當一乳癌患者被鑑定為缺乏ER (estrogen receptor) 、 PR (progesterone receptor)及HER2蛋白時，即稱為三陰性乳癌(triple-negative breast carcinomas)。三陰性乳癌具有相當高機會復發、復發時間較早、一旦復發後治療工作相當困難等特性。
在本研究中，我們將三陰性乳癌病人的檢體組織區分為tumor burden zones、distal normal zones及介於兩區域中間的interface zones，並且自這三區中分離出纖維母細胞，分別命名為cancer-associated fibroblasts (CAFs)、normal zone fibroblasts (NFs)及interface zone fibroblasts (INFs) ，我們發現INFs相較於NFs和CAFs具有較快的生長速度。我們接著透過體外共同培養模式，研究不同部位的纖維母細胞與三陰性乳癌細胞株的分子訊息交互作用，我們發現， INFs最能有效地誘發乳癌細胞株從上皮細胞形態轉變成間質細胞形態，並且，INFs也能誘導乳癌細胞株vimentin的表現量增加及促進癌細胞移行的能力。這個發現闡明了INFs相較於NFs及CAFs，具有特別的生化調控意義，這項研究說明了INFs是一個具有複雜分子交互作用的區域，因此這些分子誘發了細胞內多條訊號傳遞路徑表現的結果使得癌症更加地惡化。
然而，我們的研究發現大黃素(emodin)抑制INFs所誘發的上皮細胞轉變成間質細胞的過程，大黃素抑制INFs誘發乳癌上皮細胞株形態的改變，增加E-cadherin的表現量及降低vimentin的表現量。此外，在細胞傷口癒合分析上發現，大黃素可抑制由INFs誘發乳癌細胞株的移行能力。
“Triple negative breast cancer” (TNBC) is defined as breast cancer which lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 proteins. TNBC is associated with a higher risk of distant recurrence, earlier time to recurrence, and worse prognosis after recurrence.
Fibroblasts were extracted from tissue in tumor burden zones, distal normal zones and interface zones between tumor and normal tissue of TNBC, and the corresponding fibroblasts were designated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). We found that INFs grow faster and expressed higher levels of vimentin than NFs and CAFs .The crosstalk between three types of fibroblasts and breast cancer cells was evaluated using an in vitro direct co-culture model. Compared with CAFs and NFs, INFs grown with breast cancer cells were significantly effective in inducing an epithelial-mesenchymal transition (EMT) in cancer cells, as indicated by induction of vimentin. Additionally, INFs promoted breast cell migration to a larger extent compared with NFs and CAFs. Taken together, these findings indicated that INFs isolated from the TNBC interface zone exhibits more robust biological modulatory activity than NFs and CAFs isolated from normal and tumor zones of the same tumor tissue, suggesting that the interface zone of the tumor represents a dynamic region vital to tumor progression.
Moreover, our results found that emodin inhibited epithelial-mesenchymal transition induced by INFs. Emodin would reverse INFs-induced morphological changes, up-regulated the expression of E-cadherin and down-regulated the expression of vimentin. Moreover, wound-healing and in vitro invasion assay showed that emodin could inhibit INFs-induced migration and invasion of TNBC cells.
