Sustained breast cancer growth and metastasis requires paracrine signals between the tumor cells and the normal surrounding host tissue. One crucial function of these signals is to recruit endothelial cells and thus new blood vessels for the nourishment of the expanding tumor mass. This proliferation and migration of endothelial cells in the vicinity of progressing tumors contrasts with the extremely low turn-over rate of endothelial cells in the healthy adult. Thus, a selective blockade of the tumor-induced endothelial cell proliferation should inhibit tumor growth and potentially metastasis with only few adverse effects. We found that the most potent endothelial cell growth factors released from breast cancer cells in vitro are heparin-binding growth factors (HBGFs) and we detected significant levels of HBGF gene expression in samples of primary tumors. We have therefore focused our search for inhibitors of growth factors in breast cancer on heparin-like polysulfates. We have demonstrated that HBGF action in vitro can be blocked by a structural analogue of heparin: pentosanpolysulfate (PPS). Furthermore, the growth of human breast cancer cell lines into tumors in athymic nude mice can be inhibited by the treatment of the animals with PPS. PPS was effective against tumors derived from in vitro PPS-sensitive and from in vitro PPS- resistant tumor cell lines. In addition PPS treatment was able to prevent carcinogen-induced development of breast cancer in rats. These data suggest that PPS blocks the hosts' reaction to the HBGF(s) released from the tumor cells. The overall goal of this project is to extend the knowledge of the role of HBGFs in tumor growth and the use of PPS to clinical samples. In particular we propose the following studies: 1. To determine to what extent endothelial cell proliferation and HBGF gene expression in normal and cancerous breast tissue can serve as biological and molecular markers of the disease state, the prognosis of the patient and her responsiveness to HBGF-targeted therapy. A close cooperation with the Tumor Bank Core Facility, with Project 0003 (Clinical Trial) and Project 0002 (FGF) is ongoing. 2. To study the effects of combined HBGF-targeted and antihormone, cytotoxic and radiation therapy of breast cancer. 3. To assay for anti-HBGF activity in serum samples from patients treated with PPS in cooperation with Project 0003 (Clinical Trial). 4. To study the preventive potential of PPS against spontaneous and carcinogen-induced breast cancer in animal models.
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