Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth

Accurate prediction of survival from adrenocortical carcinoma (ACC) is difficult and current staging models are unreliable. Central sarcopenia as part of the cachexia syndrome is a marker of frailty and predicts mortality. This study seeks to confirm that psoas muscle density (PMD), lean psoas muscle area (LPMA), lumbar skeletal muscle index (LSMI), and intra-abdominal (IA) or subcutaneous fat (SC) can be used in combination to more accurately predict survival in ACC patients. PMD, LPMA, IA, and SC fat were measured on serial CT scans of patients with ACC. Clinical outcome was correlated with quantitative data from patients with ACC and analyzed. A linear regression model was used to describe the relationship between PMD, LPMA, LSMI, IA, and SC fat, time to recurrence, and length of survival according to tumor stage. One hundred twenty-five ACC patients (94 females) were treated from 2005 to 2011. Significant morphometric predictors of survival include PMD, LPMA, and IA fat (p ≤ 0.0001, ≤ 0.0024, <0.0001, respectively) and improve prediction of survival compared to using stage alone. A 100-mm(2) increase in LPMA confers an 8 % lower hazard of death. LSMI does not change significantly between stages (p = 0.3196). Decreased PMD, LPMA, and increased IA fat suggest decreased survival in ACC patients and correlate with traditional staging systems. A more precise prediction of survival may be achieved when staging systems and morphometric measures are used in combination. Serial measurements of morphometric data are possible. The rate of change of these variables over time may be more important than the absolute value.

The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins are members of the basic helix-loop-helix-leucine zipper (bHLH-Zip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.