The overall objective of this research program is to study interrelationships between the differential production of angiogenic growth factors such as the transforming growth factors-a and -b(1,2,3), and members of the fibroblast growth factor family (acidic FGF, basic FGF, FGF-5, KGF) produced by human tumor cells to growth rates and levels of intraneoplastic hypoxia in xenografted solid tumors. We hypothesize that there is an Inverse correlation between in tumor hypoxic levels and the extent of angiogenic growth factor(s) available to support tumor neovascularization. We also hypothesize that the extracellular matrix (ECM) within neoplasms is a critical component of this relationship because the ECM (specifically heparan sulfate proteoglycan) can act as a reservoir for storage of growth factors such as b FGF. Interactions among growth factors such as TGF-b, b FGF and the ECM, may play Important roles In the overall expression of tumor hypoxia. A battery of human colon cancer lines have been extensively characterized In terms of In vitro growth factor production and extent of In vivo hypoxia, and correlations between these endpoints support the hypothesis that tumor hypoxia Is Inversely related to angiogenic growth factor status. We will continue to Investigate levels of growth factor production using cellular and radioimmunoassays. Also, mRNA levels for these selected growth factors and ECM molecules will be studied using polymerase chain reaction technology, both in vitro and In vivo. Results from tumor tissue will be compared to results from normal human colon epithelial tissue. The levels of heparan sulfate proteoglycan in xenografted tumors will be studied by high pressure liquid chromatography. The relationship between the host and tumor will be perturbed by preirradiation of the tumor cell Implantation site which produces marked changes In tumor growth rate and hypoxic fractions (tumor bed effect or THE). The magnitude of the THE will be related to pre- and postirradiation growth factor and ECM status. Other challenges Include treatment of tumor bearing animals with agents that block growth factors or growth factor receptors (e.g., suramin, neutralizing antibodies), and treatment with exogenously applied growth factors (i.e., b FGF). Assessment of hypoxic fraction status and tumor radiocurability will be done In studies using multifractionated x-irradiation of appropriate chosen xenografts to test the hypothesis that growth factor/ECM status Is a critical co-variate of tumor radiocurability In a clinically relevant setting. Lastly, we will generate a biomathematical framework within which results can be modeled and interpreted. The relationship of this project to health concerns arises from the insight to be gained with regard to tumor response and curability as a function of growth factor status, and raises the possibility that modulation of neoplastic growth factor/ECM status could influence therapeutic response.
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