Abstract
Altered lipid metabolism is a well-documented hallmark of neoplastic transformation and impacts disease progression. Two major lipoprotein receptors, the low-density lipoprotein receptor (LDL-R) and scavenger receptor class B, type 1 (SR-BI) are overexpressed in a number of cancer types in people. These receptors serve to deliver cholesterol to the tumor cells and have been used to target drug therapies. In this study, we performed a retrospective analysis of LDL-R and SR-B1 expression in canine lymphoma using archived formalin-fixed tissue samples. Cases were immunophenotyped and classified according to World Health Organization (WHO) standards prior to immunostaining for the LDL_R and SR-B1. A total of 45 cases were evaluated; 21 high grade B (HGB), 11 low grade B (LGB), 7 high grade T (HGT), and 6 low grade T (LGT) lymphomas. One sided Wilcoxon rank sum tests were used to compare staining intensity between neoplastic and hyperplastic lymphoid tissue. The relationships between histological score and tumor grade and score and stage at presentation were assessed using non-parametric Kruskal-Wallis tests. Neoplastic lymphoid tissue expressed higher levels of both receptors compared to reactive lymph nodes. Median LDL-R score was 85.0 (interquartile range = 101.7), Median SR-B1 score was 209.0 (interquartile range 105.2). No relationship between LDL-R or SR-B1 staining score and tumor grade or phenotype was found. Serum cholesterol concentration was compared between dogs with high and low grade tumors using a two sample T-test, and correlations between cholesterol concentration and histological score, and between the score for the two receptors were determined using a Spearman correlation. The high expression level of these lipoprotein receptors on most of the tumors could underlie the lack of relationship between score and tumor grade. The overexpression of LDL-R and SR-B1 in canine lymphoma holds therapeutic potential particularly in dogs that overexpress one or both of these receptors, and this warrants further investigation.
Highlights
There is a substantial and growing body of evidence documenting a role for cholesterol utilization by cells in tumor development, progression, and metastasis
Clinical sub-stage was not included in the analysis due to the lack of standardized criteria [26] 1 case was removed due to poor low density lipoprotein (LDL) receptor (LDL-R) immunohistochemical staining on the paired liver control tissue, and 11 cases were not evaluated for SRB1 staining due to limited tissue availability in the archived block
No correlation was found between tumor grade, phenotype or clinical stage at presentation and serum cholesterol concentration. This is the first study investigating LDL-R and SR-BI immunolabeling in canine cancer
Summary
There is a substantial and growing body of evidence documenting a role for cholesterol utilization by cells in tumor development, progression, and metastasis. Lipoprotein receptors provide conduits for cholesterol delivery to cells. The scavenger receptor class B, type I (SRBI) binds high density lipoproteins (HDL) and facilitates the transport of cholesteryl esters from HDL into cells [8]. Apolipoprotein B in low density lipoprotein (LDL) binding to the LDL receptor (LDL-R) targets the lipoprotein-receptor complex to the endocytic pathway transporting cholesterol directly into the cell [7]. The SR-B1 receptor is aberrantly or overexpressed in a number of malignancies including; prostatic carcinoma, breast cancer, renal cell carcinoma, and hematopoietic tumors [8,9,10,11]. High LDL-R expression has been documented in breast cancer cell lines [12]. Alterations in the expression levels of these receptors often co-exist with changes in the lipoproteins they shuttle from the blood into the tumor cells
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