In vitro cobalt-stimulated hypoxia-inducible factor-1 overexpression does not correlate with cancer risk from cobalt exposure in humans

Chemical-induced pulmonary carcinogenesis in humans is usually a multi-decade process. The average age at diagnosis of lung cancer in cigarette smokers, and mesothelioma in asbestos workers, is approximately 70. The carcinogenic process consists of genetic changes to normal cells usually sequenced as initiation (mutations), promotion (clonal expansion of initiated cells), and progression (carcinoma in situ to invasive carcinoma to metastatic carcinoma). Angiogenesis, the sprouting of new vessels from preexisting capillaries, plays an important role in the progression of small avascular tumors to vascularized invasive carcinomas and metastatic carcinomas. While the overall carcinogenic process is multi-decade, the transition from avascular to vascularized carcinoma is believed to take place over the course of a much more limited time span. Tumor progression is a late-stage event in carcinogenesis. About 70% of human cancers including lung cancer express hypoxia-inducible factor (HIF)-1 in the absence of cobalt exposure. Cobalt compounds administered to transformed cell lines and primary cultures of human endothelial cells, smooth muscle cells, and mesenchymal stem cells can elicit overexpression of HIF-1. Cobalt-induced expression of HIF-1 would not be expected to interact with either the avascular initiation or promotion phases of carcinoma development. Humans exposed long-term to cobalt leaching from implants do not have an elevated cancer risk, and neither do goats ingesting up to 667 times the recommended daily human cobalt dietary requirement throughout their 15- to 18-year life span. In vitro hypoxia-mimetic characteristics of cobalt compounds do not correlate with the absence of increased risk following long-term systemic exposure to cobalt in humans.