TY - JOUR
T1 - Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas
AU - Shindo, Koji
AU - Aishima, Shinichi
AU - Ohuchida, Kenoki
AU - Fujiwara, Kenji
AU - Fujino, Minoru
AU - Mizuuchi, Yusuke
AU - Hattori, Masami
AU - Mizumoto, Kazuhiro
AU - Tanaka, Masao
AU - Oda, Yoshinao
PY - 2013/12/20
Y1 - 2013/12/20
N2 - Background: 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.Methods: 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.Results: 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.Conclusions: 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.
AB - Background: 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.Methods: 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.Results: 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.Conclusions: 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.
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U2 - 10.1186/1476-4598-12-168
DO - 10.1186/1476-4598-12-168
M3 - Article
C2 - 24354864
AN - SCOPUS:84890445450
VL - 12
JO - Molecular Cancer
JF - Molecular Cancer
SN - 1476-4598
IS - 1
M1 - 168
ER -