泌尿上皮癌就是起源於從腎盞到膀胱，甚至到前列腺尿道之所謂泌尿道上皮細胞長出來的癌症。現今，雖然根除性的手術或輔以術後化學療法的進步，病人罹患肌肉侵入性或進行性的泌尿上皮癌最後常常還是會面臨死亡。因此，需要發展有效的治療策略來治療這些病人。先前的研究顯示表皮生長因子接受體家族(EGFR)在膀胱癌的預後佔有一重要的角色。然而，仍然有一些重要的問題有待釐清與研究。
利用免疫組織染色，我們探討人類表皮生長因子接受體乙型(HER2)在侵入性膀胱癌病人的臨床病理上的相關，人類表皮生長因子接受體甲、乙、丙型(HER1, HER2, and HER3) 在上泌尿道上皮癌(UUC) 病人的臨床病理上的相關、及HER2表現在進行性的泌尿上皮癌病人與術後化學療法的交互作用。我們發現在侵入性膀胱癌HER2與p53均有很高比率之表現，如果p53與HER2兩者同時不正常表現時，病人有較高比率的淋巴結轉移，造成較短的預後；在上泌尿道上皮癌病人上，HER2與腫瘤的侵入性及預後有關，HER2過度表現的進行性泌尿上皮癌在接受全身化學治療後預後比沒表現要來的差，但是統計上沒看到與術後化學療法之間的交互作用。
為了增加的腫瘤內免疫力，透過以HER2為標的，治療膀胱癌，利用抗HER2的單鏈抗體變異片段(antiHER2scFv)及介白素-12(IL-12)，我們發展兩個治療策略。首先，將antiHER2scFv插入反轉錄病毒外套膜之PRR處，來改造以HER2為標的的反轉錄病毒且攜帶IL-12基因，動物實驗之結果顯示相較於未改造之病毒，此一改造外套膜的攜帶有IL-12基因的反轉錄病毒，擁有更好更強的抗腫瘤能力及使小鼠延長存活，此一現象與增加細胞凋亡、腫瘤內的IL-12、IFN-γ、IL-1β、TNF-α等細胞激素的濃度有關。其次，利用DNA重組的技術來改造HER2抗體單鏈變異片段，使其與IL-12連接，組成具有encoded一專一性高、侷限性高且具有抗腫瘤能力的antiHER2scfv-IL12蛋白之融合基因，透過小腿肌肉內注射基因使其於肌肉內生產蛋白，而選擇性分佈於腫瘤處，可以擁有更強的抗腫瘤能力及使小鼠延長存活。其機轉與增加毒殺性T細胞活性、增加腫瘤內IL-12、IFN-γ、CD4+、CD8+淋巴球、及降低雪血管內皮細胞生長因子(VEGF)有關。我們的研究結果顯示這兩個治療策略均可用來治療HER2表現的膀胱癌。
金奈米(AuNP)已經被報導在臨床應用上是一個大有可為的物質，包括影像、生物偵測、藥物攜帶、甚至是基因治療方面。先前的研究顯示金奈米有與生物分子結合的特性，它透過金硫(Au-S)鍵結而俱有治療上的濳力。在探討它的治療上的濳力中，我們發現金奈米本身能和乙型細胞變形生長因子(TGF-β1)與VGEF透過半胱胺酸(cysteine)鍵結，兩者皆屬半胱胺酸結家族且在腫瘤內俱有免疫抑制作用。透過化學結構分析，證明金奈米係透過cysteine鍵結。此一特性，使得金奈米透過減弱TGF-β1的免疫抑制作用，進而調節腫瘤內淋巴細胞的活化及抑制腫瘤的生長。
我們未來的工作，將針對如何透過以HER2為標的將金奈米”減弱TGF-β1的免疫抑制作用”之特性，送到腫瘤內之臨床應用前之動物研究。

Urothelial carcinoma (UC) can be defined as neoplasms that arise from the epithelial lining of the urinary tract from the renal calyces to the urinary bladder, even to the prostatic urethra. Currently, muscle-invasive or advanced diseases still frequently lead to mortalities despite of advances in radical surgery with or without adjuvant chemotherapy. It is mandatory to develop some promising strategies to treat them. Previous studies have shown that epidermal growth factor receptor (EGFR) family receptors may play an important role in the outcome of bladder cancer. However, there are some critical issues to be investigated. Using immunohistochemic studies, we explored the clinicopathologic correlates of human epidermal growth factor receptor (HER)-2 expression in invasive bladder cancer patients, of HER1, HER2, and HER3 in upper UC patients, and the interaction of HER2 and poly-chemotherapy in advanced UC patients. We found that a high frequency of HER2 expression occurred in invasive bladder cancer and was associated with nodal metastases when co-expressed with p53. Also, HER2 expression predicted for rapid disease progression and short disease-related survival in upper UC.
To enhance intratumoral immunity for bladder cancer therapy through HER2-targeting, we have created two strategies using antiHER2 single chain variable fragment (antiHER2scFv) and interleukin-12 (IL-12). First, an HER2-targeted, envelope-modified Moloney murine leukemia virus (MoMLV)-based gammaretroviral vector carrying interleukin (IL)-12 gene was created by inserting the fragment of anti-erbB2scFv into the proline-rich region of the viral envelope of the packaging vector lacking a transmembrane subunit of the carboxyl terminal region of surface subunit. Tumor-bearing mice treated with recombinant viruses showed that envelope-modified gammaretroviruses carrying IL-12 gene exerted higher antitumor activity in terms of retarding tumor growth and prolonging the survival of tumor-bearing mice than unmodified ones, which were associated with enhanced tumor cell apoptosis as well as increased intratumoral levels of IL-12, interferon-γ, IL-1β, and tumor necrosis factor (TNF)-α proteins. Second, intramuscular electrogene transfer of an expression vector encoding a fusion protein antiHER2scFv-IL12 significantly retarded tumor growth and prolonged the survival in a syngeneic bladder tumor model. Elevated IL-12 and interferon-γ(IFN-γ)levels, increased infiltration of CD4+ and CD8+ T cells, and reduced vascular endothelial growth factor (VEGF) expression in the tumors, as well as enhanced cytolytic activity of splenocytes were noted in the treated mice. Our results suggest that both strategies may be effective for the treatment of HER2-expressing tumors.
Gold nanoparticle (AuNP) has been reported to be a promising agent in clinical utilities, including imaging, biosensing, drug carrier, and even gene therapy. Previous studies have shown its ability to conjugate with some biological molecules and exert some therapuetical potentials through Au-thio binding. During exploring its therapeutic potential, we demonstrated that AuNPs itself can conjugate with TGF-β1 and VGEF, both of which are belonging to cysteine-knot superfamily and immunosuppressive factors within the tumor microenvironment. Though chemical structural analysis, the binding with TGF-β1 is through cysteine residues. With such characteristics, AuNPs could modulate the lymphocyte activation within the tumor microenvironment and inhibit tumor growth by attenuating the immunosuppressive activity of TGF-β1.
Our further work will focus on how to translate the characteristics of attenuating intratumoral immunosuppression of AuNPs into the preclinical animal studies though selective targeting to HER2-expressing UC.

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