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Abstract
Introduction/Background The scavenger receptor CD36 has gained increasing interest in cancer research, with various functions in cell metabolism, angiogenesis, and immune response. The aim of this study was to investigate the molecular role of CD36 expression on intratumoral vessels of advanced high grade serous ovarian cancer (HGSOC) and its prognostic implication.
Methodology Immunohistochemical staining for CD36 was performed on whole tissue slides of 109 patients with advanced HGSOC. Patients were divided in two groups based on CD36 expression, i.e. positive versus negative, and correlated to clinicopathologic and survival data. Within a subpopulation (n=22), results from RNA sequencing, metabolomics and proteomics were correlated to CD36 expression.
Results CD36 expression in intratumoral vessels was significantly associated with overall survival, both in univariate (HR 1.71, p=0.039) and multiple Cox regression analyses (HR 1.91, p=0.021), considering age, FIGO stage, postoperative residual tumor, and bevacizumab treatment. Positive CD36 expression was significantly associated with postoperative residual tumor (p=0.042). RNA sequencing from isolated tumor cells revealed an activated ‘regulation of lipolysis in adipocytes’ pathway significantly associated with CD36 expression. Co-association gene expression network analysis revealed an increase of ribosomal activity and protein translation in CD36 positive specimens. Proteomics analysis showed three overexpressed proteins involved in lipid metabolism (LCN2, CFHR1 and CFHR4) out of 21 significantly deregulated proteins. Metabolomic analyses of serum showed a significant decrease of 60 glycerophospholipids (mainly unsaturated) and eight amino acids, four essential proteinogenic, in patients with CD36 positive vessels.
Conclusion Positive CD36 intratumoral vessel expression was associated with unfavorable overall survival in patients with advanced HGSOC. Our analyses support a role of CD36 in tumor metabolism, possibly via CD36+-endothelial cell mediated glycerophospholipid/oxLDL uptake. Signs for increased tumor metabolism were found, as well as a decrease of metabolic building blocks (glycerophospholipids and amino acids) in patients’ peripheral blood, indicating a higher presumably CD36 mediated uptake capacity.
Disclosures Funding by the Austrian Research Promotion Agency FFG: BRIDGE project ‘DECIMA’ (project no. 880603) and the City of Vienna Fund for Innovative Interdisciplinary Cancer Research (project no. 21021).
(a) Forrest-Plot of the multiple Cox regression model for overall survival based on CD36 intratumoral vessel expression including relevant clinicopathologic co-factors. b) Overall survival curves for negative and positive CD36 expression according to the multiple Cox regression model (a). Dotted lines show median survival. As this survival curve is generated from a Cox regression model, no censored patients are indicated