Cholesterol crystals induce mechanical trauma, inflammation, and neo-vascularization in solid cancers as in atherosclerosis

• Published in: American heart journal plus Vol. 35; p. 100317
• Main Authors: Abela, George S., Katkoori, Venkat R., Pathak, Dorothy R., Bumpers, Harvey L., Leja, Monika, ul Abideen, Zain, Boumegouas, Manel, Perry, Daniel, Al-Janadi, Anas, Richard, James E., Barnaba, Carlo, Medina Meza, Ilce G.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-11-2023; Elsevier
• Subjects: Atherosclerosis; Biomarkers; Cancer; Cholesterol crystals; Neovascularization; Biomarkers; Neovascularization; Cholesterol crystals; Atherosclerosis; Cancer
• ISSN: 2666-6022; 2666-6022
• DOI: 10.1016/j.ahjo.2023.100317

Cancer and atherosclerosis share common risk factors and inflammatory pathways that promote their proliferation via vascular endothelial growth factor (VEGF). Because CCs cause mechanical injury and inflammation in atherosclerosis, we investigated their presence in solid cancers and their activation of IL-1β, VEGF, CD44, and Ubiquityl-Histone H2B (Ub-H2B), that promote cancer growth.
Tumor specimens from eleven different types of human cancers and atherosclerotic plaques were assessed for CCs, free cholesterol content and IL1-β by microscopy, immunohistochemistry, and biochemical analysis. Breast and colon cancer cell lines were cultured with and without CCs to select for expression of VEGF, CD44, and Ub-H2B. Western blot and immunofluorescence were performed on cells to assess the effect of CCs on signaling pathways.
Cancers displayed higher CC content (+2.29 ± 0.74 vs +1.46 ± 0.84, p < 0.0001), distribution (5.06 ± 3.13 vs 2.86 ± 2.18, p < 0.001) and free cholesterol (3.63 ± 4.02 vs 1.52 ± 0.56 μg/mg, p < 0.01) than cancer free marginal tissues and similarly for atherosclerotic plaques and margins (+2.31 ± 0.51 vs +1.44 ± 0.79, p < 0.02; 14.0 ± 5.74 vs 8.14 ± 5.52, p < 0.03; 0.19 ± 0.14 vs 0.09 ± 0.04 μg/mg, p < 0.02) respectively. Cancers displayed significantly increased expression of IL1-β compared to marginal tissues. CCs treated cancer cells had increased expression of VEGF, CD44, and Ub-H2B compared to control. By microscopy, CCs were found perforating cancer tumors similar to plaque rupture.
These findings suggest that CCs can induce trauma and activate cytokines that enhance cancer growth as in atherosclerosis.
Mechanisms of cholesterol crystal induced trauma, inflammation, and neo-vascularization in cancer and atherosclerosis: The pathogenesis of atherosclerosis is greatly influenced by cholesterol crystals (CCs). Our study demonstrated substantial quantities of CCs in solid cancer tumors as has been reported in atherosclerosis and they were found to activate IL-1β, CD44, VB-H2B and VEGF that stimulate inflammation and neovascularization respectively. CCs can enhance tumor growth and metastasis by disruption of tissues with local spread, causing intra tumor hemorrhage with access to the circulation, activating cytokines and triggering inflammation, as is known for atherosclerosis. [Display omitted]