Abstract
Abstract Lipoprotein(a), composed of LDL and an adhesive protein apo(a), is produced in humans and primates, the species which lost an ability to synthesize vitamin C endogenously. We have shown earlier that Lp(a), due to its strong ECM binding properties, may be considered a biological ‘stability’ molecule for the structurally weakened connective tissue in the vascular wall. The development and progression of cancer is characterized by loss of ECM integrity which facilitates tumor growth and metastasis. We developed a unique mouse model lacking endogenous vitamin C production (Gulo-/-) and synthesizing human Lp(a) (lp(a)+), which has been used in this study to investigate the role of Lp(a) and other lipoproteins in cancer. The female Gulo-/-:Lp(a)+ and control wild type Balb/c mice were orthotopically inoculated with 4T1 breast cancer cells (500,000) The transgenic and control mice were divided into 4 different dietary groups in respect to dietary vitamin C intake: A) low ascorbate intake for 6 weeks; B) high ascorbate intake for 6 weeks; C) low ascorbate intake for 3 weeks followed by high ascorbate for 3 weeks; D)high ascorbate intake for 3 weeks followed by low ascorbate for 3 weeks. Control groups of Lp(a)+;Gulo(-/-) mice without tumor inoculation were put on the same Vitamin C regimens. Wild type controls included mice without and with 4T1 inoculation kept on regular mouse chow for 6 weeks. After 6 weeks all (100%) wild type mice developed tumors, while 50% of Lp(a)+;Gulo(-/-) mice kept on high ascorbate diet for 6 weeks did not develop primary tumors and in only a small number of mice some residual tumor cells or inflammatory infiltrates were detected in the lungs by histology. In transgenic mice supplemented with low vitamin C for 6 weeks, the reduction of primary tumors incidence was 33% compared to wild type mice. In addition, primary tumors from wild type mice were on average over 2-fold larger (1.80+/-0.62g) than tumors from Lp(a)+;Gulo(-/-) mice on continual low Vitamin C (0.77+/-0.98g) or continual high Vitamin C (0.63+/-1.09g. Primary tumors from Lp(a)+;Gulo(-/-) mice immunostained positively for Lp(a) and their size was inversely proportional Lp(a) cholesterol serum levels. Lp(a) could not be detected in tumors from wild type mice and the presence of tumors was associated with higher LDL serum levels. The results implicate that Lp(a) may play a role in controlling tumor growth and expansion through its ECM adhesive properties. Citation Format: John Cha, M. Waheed Roomi, Aleksandra Niedzwiecki, Matthias Rath. Lipoprotein(a) and vitamin C affect the development of breast cancer tumors in Lp(a)+; Gulo-/- mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2288. doi:10.1158/1538-7445.AM2015-2288
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