Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas
Open Access
- 20 December 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Cancer
- Vol. 12 (1), 168
- https://doi.org/10.1186/1476-4598-12-168
Abstract
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.Keywords
This publication has 49 references indexed in Scilit:
- StellaTUM: current consensus and discussion on pancreatic stellate cell researchGut, 2011
- Podoplanin Is Regulated by AP-1 and Promotes Platelet Aggregation and Cell Migration in OsteosarcomaThe American Journal of Pathology, 2011
- FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cellsBMC Cancer, 2011
- Podoplanin in cancer cells is experimentally able to attenuate prolymphangiogenic and lymphogenous metastatic potentials of lung squamoid cancer cellsMolecular Cancer, 2010
- Interaction of Stellate Cells with Pancreatic Carcinoma CellsCancers, 2010
- Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent MannerCancer Cell, 2010
- Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor ProgressionCancer Research, 2008
- The potential role of podoplanin in tumour invasionBritish Journal of Cancer, 2006
- Fibroblasts in cancerNature Reviews Cancer, 2006
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002