Combination immunotherapy improves survival in mouse models of mesothelioma

Investigators have found that combined treatment with two cancer immunotherapy drugs — one a novel immune modulator and one that focuses and activates the anti-tumor immune response — significantly prolonged survival in mouse models of the aggressive cancer malignant mesothelioma. (Mehr in: Cancer News — ScienceDaily)

The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats

Non-neoplastic histopathological findings in the abdominal cavity. A: High-power view of anti-podoplanin immunohistochemistry showing single MWCNT A (high dose) nanotubes in the tissue (arrows). B: High-power view of anti-podoplanin immunohistochemistry showing single asbestos fibers in the tissue (arrows). C: H & E, high-power view of granuloma induced by MWCNT A (low dose) nanotubes including single nanotube (arrow, 25×). D: H & E, high-power view of granuloma induced by asbestos including single fiber (arrow, 40×). Rittinghausen et al. Particle and Fibre Toxicology 2014 11:59   doi:10.1186/s12989-014-0059-z
Non-neoplastic histopathological findings in the abdominal cavity. A: High-power view of anti-podoplanin immunohistochemistry showing single MWCNT A (high dose) nanotubes in the tissue (arrows). B: High-power view of anti-podoplanin immunohistochemistry showing single asbestos fibers in the tissue (arrows). C: H & E, high-power view of granuloma induced by MWCNT A (low dose) nanotubes including single nanotube (arrow, 25×). D: H & E, high-power view of granuloma induced by asbestos including single fiber (arrow, 40×).
Rittinghausen et al. Particle and Fibre Toxicology 2014 11:59 doi:10.1186/s12989-014-0059-z

Susanne Rittinghausen, Anja Hackbarth, Otto Creutzenberg, Heinrich Ernst, Uwe Heinrich, Albrecht Leonhardt and Dirk Schaudien

Abstract

Background

Biological effects of tailor-made multi-walled carbon nanotubes (MWCNTs) without functionalization were investigated in vivo in a two-year carcinogenicity study. In the past, intraperitoneal carcinogenicity studies in rats using biopersistent granular dusts had always been negative, whereas a number of such studies with different asbestos fibers had shown tumor induction. The aim of this study was to identify possible carcinogenic effects of MWCNTs. We compared induced tumors with asbestos-induced mesotheliomas and evaluated their relevance for humans by immunohistochemical methods.

Methods

A total of 500 male Wistar rats (50 per group) were treated once by intraperitoneal injection with 109 or 5 × 109 WHO carbon nanotubes of one of four different MWCNTs suspended in artificial lung medium, which was also used as negative control. Amosite asbestos (108 WHO fibers) served as positive control. Morbid rats were sacrificed and necropsy comprising all organs was performed. Histopathological classification of tumors and, additionally, immunohistochemistry were conducted for podoplanin, pan-cytokeratin, and vimentin to compare induced tumors with malignant mesotheliomas occurring in humans.

Results

Treatments induced tumors in all dose groups, but incidences and times to tumor differed between groups. Most tumors were histologically and immunohistochemically classified as malignant mesotheliomas, revealing a predominantly superficial spread on the serosal surface of the abdominal cavity. Furthermore, most tumors showed invasion of peritoneal organs, especially the diaphragm. All tested MWCNT types caused mesotheliomas. We observed highest frequencies and earliest appearances after treatment with the rather straight MWCNT types A and B. In the MWCNT C groups, first appearances of morbid mesothelioma-bearing rats were only slightly later. Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D – the most curved type of nanotubes. Malignant mesotheliomas induced by intraperitoneal injection of different MWCNTs and of asbestos were histopathologically and immunohistochemically similar, also compared with mesotheliomas in man, suggesting similar pathogenesis.

Conclusion

We showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.

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