High density lipoprotein cholesterol and cancer: Marker or causative?

The relationship between high-density lipoproteins (HDLs), HDL-cholesterol (HDLC) and cancer incidence and mortality is controversial. Although most studies conducted so far, including well-designed prospective studies and meta-analyses, have revealed a significant inverse association between HDL-C levels and cancer risk, several confounding factors and opposite results showing either a direct or an inverse association between HDL-C levels and cancer mortality have hindered the possibility to derive definitive conclusions. Moreover, different lines of research also pointed out that this association might actually reflect an inverse causality, which would imply that low HDL-C levels merely represent an epiphenomenon of cancer-related inflammation and cancer cell renewal. Accordingly, the pharmacological increase of plasma HDL-C levels in large lipid modifying trials has not resulted in an amelioration of cancer-related outcomes. In such an intricate scenario, we conducted a comprehensive review of the literature with the aim to provide a wide perspective on the association between HDLs, mild and extreme changes in plasma HDL-C levels and cancer incidence and mortality, touching upon the certainties, the failures and the open issues in this intriguing area of research.