Ma Xiao-Jun, Dahiya Sonika, Richardson Elizabeth, Erlander Mark, Sgroi Dennis C
bioTheranostics, Inc, 11025 Roselle Street, San Diego, CA 92121, USA.
Breast Cancer Res. 2009;11(1):R7. doi: 10.1186/bcr2222. Epub 2009 Feb 2.
The importance of the tumor microenvironment in breast cancer has been increasingly recognized. Critical molecular changes in the tumor stroma accompanying cancer progression, however, remain largely unknown. We conducted a comparative analysis of global gene expression changes in the stromal and epithelial compartments during breast cancer progression from normal to preinvasive to invasive ductal carcinoma.
We combined laser capture microdissection and gene expression microarrays to analyze 14 patient-matched normal epithelium, normal stroma, tumor epithelium and tumor-associated stroma specimens. Differential gene expression and gene ontology analyses were performed.
Tumor-associated stroma undergoes extensive gene expression changes during cancer progression, to a similar extent as that seen in the malignant epithelium. Highly upregulated genes in the tumor-associated stroma include constituents of the extracellular matrix and matrix metalloproteases, and cell-cycle-related genes. Decreased expression of cytoplasmic ribosomal proteins and increased expression of mitochondrial ribosomal proteins were observed in both the tumor epithelium and the stroma. The transition from preinvasive to invasive growth was accompanied by increased expression of several matrix metalloproteases (MMP2, MMP11 and MMP14). Furthermore, as observed in malignant epithelium, a gene expression signature of histological tumor grade also exists in the stroma, with high-grade tumors associated with increased expression of genes involved in immune response.
Our results suggest that the tumor microenvironment participates in tumorigenesis even before tumor cells invade into stroma, and that it may play important roles in the transition from preinvasive to invasive growth. The immune cells in the tumor stroma may be exploited by the malignant epithelial cells in high-grade tumors for aggressive invasive growth.
肿瘤微环境在乳腺癌中的重要性已得到越来越多的认可。然而，伴随癌症进展的肿瘤基质中的关键分子变化在很大程度上仍不清楚。我们对乳腺癌从正常状态发展到原位癌再到浸润性导管癌过程中基质和上皮成分的全基因表达变化进行了比较分析。
我们结合激光捕获显微切割和基因表达微阵列技术，分析了14例患者匹配的正常上皮、正常基质、肿瘤上皮和肿瘤相关基质标本。进行了差异基因表达分析和基因本体分析。
肿瘤相关基质在癌症进展过程中经历了广泛的基因表达变化，其程度与恶性上皮细胞中的变化相似。肿瘤相关基质中高度上调的基因包括细胞外基质成分、基质金属蛋白酶和细胞周期相关基因。在肿瘤上皮和基质中均观察到细胞质核糖体蛋白表达降低，线粒体核糖体蛋白表达增加。从原位癌到浸润性生长的转变伴随着几种基质金属蛋白酶（MMP2、MMP11和MMP14）表达的增加。此外，正如在恶性上皮细胞中观察到的那样，基质中也存在组织学肿瘤分级的基因表达特征，高级别肿瘤与免疫反应相关基因表达增加有关。
我们的结果表明，肿瘤微环境甚至在肿瘤细胞侵入基质之前就参与了肿瘤发生，并且它可能在从原位癌到浸润性生长的转变中发挥重要作用。高级别肿瘤中的恶性上皮细胞可能利用肿瘤基质中的免疫细胞进行侵袭性生长。
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