Decreased metastatic spread in mice homozygous for a null allele of the cystatin C protease inhibitor gene

Abstract

Aims-Increased or altered activities of cysteine proteases have been implicated in serious human disorders such as cancer, rheumatoid arthritis, sepsis, and osteoporosis. To improve the current knowledge of the regulatory role of a major mammalian cysteine protease inhibitor, cystatin C, in such disease processes, a cystatin C deficient mouse was generated and characterised. Methods-The mouse cystatin C gene was inactivated by insertion of a bacterial neo gene through homologous recombination in 129/Sv embryonic stem cells. Embryonic stem cell clones were injected into C57BL/6J blastocysts followed by injection of the blastocysts into pseudopregnant female mice. F1 oVspring with agouti coat colour after mating of chimaeric males with C57BL/6J females were examined by DNA analysis, and mice carrying the targeted mutation were intercrossed to obtain homozygous cystatin C deficient (CysC

Reduction of Experimental Human Fibrosarcoma Lung Metastasis in Mice by Adenovirus-Mediated Cystatin C Overexpression in the Host

“…Alternatively, elevated cystatin C levels may be a reflection of increased cathepsin activity in tumors or the stromal host cells, respectively, as it is also discussed for other natural protease inhibitors. Interestingly, in cystatin C knock-out mice, experimental metastasis of murine melanoma cells is promoted (23). However, as to whether the absence of cystatin C could lead to counter-regulation of metastasis-related effector molecules during the development of these mice has not been described.…”

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

“…This concept has been proposed following the survival results in the carcinoma of the breast , lung (Knoch et al, 1994;Ebert et al, 1997), and head and neck (Strojan et al, 2000). Two studies apparently contradict this assumption, specifically regarding cystatin C. In colorectal cancer (Kos et al, 2000a) and lung cancer (Kos et al, unpublished results), the patients with high serum levels of cystatin C exhibited a significantly higher risk of death than those with lower levels of inhibitor, whereas a decreased metastatic spread was found in cystatin C deficient mice compared to wild-type mice (Huh et al, 1999). As mentioned above, alterations in secretion may result in higher extracellular and lower intracellular levels of cystatin C and, therefore, the reverse correlation of serum cystatin C with patients' survival is to be expected.…”

Cystatin C: current position and future prospects

“…Specifically, seven times fewer pulmonary metastatic colonies developed following intravenous injection of the highly metastatic B16-F10 murine melanoma line in mice inactivated for the CysC gene, compared to wild type animals (247). Our understanding of the relationships between CysC expression and oncogenesis appears therefore only to be in its infancy.…”