Podoplanin promotes progression of MPM

Malignant pleural mesothelioma (MPM) is characterized by dissemination and aggressive growth in the thoracic cavity. Podoplanin (PDPN) is an established diagnostic marker for MPM, but the function of PDPN in MPM is not fully understood. The purpose of this study was to determine the pathogenetic function of PDPN in MPM. Forty-seven of 52 tumors (90%) from Japanese patients with MPM and 3/6 (50%) MPM cell lines tested positive for PDPN. Knocking down PDPN in PDPN-high expressing MPM cells resulted in decreased cell motility. In contrast, overexpression of PDPN in PDPN-low expressing MPM cells enhanced cell motility. PDPN stimulated motility was mediated by activation of the RhoA/ROCK pathway. Moreover, knocking down PDPN with short hairpin (sh) RNA in PDPN-high expressing MPM cells resulted in decreased development of a thoracic tumor in mice with severe combined immune deficiency (SCID). In sharp contrast, transfection of PDPN in PDPN-low expressing MPM cells resulted in an increase in the number of Ki-67-positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice. Interestingly, PDPN promoted focus formation in vitro, and a low level of E-cadherin expression and YAP1 activation was observed in PDPN-high MPM tumors. These findings indicate that PDPN is a diagnostic marker as well as a pathogenetic regulator that promotes MPM progression by increasing cell motility and inducing focus formation. Therefore, PDPN might be a pathogenetic determinant of MPM dissemination and aggressive growth and may thus be an ideal therapeutic target

Podoplanin: An Emerging Cancer Biomarker and Therapeutic Target

Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition, migration, invasion, metastasis and inflammation. Antibodies, CAR-T cells, biologics and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer, including glioma, squamous cell carcinoma, mesothelioma and melanoma

Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation

Malignant pleural mesothelioma (MPM) is characterized by dissemination and aggressive growth in the thoracic cavity. Podoplanin (PDPN) is an established diagnostic marker for MPM, but the function of PDPN in MPM is not fully understood. The purpose of this study was to determine the pathogenetic function of PDPN in MPM. Forty-seven of 52 tumors (90%) from Japanese patients with MPM and 3/6 (50%) MPM cell lines tested positive for PDPN. Knocking down PDPN in PDPN-high expressing MPM cells resulted in decreased cell motility. In contrast, overexpression of PDPN in PDPN-low expressing MPM cells enhanced cell motility. PDPN stimulated motility was mediated by activation of the RhoA/ROCK pathway. Moreover, knocking down PDPN with short hairpin (sh) RNA in PDPN-high expressing MPM cells resulted in decreased development of a thoracic tumor in mice with severe combined immune deficiency (SCID). In sharp contrast, transfection of PDPN in PDPN-low expressing MPM cells resulted in an increase in the number of Ki-67-positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice. Interestingly, PDPN promoted focus formation in vitro, and a low level of E-cadherin expression and YAP1 activation was observed in PDPN-high MPM tumors. These findings indicate that PDPN is a diagnostic marker as well as a pathogenetic regulator that promotes MPM progression by increasing cell motility and inducing focus formation. Therefore, PDPN might be a pathogenetic determinant of MPM dissemination and aggressive growth and may thus be an ideal therapeutic target. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association

Tumor-identification method for predicting recurrence of early-stage lung adenocarcinoma using digital pathology images by machine learning

Lung cancer is one of the cancers with the highest morbidity and mortality in the world. Recurrence often occurs even after complete resection of early-stage lung cancer, and prediction of recurrence after resection is clinically important. However, the pathological characteristics of the recurrence of pathological stage IB lung adenocarcinoma (LAIB) have not yet been elucidated. Therefore, the problem is what type of histological image of lung adenocarcinoma recurs, and it is important to examine the histological image of recurrence. We attempted to predict recurrence of early lung adenocarcinoma after resection on the basis of digital pathological images of hematoxylin and eosin-stained specimens and machine learning applying a convolutional neural network. We constructed a model that extracts the features of two-color spaces and a switching model that automatically switches between our extraction model and one that extracts the features of one-color space for each image. We then developed a tumor-identification method for predicting the presence or absence of LAIB recurrence using these models. We conducted an experiment involving 55 patients with LAIB who underwent surgical resection to evaluate the proposed method. The proposed method determined LAIB recurrence with an accuracy of 84.8%. The use of digital pathology and machine learning can be used for highly accurate prediction of LAIB recurrence after surgical resection. The proposed method has the potential for objective postoperative follow-up observation

Stapling cartridge lavage cytology in limited resection for pulmonary malignant tumors: assessment of cytological status of the surgical margin

Introduction: Sublobar resection in primary lung cancer and pulmonary metastatic tumor can result in recurrence at the surgical margin. Confirming the absence of tumor cells at the cut-end is important. We sought to evaluate the efficacy of intraoperative lavage cytology (ILC) of autostapling cartridges in preventing local failure. Materials and methods: An intraoperative cytology examination was performed in 262 consecutive patients undergoing wedge or segmental resection for 311 lesions, including primary lung cancers and pulmonary metastatic tumors, between April 2004 and April 2010. The data of patients with positive cytology results and those who developed local failure were retrospectively reviewed. Results: A total of 139 primary lung cancers and 172 pulmonary metastatic tumors (primary site: 120 colorectal and 52 others) were investigated. The results revealed 22 (7%) positive cytology results (11 primary and 11 metastatic). The resection margins of 19 of the 22 lesions with positive cytology were additionally resected. With a median follow-up period of 42 months, recurrence at the margin developed in 2 of the 19 lesions in which additional resection was performed (11%, 1 primary and 1 metastatic). Recurrence at the margin developed in 2 (67%, 1 primary and 1 metastatic) of the 3 lesions in which additional resection was abandoned. Among the 289 lesions showing negative cytology results, recurrence at the margin developed in 7 (2%, 6 primary and 1 metastatic). Conclusions: ILC of autostapling cartridges in sublobar resection for pulmonary malignant tumor may be useful for assessing the cytological status of the surgical margin

Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer.

ATP-binding cassette (ABC) transporter and DNA excision repair proteins play a pivotal role in the mechanisms of drug resistance. The aim of this study was to investigate the expression of ABC transporter and DNA excision repair proteins, and to elucidate the clinical significance of their expression in biopsy specimens from patients with small-cell lung cancer (SCLC)