Editors' ChoiceCancer

Small But Powerful

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Science Translational Medicine  08 Sep 2010:
Vol. 2, Issue 48, pp. 48ec141
DOI: 10.1126/scitranslmed.30001656

Almost 20 years ago, Vogelstein and Kinzler proposed the famous adenoma-to-carcinoma model in which tumorigenesis is a sequential accumulation of mutations leading to a progressively more malignant phenotype. What would happen if one of these mutations is reversed—either through drug treatment or through genetic engineering? The Vogelstein and Kinzler model would predict that the tumor would inch one step back, closer to normal tissue. But sometimes in reality, tumors shrink dramatically or even disappear entirely. This led to the notion that even though a mutation may be one of many, the tumor cells can be “addicted” to it—that is, be dependent on that mutation for survival. Such addiction can be seen to oncogenes such as c-MYC, Ras, and epidermal growth factor receptor (EGFR).

Recently, another class of tumorigenic molecules has been described: microRNAs (miRNAs). These single-stranded RNAs are encoded by tiny genes and control multiple messenger RNAs through binding and inactivation, thus affecting several proteins. Whether deleted or overexpressed in cancer, miRNAs are known as “oncomirs.” miR-21 is a well-studied oncomir that is overexpressed in many tumor types, including lymphomas, but how dependent tumors are on miR-21 has been unknown.

Medina and colleagues created a transgenic mouse in which miR-21 can be turned on and off at will. When miR-21 was turned on at birth, the mice developed aggressive lymphomas at about 2 months of age, with massively enlarged lymph nodes. When miR-21 was then turned off, the lymph nodes normalized in size within 2 to 4 days in 100% of the mice—a consequence of tumor cell apoptosis, as seen on tumor sections. Approaches to attack overexpressed oncomirs in human cancers (for example, through anti-miRNA oligonucleotides) are actively being explored and may help us gain control over tumors addicted to miRNAs such as miR-21.

P. P. Medina et al., OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467, 86–90 (2010). [Full Text]

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