這份研究計劃的主要目標是要了解腦部微環境對腦部轉移的肺癌細胞其生物行為的影響。由於我們實驗室先前的研究成果顯示活化的Akt 會誘發CXCR4的表現，並進而促進乳癌轉移；阻斷Akt 的活性可抑制轉移的可能。目前的計劃，將試驗CXCR4在“肺癌腦轉移”中是否亦扮演一重要的角色。此項研究計畫提出假設認為當轉移的肺癌細胞穿越血腦屏障(BBB)時，腦部組織的微環境會引起Akt 的活化，進而誘發CXCR4的表現。在此項研究計畫中，我們也將深入研究CXCR4 的表現情形是否會促進腦部轉移的肺癌細胞在轉移處的存活能力，並探討CXCR4 在腦部轉移的肺癌細胞和其他腦部微環境細胞之間的交互作用。為了達成這樣的目標，我們將重點放在 CXCR4 如何利用新的訊息傳導路徑影響癌化程度、肺癌的腦轉移，並且建立了五個確切的目標( five SPECIFIC AIMS) : 目標一：研究在肺癌細胞穿越血腦屏障(BBB)時CXCR4的生物功能為何。目標二：對在肺癌細胞腦部轉移的微環境中CXCR4的功能為何以體外試驗模式進行探討。目標三：利用肺癌細胞腦轉移的動物實驗，證實CXCR4在肺癌腦轉移中的角色，並對CXCR4表現量與人類肺癌病人是否發生腦部轉移潛力的臨床相關性加以研究。目標四：研究Akt/mTOR&GSK3β訊息傳導路徑於腦轉移肺癌和腦轉移肺癌微環境中的角色。目標五：證實Akt/mTOR&GSK3β 訊息傳導路徑於體內腦轉移動物實驗中的重要性，及與人類肺癌病人腦轉移發生的相關性。藉由這些確切目標的結果，可以幫助我們建立完整的訊息傳遞網路，以更加了解肺癌轉移細胞在腦部微環境中促進其增生和血管生成的分子機制，例如與星狀細胞和腦部血管內皮細胞之間的交互作用。因此探討肺癌腦轉移之分子機轉便成為重要之研究課題，此研究議題不僅是在基礎研究上具有重要性，更是具有其臨床意義。
The primary goal of this research project is to understand the influence of brain microenvironment to the biologic behavior of brain metastatic lung cancer cells. Previous work from our lab has shown that activated Akt induces CXCR4 expression and subsequently contributes to the breast cancer lung metastasis, and the blockage of Akt activity inhibits metastatic potentials. The current proposal will test whether CXCR4 also plays a role in the brain metastasis of lung cancer. We now hypothesize that when metastatic lung cancer cells pass through the Blood-Brain Barrier (BBB), the microenvironment of brain will cause the activation of Akt, which in turn induce the expression of CXCR4. We will also ask whether the elevated CXCR4 in the brain metastatic lung cancer cells will promote the interaction between cancer cells with the brain microenvironment and the survival of the cancer cells in the host environment. To reach the goal, we will focus on how CXCR4 may interact with the novel signaling pathways and exert effects on tumor progression and brain metastasis in lung cancer and five SPECIFIC AIMS are proposed. SPECIFIC AIM 1: To investigate the biological function of CXCR4 in lung cancer cells to cross the Blood-Brain Barrier (BBB) in vitro. SPECIFIC AIM 2: To study the biological function of CXCR4 in microenvironment of brain metastatic lung cancer in vitro. SPECIFIC AIM 3: To validate the role of CXCR4 in lung cancer brain metastasis in in vivo brain metastasis animal model and clinical correlation of the expression of CXCR4 with the metastatic potential of human lung cancer. SPECIFIC AIM 4: To study the role of Akt/mTOR & GSK3β signaling pathways in brain metastatic lung cancer and microenvironment of brain metastatic lung cancer SPECIFIC AIM 5: To validate the importance of Akt/mTOR & GSK3β signaling pathways in brain metastasis animal model and the correlation with the human lung cancer brain metastasis tissue. Success of these SPECIFIC AIMS will help us to establish signaling networks to understand better the molecular mechanisms that may contribute to the cell proliferation and angiogenesis of metastatic lung cancer cells in brain contribute by the brain environment, such as astrocyte and brain endothelial cells. Identify novel molecular mechanisms involved in lung cancer brain metastasis, both in vitro and in vivo, will be important for the further investigations of novel target therapeutic strategy.
