Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas

Abstract

BackgroundInteractions 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.MethodsExpression 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.ResultsPDPN 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.ConclusionsPDPN-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.

Podoplanin-expressing cancer-associated fibroblasts lead and enhance the local invasion of cancer cells in lung adenocarcinoma

“…They have illustrated that cancer cells invade by following the CAFs into the matrix. However, these studies have assayed CAFs as a uniform population, while a diversity of phenotypes and functions in CAFs have been reported in other studies . In this study, we demonstrated that CAFs expressing PDPN invaded a collagen matrix to a greater extent and enhance the local invasion of cancer cells.…”

Quantitative evaluation of the intratumoral distribution of platinum in oxaliplatin‐treated rectal cancer: In situ visualization of platinum via synchrotron radiation X‐ray fluorescence spectrometry

“…Immunohistochemical staining was performed as described previously . Briefly, FFPE tissue samples were sliced and deparaffinized with xylene and ethanol.…”

Antitumor effect of novel anti‐podoplanin antibody NZ‐12 against malignant pleural mesothelioma in an orthotopic xenograft model

“…Podoplanin, which binds to the platelet aggregation‐stimulating domain of PDPN–C‐type lectin‐like receptor 2 in platelets, induces platelet aggregation, resulting in cancer metastasis . Furthermore, high expression of podoplanin in cancer‐associated fibroblasts is associated with severe malignancy and poor prognosis in cancer patients . Therefore, it is expected that podoplanin will become a target for cancer diagnosis and therapies.…”

“…(4,10) Furthermore, high expression of podoplanin in cancer-associated fibroblasts is associated with severe malignancy and poor prognosis in cancer patients. (11)(12)(13)(14) Therefore, it is expected that podoplanin will become a target for cancer diagnosis and therapies.Malignant pleural mesothelioma, which is mainly caused by exposure to asbestos, develops in the pleural cavity with a high likelihood of malignancy. (15) It is expected that the number of MPM patients will increase from 2030 to 2040 in Asia, and from 2010 to 2020 in Europe.…”

“…(4,10) Furthermore, high expression of podoplanin in cancer-associated fibroblasts is associated with severe malignancy and poor prognosis in cancer patients. (11)(12)(13)(14) Therefore, it is expected that podoplanin will become a target for cancer diagnosis and therapies.…”