Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line

Krüger, Achim; Oh, Sanchez-Sweatman; Dc, Martin; Je, Fata; At, Ho; Fw, Orr; Rüther, Ulrich; Khokha, Rama

doi:10.1038/sj.onc.1201774

Cited by 90 publications

(52 citation statements)

References 14 publications

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“…TIMP-1, identified originally for its erythroid-potentiating activity (5), induces proliferation in a wide range of cell types (6 -8) by mechanisms that are apparently independent of MMPs (9). In addition, TIMP-1 is known to promote activation of angiogenesis (4,10,11), regulate apoptosis (12), amplify inflammation (13), and regulate metastasis formation (14). Similar pleiotropic activities have also been demonstrated for TIMP-2 (15), TIMP-3 (16), and TIMP-4 (17).…”

Section: Introductionmentioning

confidence: 74%

TIMP-1 Alters Susceptibility to Carcinogenesis

Rhee¹,

Diaz²,

Korets³

et al. 2004

Cancer Research

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Tissue inhibitors of metalloproteinases (TIMPs) are a family of multifunctional proteins known to possess a broad range of biological activities, including inhibition of metalloproteinase activity, regulation of proliferation and apoptosis of a variety of cell types, and, depending on the context, differential regulation of angiogenic and inflammatory responses. Elevated mRNA expression of TIMP family members correlates with malignancy and clinical outcome in many human cancer types; however, a protective role for TIMPs also has been observed in various mouse models of human cancer. In the current study, we found distinct spatial-temporal expression patterns for the mRNA of TIMP family members in a mouse model of epithelial carcinogenesis [i.e., keratin 14-human papillomavirus 16 (K14-HPV16) transgenic mice]. To test the hypothesis that elevated expression of TIMP-1 functionally regulates epithelial carcinogenesis, we introduced a human TIMP-1 transgene into K14-HPV16 transgenic mice and assessed neoplastic progression. Results from these studies suggest that TIMP-1 enhances tumorgenicity by potentiating keratinocyte hyperproliferation and appearance of chromosomal aberrations in premalignant cells, thereby increasing their risk to undergo malignant conversion. In addition, TIMP-1 inhibits tissue gelatinolytic activity in tumor stroma, affects stabilization of collagen fibrils, but does not inhibit malignant conversion of dysplasias into carcinomas or development of metastases. The combined implications of these studies suggest that TIMP-1 is an important contributor to epithelial neoplastic progression and supports the concept that TIMP-1 exerts differential regulation on tissues in a stage-dependent manner.

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Section: Introductionmentioning

confidence: 74%

TIMP-1 Alters Susceptibility to Carcinogenesis

Rhee¹,

Diaz²,

Korets³

et al. 2004

Cancer Research

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“…Scavenging of uPA by suPAR interferes with the binding of uPA to its cellular receptor and leads to a reduction in the proteolytic activity of breast carcinoma cells and to a reduction in the orthotopic tumor growth and lung colonization of these tumor cells in vivo. So far, experimental 4,[25][26][27][28] and also preliminary clinical approaches 29 to achieve inhibition of the proteolytic activity of tumor cells to inhibit tumor progression have concentrated on the use of natural [25][26][27] or synthetic 4,28,29 inhibitors that are capable of interacting directly with the enzymatic center of the proteases.…”

Section: Discussionmentioning

confidence: 99%

Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the soluble urokinase-type plasminogen activator receptor (CD87)

et al. 2000

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The serine protease urokinase-type plasminogen activator, uPA, when bound to its specific receptor, uPAR (CD87), plays a significant role in tumor cell invasion and metastasis. In breast cancer, enhanced uPA antigen in the primary tumor is correlated with poor prognosis of the patient. In an in vivo nude mouse model, we tested tumor growth and metastasis of human breast carcinoma cells that had been transfected with an expression plasmid encoding a soluble form of uPAR (suPAR). We explored, whether suPAR/uPA interaction reduces the binding of uPA to cell surface-associated uPAR, and, as a consequence, could suppress tumor growth and metastasis of the human breast cancer cell line MDA-MB-231 BAG. Overexpressed, secreted suPAR was shown to bind and thus scavenge the uPA secreted by the transfected lines suPAR3 and suPAR10. In vitro, an overexpression of suPAR did not alter the proliferation rate of the transfected tumor cells, nor did it affect the expression of uPA. Overexpression of suPAR led to a reduction in the plasminogen activation-related proteolytic activity of breast carcinoma cells. Primary tumor growth in the mammary fat pad of nude mice was followed up for 52 days. Overexpression of suPAR correlated with a reduction in tumor growth (from day 21, reaching 30% by day 34) as well as lung colonization (lung metastasis-positive mice in suPAR3: 4 of 17; suPAR10: 3 of 10; parental MDA-MB-231 BAG: 13 of 18). We conclude that suPAR overexpression leading to effective scavenge of uPA impairs proteolysis as well as the tumor growth and metastatic potential of breast carcinoma cells in vivo. Cancer Gene Therapy (2000) 7, 292-299

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“…Likewise, use of recombinant TIMP-1 on glioma cells showed reduced glioma invasion (VanMeter et al 2001). Also, TIMP-1 was shown to cause significant reduction in brain metastasis of implanted fibrosarcoma cells (Kruger et al 1998) and a decrease in TIMP-2 levels in glioblastomas has been noted as well (Lampert et al 1998). TIMP-3 overexpression suppresses glioma cell infiltration (Baker et al 1999).…”

Section: Tissue Inhibitors Of Matrix Metalloproteinases (Timps) In Glmentioning

confidence: 99%