Cell-transforming potential of low-density lipoproteins

Arterial smooth muscle cell proliferation is thought to be essential for the development of atherosclerotic lesions. The monoclonal hypothesis of atherogenesis proposes that the proliferative smooth muscle cells are derived from a stable transformed cell population. The present study demonstrates for the first time evidence that, in addition to carcinogens such as 3-methylcholanthrene (MCA), 'atherogenic' low-density lipoproteins (LDL) also possess cell-transforming potential. LDL caused dose-dependent cytotoxicity and transformation of C3H/10T1/2 cells of type II and type III morphology of up to six transformed cell clones per 10(4) survivors in the concentration range of 50-200 micrograms cholesterol/ml after 72 h treatments. MCA (0.1 micrograms/ml) induced morphological transformation of 2.6 foci per 10(4) survivors. In a two-stage in vitro transformation assay LDL (5-25 micrograms cholesterol/ml) enhanced MCA-induced cell transformation 2- to 2.4-fold in a dose-dependent way. 'Non-atherogenic' high-density lipoproteins did not induce cell transformation by themselves or in an initiation-promotion model. These results show that LDL could act as (co)carcinogens.