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 (5×105). 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.

Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies

“…In a very recent study Lp(a) and vitamin C were found to impair development of breast cancer in a mouse model, transgenic for human Lp(a) and deficient in endogenous vitamin C production [42]. …”

Role of extracellular matrix in breast cancer development: a brief update

“…The heparin and nanoheparin derivatives show their anti-cancer activities by reducing BC cell proliferation and metastasis 55 . Loss of ECM integrity by plasmin facilitates cancer cell spread and plasmin-induced ECM degradation may be controlled by lipoprotein-A (competitive inhibitor of plasminogen) 56 – 58 . Vitamin C seems to be very important curbing tumor growth, and metastasis as ECM integrity requires vitamin C 58 .…”

Lipoprotein (a): a promising prognostic biomarker in patients with hepatocellular carcinoma after curative resection

“…Serum Lp(a) levels were found to be inversely proportional to tumor mass. 9 , 13 Furthermore, Lp(a) levels were significantly lower in HCC patients than in the controls. 7 , 14 – 16 Lp(a) may play a crucial role in controlling tumor growth and expansion as a competitive inhibitor of plasmin-induced proteolysis and through its adhesive properties to extracellular matrix components because of its unique structure.…”

“…High Lp(a) levels may protect against tumors, which participate in mitigating extracellular matrix damage during cancer progression, in particular by inhibiting proteolytic processes characteristic of all types of cancer cells. 13 , 17 – 23 All of these factors might suggest that Lp(a), as one of the major moleculars, affects tumor progression through modulating proteolytic processes during extracellular matrix damage. However, the value of serum Lp(a) in monitoring the recurrence and survival of HCC patients has not been investigated.…”