乳腺癌中淋巴結(jié)轉(zhuǎn)移及不良預(yù)后的關(guān)系10年以前就已經(jīng)被發(fā)現(xiàn)。然而,，癌細(xì)胞侵入淋巴系統(tǒng)的機(jī)理還沒有被完全闡明,。
最近的研究發(fā)現(xiàn)，在轉(zhuǎn)移性傳播中,，由于腫瘤分泌的生長(zhǎng)因子刺激了淋巴管的形成,，淋巴系統(tǒng)起到了一個(gè)積極的作用。
SIX1是一種與乳腺癌有關(guān)的同源結(jié)構(gòu)域轉(zhuǎn)錄因子,，它是否與淋巴管形成及淋巴轉(zhuǎn)移有關(guān)還未可知,，對(duì)此，美國(guó)科羅拉多大學(xué)丹佛醫(yī)學(xué)院的研究人員開展了一項(xiàng)研究,。
在一個(gè)注入了人類乳腺癌細(xì)胞的免疫缺陷小鼠模型中,，他們發(fā)現(xiàn)SIX1的表達(dá)促進(jìn)了癌周及癌內(nèi)的淋巴管形成、淋巴入侵以及乳腺癌細(xì)胞的遠(yuǎn)端轉(zhuǎn)移,。
SIX1能夠引起促淋巴生成因子VEGF-C的轉(zhuǎn)錄,，這對(duì)淋巴管生成及淋巴轉(zhuǎn)移也是必需的,。通過(guò)使用一個(gè)老鼠乳腺癌模型，結(jié)果發(fā)現(xiàn)VEGF-C不足以介導(dǎo)SIX1所有的轉(zhuǎn)移效應(yīng),，這表明SIX1通過(guò)了額外的不依賴VEGF-C的通路來(lái)行使作用,。
最后，他們通過(guò)闡明SIX1及VEGF-C在人類乳腺癌的聯(lián)合表達(dá),，驗(yàn)證了SIX1/VEGF-C的臨床意義,。
這些數(shù)據(jù)明確了SIX1在乳腺癌淋巴擴(kuò)散中關(guān)鍵性的作用，闡明了乳腺癌中VEGF-C的表達(dá)是如何上調(diào)并導(dǎo)致淋巴管生成及轉(zhuǎn)移,。相關(guān)論文發(fā)表在4月2日的The Journal of Clinical Investigation（生物谷Deepblue編譯）
doi: 10.1172/JCI59858
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PMID:
SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer
Chu-An Wang, Paul Jedlicka, Aaron N. Patrick, Douglas S. Micalizzi, Kimberly C. Lemmer, Erin Deitsch, Matias Casás-Selves, J. Chuck Harrell and Heide L. Ford.
An association between lymph node metastasis and poor prognosis in breast cancer was observed decades ago. However, the mechanisms by which tumor cells infiltrate the lymphatic system are not completely understood.Recently, it has been proposed that the lymphatic system has an active role in metastatic dissemination and that tumor-secreted growth factors stimulate lymphangiogenesis.We therefore investigated whether SIX1, a homeodomain-containing transcription factor previously associated in breast cancer with lymph node positivity, was involved in lymphangiogenesis and lymphatic metastasis.In a model in which human breast cancer cells were injected into immune-compromised mice, we found that SIX1 expression promoted peritumoral and intratumoral lymphangiogenesis, lymphatic invasion, and distant metastasis of breast cancer cells.SIX1 induced transcription of the prolymphangiogenic factor VEGF-C, and this was required for lymphangiogenesis and lymphatic metastasis. Using a mouse mammary carcinoma model, we found that VEGF-C was not sufficient to mediate all the metastatic effects of SIX1, indicating that SIX1 acts through additional,VEGF-C–independent pathways.Finally, we verified the clinical significance of this prometastatic SIX1/VEGF-C axis by demonstrating coexpression of SIX1 and VEGF-C in human breast cancer.These data define a critical role for SIX1 in lymphatic dissemination of breast cancer cells, providing a direct mechanistic explanation for how VEGF-C expression is upregulated in breast cancer, resulting in lymphangiogenesis and metastasis
