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Cited by 119Protease and Inhibitor MechanismsMechanisms of cancer metastasisUbiquitin and proteasome pathways

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

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Huh, C G, Håkansson, K, Nathanson, C M, Thorgeirsson, U P, Jonsson, N, Grubb, A, Abrahamson, M, Karlsson, S·1999·Molecular Pathology
DOI 10.1136/mp.52.6.332PMC PMC395718
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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 characterized. 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 offspring 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-/-) mice. To study the role of cysteine proteases and their inhibitors in metastasis, the spread of B16-F10 melanoma cells in CysC-/- and wild-type mice was compared. Analysis of the formation of remote metastases was carried out by intravenous injection of beta-galactosidase transfected B16-F10 cells and subsequent determination of cancer cell colonies in the lungs. RESULTS: Cystatin C deficient mice were fertile and showed no gross pathological abnormality up to 6 months of age. Compared with wild-type mice, seven times fewer large metastatic colonies were counted by means of a dissecting microscope in CysC-/- mice two weeks after tail vein injection of B16-F10 cells. At all of eight time points from 15 minutes to two weeks after intravenous injection of tumour cells, the CysC-/- mice had significantly fewer lung metastases. The observed differences were smaller when beta-galactosidase transfected cells were used to allow counting of small colonies. Subcutaneous and intracerebral tumour growth was not different in the CysC-/- mice. CONCLUSIONS: Cystatin C concentrations in vivo might influence metastasis in some tissues. The decreased metastatic spread of B16-F10 cells in CysC-/- mice is the result of both reduced seeding and reduced growth of tumour cells in their lungs.

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  • Germline CST3 knockout abrogates metastasis in vivo.

    “consistent with evidence that germline CST3 knockout abrogates metastasis in vivo.86”

    From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [86]

    The Generation of Cystatin C Null Mice section describes germline transmission of the disrupted allele. The Abstract reports seven times fewer large lung metastatic colonies in homozygous null mice after B16-F10 cell injection—not an absence of metastasis. Thus the in vivo reduction is supported, but “abrogates” overstates the result. (LLM, conf=0.92)

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Cited by

Sorted by citations

Authors
Huh, C. G., Håkansson, K., Nathanson, C. M., Thorgeirsson, U. P., Jonsson, N., Grubb, A., Abrahamson, M., & Karlsson, S.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Molecular Pathology
Publisher
BMJ
Published
1999-12
Volume
52
Issue
6
Pages
332-340
ISSN
  • 1366-8714 (ISSN-L)
  • 1472-4154
DOI
10.1136/mp.52.6.332
PMC
PMC395718
OpenAlex
W2160296988
Cited by
119
References
0
Citations by year
2025: 1 · 2024: 2 · 2023: 2 · 2021: 11 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 4 · 2013: 2 · 2012: 4
FWCI
1.12
Type
journal article
Language
en
Open access
Locations
  • Molecular Pathology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
cystatin C, cysteine protease inhibitors, metastasis, lung metastasis, B16F10 melanoma, gene targeting, tumor seeding, chimeric mice
MeSH terms
Alleles, Animals, Homozygote, Genetic Linkage, Lung Neoplasms, Melanoma, Mice, Inbred C57BL, Cysteine Proteinase Inhibitors, Cystatins, Mice, Knockout, Mice, Cystatin C

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