Phytosterols and phytostanols and the hallmarks of cancer in model organisms: A systematic review and meta-analysis

Abstract

Phytosterols and phytostanols are natural products present in vegetable oils, nuts, and seeds, or added to consumer food products whose intake is inversely associated with incidence and prognosis of several cancers. Randomized cancer prevention trials in humans are unfeasible due to time and cost yet the cellular processes and signaling cascades that underpin anti-cancer effects of these phytochemicals have been explored extensively in vitro and in preclinical in vivo models. Here we have performed an original systematic review, meta-analysis, and qualitative interpretation of literature published up to June 2020. MEDLINE, Scopus, and hand-searching identified 408 unique records that were screened leading to 32 original articles that had investigated the effects of phytosterols or phytostanols on cancer biology in preclinical models. Data was extracted from 22 publications for meta-analysis. Phytosterols were most commonly studied and found to reduce primary and metastatic tumor burden in all cancer sites evaluated. Expression of pAKT, and markers of metastasis (alkaline phosphatase, matrix metalloproteases, epithelial to mesenchymal transcription factors, lung and brain colonization), angiogenesis (vascular endothelial growth factor, CD31), and proliferation (Ki67, proliferating cell nuclear antigen) were consistently reduced by phytosterol treatment in breast and colorectal cancer. Very high dose treatment (equivalent to 0.2-1 g/kg body weight not easily achievable through diet or supplementation in humans) was associated with adverse events including poor gut health and intestinal adenoma development. Phytosterols and phytostanols are already clinically recommended for cardiovascular disease risk reduction, and represent promising anti-cancer agents that could be delivered in clinic and to the general population at low cost, with a well understood safety profile, and now with a robust understanding of mechanism-of-action.

Pharmacologic and genetic inhibition of cholesterol esterification reduces tumour burden: a pan-cancer systematic review and meta-analysis of preclinical models

“…Furthermore, of the studies that reported randomisation of groups, none reported their method of randomisation. Additionally, no studies reported rationale behind the size of study groups, with this issue noted in previous meta-analyses on pre-clinical models of cancer [33, 76]. Comparably, studies assessing CE content in tissue exhibited poorer reporting on our risk of bias survey (Fig8B), however this is likely due to the papers within this cohort being considerably older (average publication date = 1986) than those assessing SOAT interventions in pre-clinical models (average publication date = 2018).…”

“…The World Cancer Research Fund (WCRF) remain unable definitively to include or exclude cholesterol in the aetiology of cancer [88], even now, more than 20 years after the International Agency for Research on Cancer (IARC) indicated that evidence is inadequate [89]. Drugs and dietary factors that reduce cholesterol levels also reduce the risk of developing and/or dying from cancer in some situations [90–92]. Cholesterol is widely utilised, both structurally in the plasma membrane, and as a precursor for an array of hormones, steroids, and vitamins.…”

“…Random effects model was used due to the anticipation of heterogeneity between studies due to expected differences in cancers assessed, animal models and mechanisms used to disrupt SOAT1 [32]. Heterogeneity was assessed using I 2 , with an I 2 value >75% used as a marker for high heterogeneity between studies due to the anticipated large variation between study design for animal studies [33]. Evidence of publication bias was examined using funnel plots.…”

“…Risk of bias (ROB) was adapted from Cioccoloni et al, and allowed assessment of bias in experimental design, animal experiments, and immunoblotting [33]. Guidelines published in British Journal of Pharmacology [34, 35] and SYRCLE [36] were closely followed.…”

Comprehensive profiling of liver x receptor splicing in triple negative breast cancer reveals existence of novel splice variants that are prognostic for survival

“…Nutritional and epidemiological studies indicate that cholesterol metabolism may play a role in the aetiology and severity of TNBC [3][4][5][6]. The liver x receptors (LXRα/NR1H3; LXRβ/NR1H2) are homeostatic regulators of cholesterol metabolism and as such have been suggested as potential therapeutic targets.…”