乳癌細胞與其微環境交互作用之探討

Microenvironment and tumorigenesis: interplay between breast cancer cell and its microenvironment

張博皓(Po-Hao Chang)

指導教授 ： 許金玉

共同指導教授 ： 李文華

國立臺灣大學/醫學院/生物化學暨分子生物學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.02984

摘要

在腫瘤發生過程中，除了癌細胞本身的生長調控之外，周圍環境因子扮演著相當重要的角色。乳房組織中，纖維母細胞（fibroblast）和脂肪細胞（adipocyte）是主要構成乳房的周圍細胞。正常乳腺發育過程中，上皮細胞（epithelial cell）和這些周圍細胞之間的交互作用是受到複雜而且嚴謹的控制。當細胞之間的調控失去控制時，則容易造成細胞的異常增殖導致癌症的發生。因此，研究這些細胞之間的調控對於腫瘤發生學是相當重要的課題。
本論文分別探討纖維母細胞和脂肪細胞對於癌細胞的影響。先前的研究發現，纖維母細胞會促進乳癌細胞生長。然而在實驗裡發現，並非所有的乳癌細胞都會被纖維母細胞所促進生長。纖維母細胞對於乳癌細胞的反應可以分成兩群，一群是會被纖維母細胞所促進生長，而在另一群乳癌細胞中，纖維母細胞反而會抑制生長。進一步的研究指出，這類會受抑制的乳癌細胞表面會表現ROBO1的膜蛋白，透過纖維母細胞釋放SLIT2來抑制癌細胞的生長。當SLIT2/ROBO1被活化後，細胞內的訊息傳導（PI3K/AKT）會被阻斷，造成β-catenin無法轉移到細胞核，進而抑制cyclin D1和c-myc的表現。在臨床檢體上，乳癌細胞中有ROBO1高表現的病人擁有比較好的預後，然而纖維母細胞中SLIT2低表現的則容易有淋巴結轉移。 在另一部分脂肪細胞的研究中，我的實驗證實脂肪細胞會促進具有表現MCT2膜蛋白的乳癌細胞生長。同樣在臨床檢體也證實，高表現MCT2的病人會有比較差的預後。 綜合以上的結果，我的實驗對於乳癌細胞與微環境細胞的交互作用，提出了新的訊息傳遞途徑，藉由了解這些訊息傳導途徑，將有助於發展出有效的癌症治療藥物。

關鍵字

癌症 ； 周圍細胞 ； 乳癌 ； 纖維母細胞 ； 脂肪細胞

並列摘要

The tumor microenvironment plays a critical role in regulating cancer progression. In breast, stromal fibroblasts and adipocytes are two major components of the microenvironment. Their roles in breast tumor formation are complex. Stromal cells can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment has also been observed. The mechanisms that underlie this paradox have remained unclear. We found that the tumorigenic potential of breast cancer cells can be determined by an interaction between ROBO1 receptors in cancer cells and its ligand SLIT2 secreted from stromal fibroblasts. The presence of an active SLIT2/ROBO1 signal blocked the translocation of β-catenin into nucleus, leading to down-regulation of c-myc and cyclin D1 via the PI3K pathway. Clinically, high ROBO1 expression in breast cancer cells was correlated with better prognosis, whereas low SLIT2 expression in the stromal fibroblasts was associated with lymph node metastasis. This clinical correlation further demonstrated the significance of the interaction between breast cancer cells and surrounding fibroblasts in suppression of tumorigenesis. In contrast to fibroblast-mediated suppression, adipocytes have been shown to promote breast tumor progression. We found that MCT2 expressed in breast cancer cells played a key role in adipocyte-mediated tumorigenesis. MCT2, a monocarboxylate transporter, enhanced tumor growth in response to adipocyte-secreted

並列關鍵字

breast cancer ； microenvironemt ； fibroblast ； adipocyte ； robo1 ； mct2

參考文獻

Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., and Flier, J.S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature 382, 250-252.

Alajez, N.M., Lenarduzzi, M., Ito, E., Hui, A.B., Shi, W., Bruce, J., Yue, S., Huang, S.H., Xu, W., Waldron, J., et al. (2011). MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer research 71, 2381-2391.

Bachelot, T., Ray-Coquard, I., Menetrier-Caux, C., Rastkha, M., Duc, A., and Blay, J.Y. (2003). Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. British journal of cancer 88, 1721-1726.

Barbareschi, M., Pelosio, P., Caffo, O., Buttitta, F., Pellegrini, S., Barbazza, R., Dalla Palma, P., Bevilacqua, G., and Marchetti, A. (1997). Cyclin-D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression. International journal of cancer Journal international du cancer 74, 171-174.

Bashaw, G.J., Kidd, T., Murray, D., Pawson, T., and Goodman, C.S. (2000). Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptor. Cell 101, 703-715.