Overexpression of podoplanin in oral cancer and its association with poor clinical outcome

Yuan, Ping; Temam, Stéphane; El‐Naggar, Adel K.; Zhou, Xian; Liu, Diane D.; Lee, John; Li, Mao

doi:10.1002/cncr.22061

Cited by 267 publications

(351 citation statements)

References 16 publications

(26 reference statements)

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“…[15][16][17][18][19][20][21] These findings suggest that podoplanin plays a role in the progression of epithelial cancer. However, the exact molecular function of cancer cell-expressed podoplanin is currently studied.…”

Section: Discussionmentioning

confidence: 89%

Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx

Huber

Fritzsche

Züllig

et al. 2011

Intl Journal of Cancer

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In patients with early head and neck squamous cell carcinoma (HNSCC), occult lymph node metastasis is difficult to predict by clinical or pathological parameters. However, such parameters are necessary to select patients either for elective neck dissection or the sentinel lymph node (SLN) procedure. The membrane glycoprotein podoplanin is normally expressed in lymphatic endothelial cells. Recently, expression of podoplanin by cancer cells was demonstrated to promote tumor cell motility and tumor lymphangiogenesis in vitro. The value of cancer cell-expressed podoplanin was to be determined as a predictive marker for SLN metastasis in early HNSCC of the oral cavity and oropharynx. One hundred twenty patients with HNSCC of the oral cavity and oropharynx undergoing a SLN biopsy were enrolled in this prospective clinical trial of SLN biopsy. Cancer cell-expressed podoplanin was determined by immunohistochemistry using tissue microarrays. Podoplanin expression was quantified by the intensity reactivity score and categorized into expression and nonexpression. SLN examination revealed occult metastasis in 45 patients (37.5%). Twenty-nine of 120 (24.2%) primary HNSCC showed podoplanin expression. Podoplanin expression correlated significantly with SLN metastasis (p 5 0.029) and remained a significant predictor for lymph node status even after controlling for tumor stage (p 5 0.028). As a predictive marker for SLN metastasis, however, podoplanin expression reached a sensitivity of a mere 36% and a specificity of 83%. Podoplanin expression is associated with metastasis to lymph nodes in vivo. Podoplanin immunohistochemistry in early HNSCC of the oral cavity and oropharynx may help to select patients for the SLN procedure and to identify patients with increased risk for presence of occult lymph node metastasis in the neck.Head and neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide and responsible for more than 7,800 deaths per year in the United States alone. 1 Despite improvements in surgical treatment and radiation technology over the last decades, survival has not significantly improved. A chief feature of malignant behavior is the capability of tumor cells to metastasize to other organs. Metastasis of many human cancers, including HNSCC, occurs primarily through the lymphatic system. The cellular mechanisms responsible for the acquisition of a metastatic phenotype include the adaptation to potential hostile environment (blood stream, lymph nodes and organ of metastasis). In addition, the ''tumor cell-to-tumor cell'' and ''tumor cell-to-stromal environment'' cross talk is recognized as an important condition for invasion and metastasis.Very recently, expression of the 38-kDa Type 1 transmembrane glycoprotein podoplanin has been shown to induce tumor lymphangiogenesis and enhance metastasis to lymph nodes. 2,3 Human podoplanin is expressed in various normal human tissues. Podoplanin is highly and specifically expressed in lymphatic endothelial cells, but not in blood vessel endothelium. 4,5...

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Section: Discussionmentioning

confidence: 89%

Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx

Huber

Fritzsche

Züllig

et al. 2011

Intl Journal of Cancer

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“…[5][6][7][8][9]34 In oral cancer, PDPN expression has been related to poor clinical outcomes, including lymph node metastasis or to malignant transformation of precancerous lesions, although its molecular function has not been well understood. [10][11][12][13]35 To elucidate its function, we carried out comparative immunohistochemical studies between PDPN and the other molecules, which are related to cell proliferation or differentiation in oral mucosal malignancies 13 or odontogenic tumors. 7 Its expression profile in oral CIS was almost identical to that of SCC, and the immunohistochemistry for PDPN was helpful in the differential diagnosis of CIS from epithelial dysplasia.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8][9][10][11] In the field of oral cancer, PDPN has also been regarded as a biomarker in predicting the risk of cancer development and poor clinical outcome. [10][11][12] We have also shown the PDPN expression profiles to be a useful immunohistochemical aid in the differential diagnosis of oral carcinoma in situ (CIS) from epithelial dysplasia because PDPN positive ( þ ) cells are distributed more widely in CIS than in epithelial dysplasia, overlapping with Ki-67 þ -proliferating cell zones. 13 In order to provide a background to the cellproliferating potentials of oral CIS, we have demonstrated the characteristic intercellular deposition and turnover of perlecan, one of the extracellular matrix (ECM) molecules, which results in the widening of intercellular space of the epithelial compartment.…”

mentioning

confidence: 99%

Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma

Tsuneki

Yamazaki

Maruyama

et al. 2013

Laboratory Investigation

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Podoplanin (PDPN), one of the representative mucin-like type-I transmembrane glycoproteins specific to lymphatic endothelial cells, is expressed in various cancers including squamous cell carcinoma (SCC). On the basis of our previous studies, we have developed the hypothesis that PDPN functions in association with the extracellular matrix (ECM) from the cell surface side. The aim of this study was to elucidate the molecular role of PDPN in terms of cell adhesion, proliferation, and migration in oral SCC cells. Forty-four surgical specimens of oral SCC were used for immunohistochemistry for PDPN, and the expression profiles were correlated with their clinicopathological properties. Using ZK-1, a human oral SCC cell system, and five other cell systems, we examined PDPN expression levels by immunofluorescence, western blotting, and real-time PCR. The effects of transient PDPN knockdown by siRNA in ZK-1 were determined for cellular functions in terms of cell proliferation, adhesion, migration, and invasion in association with CD44 and hyaluronan. Cases without PDPN-positive cells were histopathologically classified as less-differentiated SCC, and SCC cells without PDPN more frequently invaded lymphatics. Adhesive properties of ZK-1 were significantly inhibited by siRNA, and PDPN was shown to collaborate with CD44 in cell adhesion to tether SCC cells with hyaluronan-rich ECM of the narrow intercellular space as well as with the stromal ECM. There was no siRNA effect in migration. We have demonstrated the primary function of PDPN in cell adhesion to ECM, which is to secondarily promote oral SCC cell proliferation.Laboratory Investigation (2013) 93, 921-932;

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“…In addition, podoplanin was also expressed in several tumors, including squamous cell carcinoma, germ cell tumor, and mesothelioma, raising a possibility that it may have biologic functions in tumor cells. [35][36][37] Thus, immunohistochemical examination of D2-40-positive non-lymphatic cells was explored to understand tumor progression.…”

mentioning

confidence: 99%

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma

et al. 2008

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Lymph node metastasis via lymphatic vessels is related with an adverse outcome in many tumors. It is unclear whether lymphatic spread needs the development of the new lymphatic vessels or the expression of lymphangiogenetic factor in intrahepatic cholangiocarcinoma. The aim of this study was to assess the role of lymphangiogenesis, vascular endothelial growth factor-C (VEGF-C) expression, and D2-40-positive myofibroblastic cells for lymphatic spread and patient outcome in 88 cases of intrahepatic cholangiocarcinoma. We also assessed VEGF-C expression in 15 cases of metastatic lymph nodes. There was a significant correlation between lower lymphatic vessel density in the tumor center and positive lymphatic invasion (P ¼ 0.0100). Poorly differentiated cholangiocarcinoma showed higher lymphatic vessel density in the tumor periphery and in the peritumoral area (P ¼ 0.0315 and P ¼ 0.0360, respectively). Lymphatic invasion was observed higher in the peritumoral area (63%, 24/38) and in the tumor periphery (79%, 30/38) than in the tumor center (27%, 9/ 38). There was no significant correlation between the proliferative lymphatic vessels and pathologic features; however, lymphatic invasion was significantly associated with VEGF-C expression (P ¼ 0.0006), and the VEGF-C expression was seen in 12 of 15 cases (80%) of metastatic lymph node. Nodal metastasis was correlated with D2-40-positive myofibroblasts (P ¼ 0.0161). VEGF-C expression was an independent prognostic factor by multivariate survival analysis (P ¼ 0.0131). Our findings suggest that VEGF-C has an important role in lymphatic invasion via the preexisting lymphatic vessels in the tumor margin, and that lymphangiogenesis does not play a direct role in lymphatic metastasis. D2-40-positive myofibroblasts may contribute to lymphatic metastasis.

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Overexpression of podoplanin in oral cancer and its association with poor clinical outcome

Cited by 267 publications

References 16 publications

Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx

Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx

Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma

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