Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Mol Cancer. 2013 Dec 20;12(1):168. doi: 10.1186/1476-4598-12-168.
Interactions between cancer cells and surrounding cancer-associated fibroblasts (CAFs) play an important role in cancer progression. Invasive ductal carcinoma (IDC) of the pancreas is characterized by abundant fibrous connective tissue called desmoplasia. Podoplanin (PDPN) is a lymphatic vessel marker (D2-40), and expression of PDPN by stromal CAFs has been reported to be a prognostic indicator in various types of cancer.
Expression of PDPN in pancreatic IDCs was assessed by immunohistochemical examination in 105 patients who underwent pancreatic resection. Primary CAFs were established from pancreatic cancer tissue obtained by surgery. Quantitative reverse transcription-polymerase chain reaction and flow cytometric analysis were performed to investigate PDPN expression in CAFs. We sorted CAFs according to PDPN expression, and analyzed the functional differences between PDPN+ CAFs and PDPN- CAFs using indirect co-culture with pancreatic cancer cell lines. We also investigated the culture conditions to regulate PDPN expression in CAFs.
PDPN expression in stromal fibroblasts was associated with lymphatic vessel invasion (P = 0.0461), vascular invasion (P = 0.0101), tumor size ≥ 3 cm (P = 0.0038), histological grade (P = 0.0344), Union for International Cancer Control classification T stage (P = 0.029), and shorter survival time (P < 0.0001). Primary CAFs showed heterogeneous PDPN expression in vitro. Moreover, migration and invasion of pancreatic cancer cell lines (PANC-1 and SUIT-2) were associated with PDPN expression in CAFs (P < 0.01) and expression of CD10, matrix metalloproteinase (MMP) 2, and MMP3. In cultured CAFs, PDPN positivity changed over time under several conditions including co-culture with cancer cells, different culture media, and addition of growth factor.
PDPN-expressing CAFs enhance the progression of pancreatic IDC, and a high ratio of PDPN-expressing CAFs is an independent predictor of poor outcome. Understanding the regulation of the tumor microenvironment is an important step towards developing new therapeutic strategies.
癌细胞与周围癌相关成纤维细胞（CAF）之间的相互作用在癌症进展中起着重要作用。胰腺浸润性导管癌（IDC）的特征是丰富的纤维结缔组织，称为纤维变性。Podoplanin（PDPN）是淋巴管标志物（D2-40），据报道，基质 CAF 中 PDPN 的表达是各种类型癌症的预后指标。
对 105 例接受胰腺切除术的患者的胰腺 IDC 组织进行免疫组织化学检查，评估 PDPN 的表达。通过手术从胰腺癌组织中建立原代 CAF。进行定量逆转录聚合酶链反应和流式细胞术分析，以研究 CAF 中的 PDPN 表达。我们根据 PDPN 表达对 CAF 进行排序，并通过与胰腺癌细胞系间接共培养分析 PDPN+CAFs 和 PDPN-CAFs 之间的功能差异。我们还研究了调节 CAF 中 PDPN 表达的培养条件。
间质成纤维细胞中 PDPN 的表达与淋巴管浸润（P=0.0461）、血管浸润（P=0.0101）、肿瘤大小≥3cm（P=0.0038）、组织学分级（P=0.0344）、国际抗癌联盟 T 分期（P=0.029）和较短的生存时间（P<0.0001）有关。体外原代 CAF 表现出 PDPN 表达的异质性。此外，胰腺癌细胞系（PANC-1 和 SUIT-2）的迁移和侵袭与 CAF 中的 PDPN 表达（P<0.01）以及 CD10、基质金属蛋白酶（MMP）2 和 MMP3 的表达有关。在培养的 CAF 中，在包括与癌细胞共培养、不同培养基和添加生长因子在内的几种条件下，PDPN 阳性率随时间而变化。
表达 PDPN 的 CAF 增强了胰腺 IDC 的进展，高比例表达 PDPN 的 CAF 是预后不良的独立预测因子。了解肿瘤微环境的调节是开发新治疗策略的重要步骤。
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