Cannistra S A, Kansas G S, Niloff J, DeFranzo B, Kim Y, Ottensmeier C
Division of Tumor Immunology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Cancer Res. 1993 Aug 15;53(16):3830-8.
Epithelial cancer of the ovary spreads by implantation of tumor cells onto the mesothelial lining of the peritoneal cavity. We have developed an in vitro binding assay using confluent monolayers of normal peritoneal mesothelial cells in order to assess the role of known adhesion proteins in this process. Cells from normal ovarian surface epithelium and the ovarian cancer cell lines CAOV-3 and SKOV-3 exhibited significant adhesion to mesothelium in vitro (range 33-56% specific binding). Although these cells expressed several adhesion molecules, including CD44 and integrins such as alpha 4 beta 1, alpha 5 beta 1, and alpha v beta 3, only anti-CD44 antibody was capable of inhibiting mesothelial binding (range 42-44% inhibition). Adhesion molecule expression was also determined for fresh ovarian specimens, with CD44 being expressed in 2 of 2 cases of normal ovarian epithelium, 15 of 16 (94%) cases of tissue-derived tumor (from primary sites or peritoneal implants), and only 2 of 8 (25%) cases of free-floating tumor cells from ascites. Three of three CD44-positive cases derived from peritoneal implants exhibited significant mesothelial binding which was partly blocked by anti-CD44 antibody, whereas 2 of 2 CD44-negative cases derived from ascites showed minimal binding. CD44-mediated binding of ovarian cancer cells was determined to be due to recognition of mesothelium-associated hyaluronate, suggesting that the CD44H isoform was involved in this process. Immunoprecipitation of the CD44 species expressed by ovarian cancer cells revealed 2 major bands at 85-90 and 180 kDa, consistent with the known molecular masses of CD44H. These results suggest that CD44H may be an important mediator of ovarian cancer cell implantation and that decreased CD44H expression may be associated with release of cells into the peritoneal space during ascites formation. It is possible that strategies to interfere with CD44H function may result in decreased intraabdominal spread of this highly lethal neoplasm.
卵巢上皮癌通过肿瘤细胞植入腹膜腔间皮衬里而扩散。我们开发了一种体外结合试验，使用汇合的正常腹膜间皮细胞单层，以评估已知粘附蛋白在此过程中的作用。来自正常卵巢表面上皮的细胞以及卵巢癌细胞系CAOV - 3和SKOV - 3在体外对间皮表现出显著的粘附（特异性结合范围为33 - 56%）。尽管这些细胞表达了几种粘附分子，包括CD44和整合素，如α4β1、α5β1和αvβ3，但只有抗CD44抗体能够抑制与间皮的结合（抑制范围为42 - 44%）。还对新鲜卵巢标本的粘附分子表达进行了测定，CD44在2例正常卵巢上皮中的2例、16例组织来源肿瘤（来自原发部位或腹膜种植体）中的15例（94%）以及腹水来源的8例游离肿瘤细胞中的2例（25%）中表达。来自腹膜种植体的3例CD44阳性病例表现出显著的间皮结合，且部分被抗CD44抗体阻断，而来自腹水的2例CD44阴性病例表现出最小的结合。确定卵巢癌细胞的CD44介导的结合是由于对间皮相关透明质酸的识别，这表明CD44H异构体参与了此过程。对卵巢癌细胞表达的CD44种类进行免疫沉淀，显示在85 - 90 kDa和180 kDa处有2条主要条带这与已知的CD44H分子量一致。这些结果表明，CD¬44H可能是卵巢癌细胞植入的重要介质，并且CD44H表达降低可能与腹水形成期间细胞释放到腹膜腔有关。干扰CD44H功能的策略可能会减少这种高度致命肿瘤的腹腔内扩散。
