Abstract
摘要:腦轉移是癌症病患失能或死亡的重要原因。由於診斷技術及治療的進步,隨著病患的存活時間延長,腦轉移的發生率快速增加,造成嚴重殘疾,然而,治療的選擇卻十分有限。因此,尋找新穎的治療標的已成為當前研究亟待突破的領域。 為了進一步了解腦轉移,我們已成功建立肺癌及乳癌的腦轉移動物模式,分離出具有高度能力轉移至腦部的腫瘤細胞,發現與胚胎發育相關之訊息傳遞路徑如 Notch、Wnt、IGF 及 SOX2 等過度表現,並觀察到腦部基質細胞(以星狀細胞為代表)會促進腫瘤生長、抗藥性與表現 SOX2。 越來越多的研究結果支持我們所觀察到的現象,包括在肺癌腦轉移的檢體發現有部分細胞會表現幹細胞的分子標記,在腦轉移的動物模式觀察到 Notch之訊息路徑處於活化狀態,腦部基質細胞會活化乳癌幹細胞之 Notch 訊息路徑、促進腫瘤在腦部生長,這些現象顯示胚胎發育相關的訊息傳遞路徑在腦轉移扮演重要的角色。此外,研究發現 SOX2 不但具有維持正常幹細胞之功能,還與腫瘤的發生、轉移、預後有關,然而,SOX2 在腦轉移的角色仍不清楚。 根據過去研究累積的結果,我們進一步提出的假說是:SOX2 是腦部微環境促進腫瘤生長與抗藥性的關鍵分子。為了驗證此一假說,我們提出此三年期的研究計畫,將朝以下四個部分來進行。首先,我們將探討 SOX2 的表現是否影響腦轉移的發生與治療。接著,將檢視 SOX2 是否為腦部基質細胞影響腫瘤生長及藥物反應的媒介分子。此外,將探討腦部基質細胞影響腫瘤細胞過度表現SOX2 的調控機制。最後,將研究 SOX2 的臨床意義。綜言之,我們期望透過對SOX2 在腦轉移的角色及相關訊息路徑有更深入的了解,尋找腦轉移的新穎治療標的。
Abstract: Brain metastasis is an important yet understudied field of health problem. The incidence is rapidly increasing with the advances in diagnostic techniques and treatment modalities, which lead to prolonged survival of cancer patients. It confers significant disability and poor outcome to the patient, but the therapeutic options are limited. Therefore, exploration of new therapeutic targets for this devastating condition is urgently needed. To further our understanding of brain metastasis, we’ve successfully established a murine xenograft model of brain metastasis, isolated the brain-seeking cancer cells, and found up-regulation of several brain development-related pathways (eg. Wnt, Notch and IGF pathways) and SOX2 in brain-seeking cancer cells. We also noted that interactions between cancer cells and astrocytes (representative of CNS stromal cells) enhance cell growth, drug resistance and expression of SOX2 (Sex-determining region Y (SRY)-Box2), a transcription factor involved in the regulation of embryonic development and stem-cell maintenance in the central nervous system. Increasing amount of evidence supports our findings that embryonic signaling pathways might play important roles in brain metastasis, including the observations such as the presence of a stem-like population in brain metastases from the lung, activation of Notch signaling in a xenograft model of brain metastasis, and metastatic growth of breast cancer stem-like cells in brain by interacting with CNS stromal cells through Notch signaling. In addition to normal stem cell functions, SOX2 over-expression is associated with cancer development and metastasis in various tumor tissues and correlated with poor prognosis. However, the role of SOX2 in brain metastasis is unclear. Based on these preliminary findings, this 3-year project aims to test our hypothesis that SOX2 is a critical molecule in the CNS niche to promote growth and drug resistance of metastatic cancer cells. Our study will proceed in four parts. First, we’ll investigate whether SOX2 promotes the development of brain metastases and influences treatment responses. Second, we’ll examine whether SOX2 mediates cancer-astrocyte interactions to enhance growth and drug resistance. Third, we’ll investigate the signaling pathways and regulatory mechanisms of astrocyte-induced SOX2 overexpression in cancer cells. Finally, we’ll evaluate the clinical implications of SOX2 expression in human brain metastasis. Overall, we aim to identify potential therapeutic targets in brain metastases to improve treatment efficacy through a better understanding of SOX2 in brain metastasis and related signaling pathways.
Keyword(s)
腦轉移
基質細胞
星狀細胞
胚胎發育相關之訊息傳遞路徑
brain metastasis
stromal cell
astrocyte
SOX2
embryonic
signaling pathway.