More than one fourth of all men diagnosed with prostate cancer die due to its malignant metastases. Current clinical experience suggests that early diagnosis and treatment for localized carcinoma is the best course for controlling its malignant progression. Evidence from studies on animal models suggests however, that the primary localized tumor itself contains subpopulations of malignant tumor cells with invasive and metastatic potential. The isolation of a subpopulation of invasive cells based on their ability to invade a basement membrane barrier, might prove the existence of such cells in primary prostatic tumors. Unique or altered forms of preexisting characteristics, such as the ability to degrade surrounding extracellular matrix, increased chemotactic motility, and the expression of certain cell surface antigens that promote cell-cell adhesion and thereby escape immune surveillance might endow these cells with invasive and metastatic potential. Judicious combinations of certain antitumor drugs and radiation might not only improve cytotoxicity on these subpopulations, but might also ablate the invasive properties of surviving cells. This study proposes to test these hypotheses. An in vitro invasion assay using a reconstituted basement membrane will be used to separate invasive and noninvasive tumor cell subpopulations from primary prostatic carcinoma specimens. New tumor lines with different degrees of metastatic potentials will be established in athymic mice by orthotopic injections of these subpopulations from the primary carcinoma. The cellular basis of the invasive and metastatic potential of these tumor lines will be characterized for the secretion of the basement membrane-degrading proteolytic enzymes (matrix metalloproteinases), inhibitors of matrix metalloproteinases, and the cell surface expression of a class of metastasis-associated cell adhesion molecules (CD44 and its variant isoforms). Novel methods to control primary tumor metastasis will be attempted by inhibiting the activities of the matrix metalloproteinases using their natural and synthetic inhibitors, as well as neutralizing antibodies. The cytotoxic and anti-metastatic effects of certain antitumor drugs individually, and in combination with radiation on orthotopic xenografts of metastatic sublines will be characterized and quantitated to develop improved treatment protocols. The isolation of tumor cell subpopulations from primary tumor and the characterization of factors responsible for invasive and metastatic behavior might suggest new and improved clinical treatment strategies for controlling the malignant progression of prostatic carcinoma.
