“Attack of the Clones”
Commonalities Between Cancer and Atherosclerosis
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Many studies have noted similarities between atherosclerosis and cancer including pronounced cellular plasticity, clonal expansion of cellular subtypes, increased DNA mutations, defective efferocytosis pathways, and an important role for proto-oncogenes in disease development. Although it is clear that these 2 diseases have disparate causes, noting the parallels between atherosclerosis and cancer may help us identify unique, targeted therapeutic strategies.
Origins of Atherosclerotic Plaque Cells: A Theme of Plasticity
Early articles described atheromas as benign neoplasms of the blood vessel comprised primarily of fibrous smooth muscle cells (SMCs). However, additional studies soon noted the presence of macrophages and other cell types, thereby promoting controversy as to which cells actually give rise to the atherosclerotic plaque. Much of this controversy results from the promiscuity of the so-called lineage-specific markers.1 For example, bone marrow–derived cells can migrate into plaques and begin to express certain SMC markers,2 whereas SMCs can upregulate macrophage-specific markers such as galectin-3, CD11b, and F4/80 as they migrate into the plaque.3,4 In addition, recent lineage tracing studies suggest that endothelial cells can acquire mesenchymal cell characteristics, and some adventitial cells may have the capability of forming SMC-like cells. Collectively, these studies demonstrate the impressive capacity of many vascular cell types to dedifferentiate or transdifferentiate in response to the atherosclerotic environment and suggest that plaques may arise from multiple vascular and circulating cell types. Clearly, cellular plasticity is a major theme in atherosclerotic plaque development—as it is in cancer—and methods to reprogram proatherosclerotic cells could have tremendous therapeutic potential.
Clonal Origins for Plaque-Resident Cells?
The clonal evolution theory of cancer development posits that certain tumors arise from a single cell that expands in response to a series of acquired mutations. In 1973, Benditt and Benditt5 performed X-inactivation studies on human atherosclerotic lesions and found evidence that atherosclerotic plaques could be derived from a single cell that underwent monoclonal expansion, …