There is an urgent need for new ways to assess the biological properties of prostate cancers that can be applied to needle biopsies. This research program will identify new molecular markers of human prostate cancer as new diagnostic and prognostic factors for clinical translation to the outcome for individual patients. These molecular markers will be correlated with the response and biological properties of prostate cancer such as structure, growth immortalization, invasion, and metastasis. Studies will focus on cell structural alterations, DNA instability and telomerase activity that are applicable to zonal analysis of needle biopsies. Alterations in nuclear and cellular shapes have long been recognized as one of the very earliest and most common cellular events associated with any type of carcinogenesis, This morphological transformation involves variation in nuclear morphology and chromatin patterns that are distinguishing features in the cytopathological identification of cancer cells. We have correlated quantitative morphometry of nuclear and chromatin changes with prognosis in human prostate cancer, and propose here to identify their molecular components, The shape of the nucleus appears to be defined by an internal nuclear scaffolding system that forms an organizing framework that we termed the nuclear matrix. The nuclear matrix provides a tissue specific 3- dimensional organization of DNA that dictates the higher order structure of the genome. The protein components of the matrix are tissue- and tumor-specific and provide DNA binding sites that define the spatial locations for tissue specific gene expression with actively expressed genes located on the nuclear matrix. DNA synthesis occurs at fixed replicating sites located near these matrix attachment sites. Telomeres are tightly attachments to the nuclear matrix. The nuclear matrix is ideally positioned to play a critical role in providing structural sites for organizing many nuclear events involved in DNA functions. Therefore, in carcinogenesis and tumor progression, the aberrations seen in the shapes of the cancer nuclei may be of prime importance in disturbing normal DNA functions that are organized on the nuclear matrix. We have observed specific changes occurring in nuclear matrix proteins associated with prostate cancer in both humans and animals. A new matrix protein, PC-1, appears in human prostate cancer, while other matrix proteins like NBP-4, disappear, Antibodies have been made to these proteins that will assist in their evaluation. We have also observed shortening in telomere lengths in human prostate cancer that accompanies induction of telomerase activity. These nuclear matrix proteins and telomerase activity will be applied to needle biopsies and translated into clinical evaluation.
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