CONTROL OF METASTATIC PROGRESSION OF PROSTATE CANCER

在所有确诊为前列腺癌的男性中，超过四分之一的人死于 它的恶性转移。目前的临床经验表明，早期 局部癌的诊断和治疗是治疗肺癌的最佳方案 控制其恶性发展。来自动物研究的证据 然而，模型表明，原发局部肿瘤本身包含 侵袭性和转移性恶性肿瘤细胞亚群 潜力。一类侵袭性细胞亚群的分离 它们入侵基底膜屏障的能力，可能证明 在原发前列腺肿瘤中存在这样的细胞。独一无二或已更改 预先存在的特征的形式，例如退化的能力 围绕细胞外基质，增加趋化运动，以及 某些细胞表面抗原的表达促进细胞-细胞间 黏附从而逃脱免疫监视可能会赋予这些细胞 具有侵袭性和转移性。某些特定的明智组合 抗肿瘤药物和放射治疗可能不仅会提高这些细胞的细胞毒性。 亚群，但也可能消融存活下来的侵袭性 细胞。本研究拟对这些假设进行检验。一次体外入侵 使用重组基底膜的化验将用于分离 原发性前列腺癌侵袭性和非侵袭性肿瘤细胞亚群 癌标本。具有不同转移程度的新肿瘤株 原位注射阿司匹林将在无瘤小鼠中建立潜能 这些亚群来自于原发癌。人类进化的细胞基础 这些肿瘤株的侵袭和转移潜能将是 以基底膜的分泌物为特征的降解 蛋白水解酶(基质金属蛋白酶)，基质抑制物 金属蛋白酶与一类细胞表面蛋白的表达 转移相关细胞黏附分子(CD44及其变异体 异构体)。控制原发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来实现 使用它们的天然和合成抑制剂，以及中和 抗体。某些抗肿瘤药物的细胞毒和抗转移作用 药物单独用药和联合放射治疗 转移性亚系的异种移植将被表征和量化为 制定改进的治疗方案。肿瘤细胞的分离 原发肿瘤亚群及其影响因素的研究 对侵袭性和转移性行为负责可能意味着新的和 改进临床治疗策略以控制恶性肿瘤 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.