卵巢癌細胞器官轉移特異性

Abstract

卵巢癌是目前最致命的婦科惡性腫瘤，癌細胞轉移是最主要的致命病因；包含卵巢癌，癌細胞的特定轉移模式被稱為「器官特異性」。 此論文中，我們使用了CB17/lcr-PRkdc scid/Crl免疫缺陷小鼠，檢視不同卵巢癌細胞在小鼠體內的器官特異性。原發腫瘤取得的A1847和A2780卵巢癌細胞株經由尾靜脈注射，會趨向卵巢轉移；而從腹水取得的Skov3卵巢癌細胞株經由尾靜脈注射，則轉移至肺臟。 藉由分析癌細胞的基本特性包含型態、移動能力、侵入能力以及增殖能力，試著去解釋不同卵巢癌細胞株的器官特異性。經由小鼠尾靜脈注射後48鐘頭，我們觀察到A1847和A2780細胞轉移至卵巢，而Skov3細胞在相同條件下則轉移至肺臟。將A1847細胞以及A2780細胞直接注射植入肺臟，細胞會轉移至卵巢；Skov3細胞原位打入卵巢，則會轉移至肺臟。 有報導指出，乳癌循環腫瘤細胞會腫瘤自播(tumor self-seeding)，我們觀察到卵巢癌Skov3細胞也有相似的現象。臨床研究顯示，兩側卵巢均有惡性腫瘤的案例有25%；我們也發現Skov3細胞能藉轉移到另外一側的卵巢，並且創傷癒合會促進此現象。 此論文說明了不同卵巢癌細胞株的特殊器官特異性，以及證實了在癌細胞轉移機制的限制步驟中，成功定殖(colonization)且生長較早期癌細胞附著於器官組織更為重要。並且也證明創傷癒療會促進細胞定殖。

Ovarian cancer is the most lethal gynecologic malignancy, and the majority of deaths occur due to metastatic disease. Many studies have identified the specific pattern of metastasis, termed organ tropism, including ovarian cancer. In this thesis, we used the CB17/lcr-PRkdc scid/Crl mice to show that different ovarian cancer cell lines had different organ tropism. The A1847 line and A2780 line derived from primary ovarian tumors displayed ovary tropism upon intravenous injection. The Skov3 cells derived from the ascites of ovarian adenocarcinoma form metastases in lung upon intravenous injection. We analyzed the properties of ovarian cancer cells including morphology, migration ability, invasion ability, and proliferation in order to explain the different organ tropism. And we observed A1847 and A2780 cells metastasized to ovary 48 hours after intravenous injection, whereas Skov3 cells metastasized to lung tissue under the similar condition. When A1847 and A2780 cells were implanted directly into lung, they metastasized to ovary. Skov3 cells which were implanted orthotopically into ovary metastasized to lung. It was shown that in breast cancer, circulating tumor cells self-seeded their tumor origin, we observed similar phenomenon in Skov3 cells. Accumulated clinical studies revealed 25% ovarian cancer cases involved bilateral ovarian carcinomas. We found that Skov3 cells were able to metastasize to contralateral ovary, and this was promoted by wound healing. This thesis demonstrates the distinctive organ tropism of ovarian cancer cell lines, and the limiting step of metastasis resides more in successful colonization than initial targeting of the organs. Wounding healing could promote cancer cell colonization.