John Cha*, M. Waheed Roomi*, Tatiana Kalinovsky, Aleksandra Niedzwiecki, Matthias Rath
Dr. Rath Research Institute, Santa Clara, California, USA
International Journal of Oncology 2016, 49(3), 895-902
Cancer progression is characterized by loss of extracellular matrix (ECM) integrity, which is a precondition for tumor growth and metastasis. In order to elucidate the precise mechanisms of ECM degradation in cancer we used a genetically modified mouse mimicking two distinct human metabolic features associated with cancerogenesis - the lack of endogenous vitamin C synthesis and the production of human Lp(a). Female Lp(a)+;Gulo(-/-) and control wild type Balb/c mice without these two metabolic features were orthotopically inoculated with 4T1 breast cancer cells (5x105).
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. After 6 weeks, all wild type mice developed tumors. In contrast, Lp(a)+;Gulo(-/-) mice developed one third less primary tumors (low ascorbate diet) or no primary tumors at all (high ascorbate diet). Significantly, tumors from Lp(a)+;Gulo(-/-) mice immunostained positively for Lp(a) and their size was inversely proportional to Lp(a) serum levels. The results implicate that Lp(a) may play a role in controlling tumor growth and expansion. The most likely mechanism is the competitive inhibition of plasmin-induced ECM degradation due to the homology of Lp(a) components to plasminogen, The confirmation of thispathomechanism could lead to a universal therapeutic target for the prevention and treatment of cancer.
Running title: Lp(a) and vitamin C inhibit breast cancer
Key Words: lipoprotein(a), Lp(a)+;Gulo (-/-) mice, vitamin C, 4T1 breast cancer cells, tumor growth, metastasis