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

Abstract

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

Overexpression of the urokinase receptor mRNA splice variant uPAR-del4/5 affects tumor-associated processes of breast cancer cells in vitro and in vivo

“…Lung is a major site for metastatic spread of cancer cells during breast cancer progression [28,29]. In order to explore the impact of uPAR-del4/5 overexpression in vivo, we intravenously injected mice with MDA-MB-231-vector, -uPAR-WT, or -uPAR-del4/5 cells and analyzed incidence, number, and size of nodules of experimental lung metastases.…”

Complex roles of tissue inhibitors of metalloproteinases in cancer

“…For example, Marimastat can cause severe joint pain, which has to be minimized by reducing the dose, but at the expense of e cacy (Steward and Thomas, 2000). Secondly, MMPI, like TIMP, can also function in favor of tumor growth by up-regulation of angiogenic factors (Kruger et al, 2001) or by inhibiting the angiostatin or endostatinconverting MMPs (Patterson and Sang, 1997;Pozzi et al, 2000) and therefore playing a positive role in angiogenesis. In consistence with this scenario, an induction of liver metastasis was reported on intraperitoneally growing esophagus and ovarial carcinoma, intravenously inoculated T-cell lymphoma cells, and human breast carcinoma, when the mice were treated daily with Batimastat (Kruger et al, 2001).…”

Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis

“…In this context, it has been reported that patients with small cell lung cancer receiving the MMP inhibitor Tanomastat (BAY12-9566) did worse than controls (Bayer, Corp., 1999), and treatment with the gelatinase inhibitor Prinomastat in patients with non small cell lung cancer did not lead to any bene®cial e ect as compared to the placebo group (Agouron, 2000). Finally, in vivo treatment with Batimastat resulted in increased liver metastases of breast carcinoma and T-cell lymphoma in nude or syngeneic mice (Kruger et al, 2001).…”