- 學位論文
化學治療誘發之間質上皮訊息及其在基質纖維化腫瘤之致癌角色
Chemotherapy-induced Stromal-epithelial Signaling and its Oncogenic Role in Desmoplastic Cancer
摘要
傳統的化學治療除了能夠殺死一部份的腫瘤細胞，它也能活化結締組織及進一步地刺激殘存腫瘤細胞的生長及存活，進而造成腫瘤的復發及轉移。依此，克服來自化學治療所產生的宿主反應將可以改善治療成效及病人的存活。腫瘤之抗藥性及轉移被認為和一群聚有幹細胞特性的腫瘤起始細胞有關。針對接受過前輔性化學治療病人及原位異種腫瘤小鼠之腫瘤結締組織的分生研究顯示，不管化學治療藥物的種類，傳統的最高容忍劑量化學治療會造成STAT-1 及 NF-κB轉錄因子在腫瘤相關纖維母細胞持續的活化。這樣的現象會促進ELR+趨化素的表現及分泌，進而藉由腫瘤細胞膜表現的CXCR-2造成腫瘤起始細胞的轉換，腫瘤的侵入表現及反向的腫瘤療效。反之，同樣劑量的化學藥物但若以低劑量節拍式化療打法投藥時卻能大幅預防來自腫瘤結締組織之ELR+趨化素支旁泌訊息傳遞，進而大幅提升治療反應及延長小鼠之存活期。我們的研究揭露了結締組織在癌症治療的重要性以及化學治療打法的改變對腫瘤治療抗性所會產生的影響。
並列摘要
Whilst traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. Resistance to treatment and metastasis have been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant-chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximal-tolerated-dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR-motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression following therapy. By contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+-chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These studies illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.