Clinical Pathology Division, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
Translational Research Unit, Institute of Pathology, University of Bern, Murtenstrasse 31, Bern, CH-3010, Switzerland.
Eur J Cancer. 2016 Sep;65:80-90. doi: 10.1016/j.ejca.2016.06.013. Epub 2016 Jul 29.
Neoplastic stroma is believed to influence tumour progression. Here, we examine phosphatase and tensin homolog deleted on chromosome ten (PTEN) status in the tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) focussing especially at the stromal cells.
We asses PTEN at protein, messenger RNA and DNA level using a well-characterised PDAC cohort (n = 117). miR-21, known to target PTEN, is assessed after RNA extraction from different laser-capture-microdissected cell populations, including cancer cells and juxta-tumoural and tumour-remote stroma.
PTEN deletion was the most frequent cause of PTEN protein loss in PDAC cells (71%) and correlated with vascular invasion (p = 0.0176) and decreased overall survival (p = 0.0127). Concomitant PTEN protein loss in tumour and juxta-tumoural stroma, found in 21.4% of PDACs, correlated with increased distant metastasis (p = 0.0045). Stromal cells with PTEN protein loss frequently showed PTEN genetic aberrations, including hemizygous PTEN deletion (46.6%) or chromosome 10 monosomy (40%). No alterations were found in the tumour-remote stroma. miR-21 was overexpressed by cancer- and juxta-tumoural stromal cells, in some cases without simultaneous PTEN gene alterations. No PTEN mutations or promoter methylation were detected.
We find various mechanisms of PTEN protein loss in the different tumour cell populations, including allelic PTEN deletions, gross chromosomal 10 aberrations and altered miR-21 expression. PTEN deletion is a major cause of PTEN protein loss in PDAC and correlates with aggressive characteristics and worse outcome. PTEN protein loss in juxta-tumoural stromal cells is mostly due to PTEN haplo-insufficiency and characterises a subgroup of PDACs with enhanced metastatic potential. In the tumour microenvironment of the invasive front, PTEN silencing by miR-21 in cancer and surrounding stromal cells acts not only cooperatively but also independently of the genetic aberrations to precipitate PTEN protein loss and promote further tumour growth.
肿瘤基质被认为会影响肿瘤的进展。在这里，我们特别关注肿瘤基质细胞，研究了磷酸酶和张力蛋白同源物缺失的染色体 10（PTEN）在胰腺导管腺癌（PDAC）肿瘤微环境中的状态。
我们使用经过充分验证的 PDAC 队列（n=117），在蛋白质、信使 RNA 和 DNA 水平上评估了 PTEN。miR-21 已知靶向 PTEN，在从不同激光捕获微切割细胞群（包括癌细胞和肿瘤旁和肿瘤远处的基质细胞）提取 RNA 后进行评估。
PTEN 缺失是 PDAC 细胞中 PTEN 蛋白丢失的最常见原因（71%），与血管侵犯（p=0.0176）和总生存期降低（p=0.0127）相关。在 21.4%的 PDAC 中发现肿瘤和肿瘤旁基质中同时存在 PTEN 蛋白丢失，与远处转移增加相关（p=0.0045）。PTEN 蛋白丢失的基质细胞常表现出 PTEN 遗传异常，包括杂合性 PTEN 缺失（46.6%）或 10 号染色体单体性（40%）。在肿瘤远处的基质中未发现改变。miR-21 在癌细胞和肿瘤旁基质细胞中过表达，在某些情况下没有同时发生 PTEN 基因改变。未检测到 PTEN 突变或启动子甲基化。
我们在不同的肿瘤细胞群中发现了各种 PTEN 蛋白丢失的机制，包括等位基因 PTEN 缺失、染色体 10 大片段异常和 miR-21 表达改变。PTEN 缺失是 PDAC 中 PTEN 蛋白丢失的主要原因，与侵袭性特征和预后不良相关。肿瘤旁基质中 PTEN 蛋白丢失主要是由于 PTEN 杂合性缺失，并构成了具有增强转移潜能的 PDAC 亚组。在侵袭前沿的肿瘤微环境中，miR-21 在癌细胞和周围基质细胞中沉默不仅协同作用，而且独立于遗传异常，导致 PTEN 蛋白丢失并促进肿瘤进一步生长。
