探討介白素三號與基質金屬蛋白酶-2於小鼠腫瘤內所扮演的角色

惡性腫瘤至今仍是人類最主要的死因，因此開發新的療法以促進癌症治療效用是目前最迫切的議題。本研究主要目的為探討腫瘤微環境對於癌症治療的影響並且利用兩種實驗模式以達到此目的：(1)過度表現介白素三號(IL-3)於TRAMP-C1 攝護腺癌細胞上以吸引或活化腫瘤相關巨噬細胞；(2)抑制基質金屬蛋白酶-2 (MMP-2)以調控ALTS1C1 腦癌之腫瘤微環境。第一個研究結果發現同時表現介白素三號會增強自殺基因系統(HSV-1tk/GCV)在動物實驗中抗腫瘤的效用，但細胞實驗則無。結合自殺基因治療會使原本由IL-3 活化而具有IL-4 顯著表現的淋巴細胞轉變成IFN-顯著表現的淋巴細胞。利用鹿角菜膠去除體內巨噬細胞或利用L-NAME 抑制一氧化氮表現都會降低結合治療的效用。這些研究證明IL-3 藉由巨噬細胞或一氧化氮相關的途徑以增強自殺基因療法的抗腫瘤效用。第二個研究結果顯示利用siRNA 將MMP-2 抑制後可以延長腦腫瘤小鼠的平均存活天數。抑制MMP-2 使得腦腫瘤大小及細胞增生指標Ki67 與ALTS1C1 腫瘤相比皆大幅下降。而從少量的浸潤小島數目及侵襲指標GLUT-1 表現降低可以證明MMP-2 抑制會導致腦瘤細胞侵襲能力下降。有趣的是血管密度並沒有因抑制MMP-2 而下降，但由周圍細胞貼覆血管的比例下降可知血管的功能卻因抑制MMP-2 已經大幅減弱。此研究也證明將MMP-2 抑制後與放射線治療結合可以延緩小鼠腦腫瘤的生長，達到顯著性的治療療效。總結來說，本篇研究提供一個可行的治療方法證明IL-3 結合自殺基因療法可以促進對於攝護腺癌的治療效用。另外也證明 MMP-2 對於ALTS1C1 小鼠腦腫瘤侵襲周邊組織的能力及吸引周圍細胞進入腫瘤內部的途徑的確扮演一個重要角色，且MMP-2 抑制後可以增強放射治療對於腦癌的治療效用。

關鍵字

介白素三號；基質金屬蛋白酶-2 ；攝護腺癌；星狀膠質瘤；前驅藥物治療；放射治療

並列摘要

Malignant tumors remain the main death-caused reason of human at present. The novel strategies are necessary to be developed for improving the efficiency of cancer therapy. This study is aimed to explore the effects of tumor microenvironment on cancer therapy and two approaches were utilized to achieve the goal: (1) To attract or activate tumor-associate macrophages (TAMs) by over-expressing interleukin-3 (IL-3) in TRAMP-C1 prostate tumor model; (2) To regulate the tumor microenvironment of ALTS1C1 brain tumor by suppressing matrix metalloproteinase-2 (MMP-2) expression. The first study showed that the co-expression of IL-3 enhanced the anti-tumor effect of HSV-TK/GCV therapy in vivo, but not in vitro. The IL3-activated IL-4 dominant lymphocytes became IFN- dominant lymphocytes after combined therapy. The therapeutic effect was inhibited by macrophage depletion using carrageen treatment or nitric oxide blockage using L-NAME administration. This study demonstrated that IL-3 enhanced HSV-TK/GCV therapy by a macrophage- or NO-dependent anti-tumor pathway. The second study showed that MMP2 expression inhibited by siRNA approach led to the prolonged median survival days of brain tumor-bearing mice. MMP2kd tumors had smaller tumor size and lower Ki67 proliferating index than parental tumors. The invasive ability was decreased as demonstrated by fewer infiltrating islands and lower invasive marker GLUT-1 expression in MMP2kd tumors. More interesting is that microvascular density (MVD) in MMP2kd tumors was not reduced but vessel function was impaired as shown by decreasing pericyte coverage on blood vessels. This study also demonstrated that radiation prolonged the survival days of MMP2kd tumor-bearing mice significantly. In summary, this study provides a feasible strategy that can improve the efficacy of prostate tumor treatment by combining IL-3 with suicide gene therapy. This study also demonstrated the critical role of MMP2 on invasiveness of brain tumors and recruitment of pericytes into brain tumor microenvironment and MMP2 inhibition enhanced the effect of radiotherapy.

並列關鍵字

Interleukin-3 ； Matrix Metalloproteinase-2 ； Prostate cancer ； Astrocytoma ； Prodrug therapy ； Radiotherapy

參考文獻

2. Bottazzi B, Polentarutti N, Acero R, Balsari A, Boraschi D, et al. (1983) Regulation of the macrophage content of neoplasms by chemoattractants. Science 220: 210-212.

3. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4: 71-78.

4. Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4: 540-550.

5. Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, et al. (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A 100: 2645-2650.

6. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357: 539-545.

國際替代計量

探討介白素三號與基質金屬蛋白酶-2於小鼠腫瘤內所扮演的角色

全文下載

主題瀏覽