Toxicological Sciences 54, 110-120 (2000)
Copyright © 2000 by the Society of Toxicology
Repeated Cadmium Exposures Enhance the Malignant Progression of Ensuing Tumors in Rats
* Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and
Department of Pathology, University of Western Ontario, London, Ontario, N6A 5C1, Canada
Prior studies show that a single subcutaneous (sc) exposure to cadmium (Cd) will induce injection site sarcomas (ISS) in rats. These tumors, thought clearly malignant, do not often metastasize or invade subdermal muscle layers because of their location. Recent evidence indicates that when tumorigenic cells chronically exposed to Cd in vitro are inoculated into mice, tumor progression and invasiveness in the mice are enhanced. Thus, we studied the effects of repeated Cd exposures on tumor incidence, progression, and metastatic potential in rats. Wistar (WF) and Fischer (F344) rats (30 per group) were injected sc in the dorsal thoracic midline with CdCl2 once weekly for 18 weeks with doses of 0, 10, 20, or 30 µmol Cd/kg. This resulted in total doses of 0, 180, 360, or 540 µmol/kg. One other group of each strain received a low, loading dose of Cd (3 µmol/kg) prior to 17 weekly injections of 30 µmol/kg (total dose 513 µmol/kg). Rats were observed for 2 years. Many F344 rats (57%) died within one week after the first injection of the highest dose, but WF rats were not affected. The low loading dose prevented acute lethality of the high dose in F344 rats. Surprisingly, latency (time to death by tumor) of ISS was the shortest in the groups given the low loading dose in both strains. ISS in these groups also showed the highest rate of metastasis and subdermal muscle layer invasion. Based on ISS incidence in the groups given the lowest total dose of Cd (180 µmoles/kg), F344 rats were more sensitive to tumor induction, showing an incidence of 37% compared to 3% in WF rats. On the other hand, Cd-induced ISS showed a higher overall metastatic rate in WF rats (18 metastatic ISS/68 total tumors in all treated groups; 27%) compared to F344 rats (6%). Immunohistochemically, the primary ISS showed high levels of metallothionein (MT), a cadmium-binding protein, while metastases were essentially devoid of MT. These results indicate that repeated Cd exposures more rapidly induce ISS. An initial low exposure to Cd further accelerates the appearance and enhances the metastatic potential and invasiveness of these tumors. The primary and metastatic ISS appear to have a differing phenotype, at least with regard to MT production. The association between multiple Cd exposures and enhanced metastatic potential of the ensuing tumors may have important implications in chronic exposures to Cd, or in cases of co-exposure of Cd with organic carcinogens, as in tobacco smoking.
Key Words: cadmium; carcinogenesis; rats; sarcoma; tumor progression; tumor invasion; tumor metastasis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Datta, S. Majumder, H. Kutay, T. Motiwala, W. Frankel, R. Costa, H. C. Cha, O. A. MacDougald, S. T. Jacob, and K. Ghoshal Metallothionein Expression Is Suppressed in Primary Human Hepatocellular Carcinomas and Is Mediated through Inactivation of CCAAT/Enhancer Binding Protein {alpha} by Phosphatidylinositol 3-Kinase Signaling Cascade Cancer Res., March 15, 2007; 67(6): 2736 - 2746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Qu, C. D. Bortner, T. Sakurai, M. J. Hobson, and M. P. Waalkes Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway Carcinogenesis, January 1, 2002; 23(1): 151 - 159. [Abstract] [Full Text] [PDF]
|
|