title: Lipoprotein(a) and vitamin C impair development of breast cancer tumors in Lp(a)+; Gulo-/- mice.
abstract: 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 carcinogenesis, 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: i) low ascorbate intake for 6 weeks; ii) high ascorbate intake for 6 weeks; iii) low ascorbate intake for 3 weeks followed by high ascorbate for 3 weeks; iv) 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 this pathomechanism could lead to a universal therapeutic target for the prevention and treatment of cancer.
authors: Dr. Rath Research Institute, Santa Clara, CA 95050, USA.
authors: John
authors: J
authors: Cha
authors: Dr. Rath Research Institute, Santa Clara, CA 95050, USA.
authors: M Waheed
authors: MW
authors: Roomi
authors: Dr. Rath Research Institute, Santa Clara, CA 95050, USA.
authors: Tatiana
authors: T
authors: Kalinovsky
authors: Dr. Rath Research Institute, Santa Clara, CA 95050, USA.
authors: Aleksandra
authors: A
authors: Niedzwiecki
authors: Dr. Rath Research Institute, Santa Clara, CA 95050, USA.
authors: Matthias
authors: M
authors: Rath
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics*; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000187:drug effects; D005260:Female; D006801:Humans; D017270:Lipoprotein(a) / Q000172:deficiency*; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D001054:Apolipoproteins A; D001055:Apolipoproteins B; D017270:Lipoprotein(a); D001205:Ascorbic Acid