 24 hr. Fragmentation of entering DNA is more prominent with asbestos than with calcium phosphate, and after 72 hr most DNA introduced by asbestos is associated with chromosomal DNA. Cells transfected with plasmid p11-4, bearing the p53 protooncogene, express this gene. Cells transfected with pSV2-neo express a gene conferring resistance of antibiotic G418, allowing isolation of colonies of transformed cells after 18 days. The introduction of exogenous DNA into eukaryotic cells could cause mutations in several ways and thus contribute to asbestos-induced oncogenesis.

• Asbestos-associated chromosomal changes in human mesothelial cells. J.F. Lechner, T. Tokiwa, M. LaVeck, et al. 1985;82(11):3884-8. PubMed · Publisher · Free full text

  Abstract

  Replicative cultures of human pleural mesothelial cells were established from noncancerous adult donors. The cells exhibited normal mesothelial cell characteristics including keratin, hyaluronic acid mucin, and long branched microvilli, and they retained the normal human karyotype until senescence. The mesothelial cells were 10 and 100 times more sensitive to the cytotoxic effects of asbestos fibers than normal human bronchial epithelial or fibroblastic cells, respectively. In addition, cultures of mesothelial cells that survived two cytotoxic exposures of amosite fibers were aneuploid with consistent specific chromosomal losses indicative of clonal origin. These aneuploid cells exhibit both altered growth control properties and a population doubling potential of greater than 50 divisions beyond the culture life span (30 doublings) of the control cells.

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