CONTROL OF METASTATIC PROGRESSION OF PROSTATE CANCER

超过四分之一的被诊断患有前列腺癌的男性死于 恶性转移目前的临床经验表明， 诊断和治疗局限性癌是最好的课程， 控制其恶性发展。来自动物研究的证据 然而，模型表明，原发性局部肿瘤本身含有 具有侵袭性和转移性的恶性肿瘤细胞亚群 潜力基于以下的侵袭性细胞亚群的分离： 它们侵入基底膜屏障的能力，可能证明 这种细胞在原发性前列腺肿瘤中的存在。独特的或改变的 预先存在的特征的形式，例如降解能力 周围的细胞外基质，增加趋化运动， 某些细胞表面抗原的表达， 粘附从而逃避免疫监视可能赋予这些细胞 具有侵袭性和转移性一些明智的组合 抗肿瘤药物和辐射不仅可以改善这些细胞的细胞毒性， 亚群，但也可能消除生存的侵入性， 细胞本研究旨在验证这些假设。体外入侵 使用复溶基底膜的测定将用于分离 原发性前列腺浸润性和非浸润性肿瘤细胞亚群 癌标本。具有不同程度转移的新肿瘤系 将通过原位注射 这些亚群来自原发癌。的细胞基础 这些肿瘤细胞系的侵袭和转移潜力将 以分泌降解基底膜的 蛋白水解酶（基质金属蛋白酶），基质抑制剂 金属蛋白酶，以及一类 转移相关细胞粘附分子（CD44及其变体 同种型）。控制原发性肿瘤转移的新方法将是 试图通过抑制基质金属蛋白酶的活性 使用它们的天然和合成抑制剂， 抗体的某些抗肿瘤药物的细胞毒作用和抗转移作用 单独使用药物，以及与原位放射联合使用 将对转移性亚系的异种移植物进行表征和定量， 改进治疗方案。肿瘤细胞的分离 原发性肿瘤的亚群和因子的表征 负责侵袭和转移行为可能表明新的， 改进的控制恶性肿瘤的临床治疗策略 前列腺癌的进展。

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.