Arsenic, stem cells, and the developmental basis of adult cancer.
That chemical insults or nutritive changes during in utero and/or postnatal life can emerge as diseases much later in life are now being accepted as a recurring phenomenon. In this regard, inorganic arsenic is a multisite human carcinogen found at high levels in the drinking water of millions of people, although it has been difficult until recently to produce tumors in rodents with this metalloid. A mouse transplacental model has been developed where maternal exposure to inorganic arsenic either acts as a complete carcinogen or enhances carcinogenic response to other agents given subsequently in the offspring, producing tumors during adulthood. Similarly, human data now have emerged showing that arsenic exposure during the in utero period and/or in early life is associated with cancer in adulthood. The mouse arsenic transplacental model produces tumors or enhances response to other agents in multiple strains and tissues, including sites concordant with human targets of arsenic carcinogenesis. It is now believed that cancer often is a stem cell (SC)-based disease, and there is no reason to think cancer induced by developmental chemical exposure is any different. Indeed, arsenic impacts human SC population dynamics in vitro by blocking exit into differentiation pathways and whereby creating more key targets for transformation. In fact, during in vitro malignant transformation, arsenic causes a remarkable survival selection of SCs, creating a marked overabundance of cancer SCs (CSCs) compared with other carcinogens once a cancer phenotype is obtained. In addition, skin cancers produced following in utero arsenic exposure in mice are highly enriched in CSCs. Thus, arsenic impacts key, long-lived SC populations as critical targets to cause or facilitate later oncogenic events in adulthood as a possible mechanism of developmental basis of adult disease.
National Toxicology Program Laboratories, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Erik J
EJ
Tokar
Wei
W
Qu
Michael P
MP
Waalkes
D000818:Animals; D020261:Arsenic Poisoning; D001152:Arsenicals / Q000009:adverse effects*; D015197:Carcinogenicity Tests; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects*; D008431:Maternal-Fetal Exchange; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D001152:Arsenicals; D002274:Carcinogens, Environmental; D014874:Water Pollutants, Chemical