| Abstract: | 血管增生(angiogenesis)是癌細胞生長和轉移的重要步驟，並與癌細胞所釋放
之血管增生因子有關，包括：血管內皮生長因子(vascular endothelial growth factor,
VEGF)、基質金屬蛋白酶(matrix metalloproteinases, MMPs)及細胞激素(cytokine)
等，而以VEGF 最為重要。研究證實，許多細胞激素皆會透過VEGF 而抑制血
管增生，如介白素(interleukin, IL)-12 和干擾素(interferon, IFN)。
流行病學研究顯示多攝取富含茄紅素的食物能降低多種癌症的發生率。茄紅
素不但具有抗氧化、提升免疫功能，且可抑制某些癌細胞生長，諸如攝護腺癌等，
其防癌與抗癌作用是目前重要的研究題目。值得注意的是，免疫作用與抑制血管
增生息息相關，而茄紅素是否可藉由免疫調節而抑制血管增生，卻少有報導。
由文獻回顧中可發現一些重要的問題，而本三年計劃將選擇二個我們有能力
介入和解決的問題。其一為：茄紅素是否可直接抑制血管增生？雖然動物試驗中
發現茄紅素具有降低血管增生因子如VEGF、MMPs，以及提升IL-12 的作用(J
Nutr., 2008)，但尚缺乏抑制血管增生的直接證據。其二為：茄紅素是否可藉免疫
調節而抑制血管增生？本計畫擬以人類臍靜脈內皮細胞作為血管增生模式，探討
下列問題：
1) 利用茄紅素刺激單核球細胞之培養液探討抗血管增生作用，主要分析包括細
胞生長、移行、脈管形成及分子機制。
2) 以餵食茄紅素的動物血漿探討抗血管增生作用，並藉由比較有無施打免疫抑
制劑之動物血漿來釐清茄紅素免疫調節作用與血管增生之關係。
3) 茄紅素於活體內及ex-vivo 中免疫調節作用與抗血管增生之關係，並藉由免疫
組織化學染色等技術釐清分子機制，包括VEGF、MMPs 及轉錄因子等。
本三年計劃預期對茄紅素抗癌研究上的觀念，提供嚴謹的科學證據。此外，
這些研究對我國基礎研究水準的提升當會有所幫助、並對人體的健康有直接或間
接的貢獻。
Angiogenesis is required to sustain primary tumor enlargement as well as
metastasis. The induction of tumor angiogenesis is mediated by the increased
production of various angiogenic molecules released by tumor cells, including
vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and
cytokine. Among the angiogenic factors, VEGF was found to be the most potent. The
expression of VEGF has been shown to be markedly associated with the secration of
cytokine, such as interleukin,(IL)-12, interferon (IFN) and tumor necrosis factor
(TNF)-α by the immune system.
Epidemiologic studies have shown that high lycopene intakes are associated with
low risk of several types of cancer. Lycopene is known to possess antioxidant,
immunomodulatory and anticancer activities, especially prostate cancer, and is an
important topic of anticancer research. It should be noted that the
immuno-regulatory action is realted with anti-angiogenesis. However, it is unclear
whether lycopene can inhibit angiogenesis via immunomodulatory action.
We have identified several important issues in review of the literature. We intend
to study two major issues that we are able to tackle and resolve. One issue is
whether lycopene can inhibit angiogenesis and how they exert these effects. We
recently showed that lycopenemediated angiogenic factors, including the inhbition of
VEGF and MMPs and and up-regulation of IL-12 secretion in nude mice (Huang et
al., J. Nutr. 2008). However, the anti-angiogenic effects and mechanisms of action of
lycopene have not been reported. Another isuue is the possible mechanism about
immunomodulation. To examine the following issues, we intend to use the human
umbilical vein endothelial cell lines (HUVEC) as in vitro angiogenesis model.
1) In the first year, we will evaluate the immunomodulatory effects of lycopene by
analyzing the production of cytokines in mononuclear cells stimulated with
lycopene in order to provide insights into the immune function that controls
angiogenesis in response to lycopene.
2) In the second year, we will investigate the anti-angiogenic effect of lycopene in an
ex-vivo model, closely mimicking physiological conditions. Gerbils will be
supplemented with lycopene orally, and their serum used in in vitro studies on
angiogenesis of HUVEC, and the imunemodulatory mechanism.
3) In the third year, we will investigate the in in ex-vivo and in vivo anti-angiogenic
effects of lycopene and the mechanisms.
This research project is expected to increase our knowledge of the
anti-angiogenic effects and immunomodulatory mechanism of lycopene. In addition,
these studies can not only promote the level of basic research in Taiwan, but also
contributes directly or indirectly to the health of people worldwide. |
