Important functional role of the protein osteopontin in the progression of malignant pleural mesothelioma.

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive cancer of the mesothelial lining associated with exposure to airborne non-degradable asbestos fibers. Its poor response to currently available treatments prompted us to explore the biological mechanisms involved in its progression. MPM is characterized by chronic non-resolving inflammation; in this study we investigated which inflammatory mediators are mostly expressed in biological tumor samples from MPM patients, with a focus on inflammatory cytokines, chemokines and matrix components. Methods: Expression and quantification of Osteopontin (OPN) was detected in tumor and plasma samples of MPM patients by mRNA, immunohistochemistry and ELISA. The functional role of OPN was investigated in mouse MPM cell lines in vivo using an orthotopic syngeneic mouse model. Results: In patients with MPM, the protein OPN was significantly more expressed in tumors than in normal pleural tissues and predominantly produced by mesothelioma cells; plasma levels were elevated in patients and associated with poor prognosis. However, modulation of OPN levels was not significantly different in a series of 18 MPM patients receiving immunotherapy with durvalumab alone or with pembrolizumab in combination with chemotherapy, some of whom achieved a partial clinical response. Two established murine mesothelioma cell lines: AB1 and AB22 of sarcomatoid and epithelioid histology, respectively, spontaneously produced high levels of OPN. Silencing of the OPN gene (Spp1) dramatically inhibited tumor growth in vivo in an orthotopic model, indicating that OPN has an important promoting role in the proliferation of MPM cells. Treatment of mice with anti-CD44 mAb, blocking a major OPN receptor, significantly reduced tumor growth in vivo. Conclusion: These results demonstrate that OPN is an endogenous growth factor for mesothelial cells and inhibition of its signaling may be helpful to restrain tumor progression in vivo. These findings have translational potential to improve the therapeutic response of human MPM.

An unusual case of chylothorax.

Pleural effusions occur in up to 70% of cases of malignant pleural mesothelioma (MPM). However, MPM rarely presents as a chylous effusion making it a diagnostic challenge. There are only six reported cases to date. Most cases of chylothoraces due to malignancy are due to lymphoma or bronchogenic carcinoma. We report an interesting case of MPM in a 75-year-old man who presented with recurrent chylothorax. He reported a four-month history of dyspnea and chest discomfort. Chest x-ray revealed a pleural effusion. Pleural fluid analysis was consistent with a chylothorax. Pleural fluid cytology was negative for malignancy. Computed tomography of the chest showed pleural calcifications, mediastinal adenopathy and left lung infiltrate. A fine needle aspirate of the lymph node and transbronchial biopsy specimen (TBBX) of the left lung infiltrate showed extensive reactive appearing mesothelial cells but none that appeared malignant. A video assisted thoracoscopic surgery was suggested but the patient declined. He returned 3 months later with recurrent pleural effusion and worsening airspace disease. Thoracentesis revealed a chylothorax again. Repeat analysis of TBBX and lymph node specimens showed extensive reactive appearing mesothelial cells. Due to concern for MPM, ancillary testing was obtained - loss of BRCA1 associated protein (BAP-1) and CDKN2A/p16 gene deletion. BAP1 staining was lost in the mesothelial cells supporting MPM. This case highlights a rare cause of MPM presenting as a chylous effusion. In a patient with an unknown etiology of chylothorax, MPM must remain in the differential.

Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma.

Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1-expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1-positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1-positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma.

Interplay of non-coding RNAs and approved antimetabolites such as gemcitabine and pemetrexed in mesothelioma.

Gemcitabine and pemetrexed are clinically approved antimetabolites for the therapy of mesothelioma diseases. These drugs are often applied in combination with platinum complexes and other drugs. The activity of antimetabolites depended on the expression levels of certain non-coding RNAs, in particular, of small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The development of tumor resistance towards antimetabolites was regulated by non-coding RNAs. An overview of the interplay between gemcitabine/pemetrexed antimetabolites and non-coding RNAs in mesothelioma is provided. Further to this, various non-coding RNA-modulating agents are discussed which displayed positive effects on gemcitabine or pemetrexed treatment of mesothelioma diseases. A detailed knowledge of the connections of non-coding RNAs with antimetabolites will be constructive for the design of improved therapies in future.

Relations between approved platinum drugs and non-coding RNAs in mesothelioma.

Malignant mesothelioma diseases feature an increasing risk due to their severe forms and their association with asbestos exposure. Platinum(II) complexes such as cisplatin and carboplatin are clinically approved for the therapy of mesothelioma often in combination with antimetabolites such as pemetrexed or gemcitabine. It was observed that pathogenic properties of mesothelioma cells and the response of mesothelioma tumors towards platinum-based drugs are strongly influenced by non-coding RNAs, in particular, by small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). These non-coding RNAs controlled drug sensitivity and the development of tumor resistance towards platinum drugs. An overview of the interactions between platinum drugs and non-coding RNAs is given and the influence of non-coding RNAs on platinum drug efficacy in mesothelioma is discussed. Suitable non-coding RNA-modulating agents with potentially beneficial effects on cisplatin treatment of mesothelioma diseases are mentioned. The understanding of mesothelioma diseases concerning the interactions of non-coding RNAs and platinum drugs will optimize existing therapy schemes and pave the way to new treatment options in future.

Foreign body granuloma mimicking recurrence of malignant pleural mesothelioma.

A 72-year-old man visited our hospital due to right pleural effusion. He had worked as a welder at a shipbuilding company and had been exposed to asbestos. Cytological examination and thoracoscopic pleural biopsy yielded a diagnosis of epithelial malignant pleural mesothelioma (MPM); extrapleural pneumonectomy (EPP) was performed. Two years later, he became aware of right-back swelling that became a fist-sized mass over 2 months. Microscopy of a tissue specimen revealed no malignant cells, but did indicate foreign body granuloma. Subcutaneous lesions that develop after EPP do not necessarily result from the recurrence of MPM, but could have benign etiologies.

A novel link between FMR gene and the JNK pathway provides clues to possible role in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive form of thoracic cancer with poor prognosis. While some studies have identified the molecular alterations associated with MPM, little is known about their role in MPM. For example, fragile X mental retardation (FMR) gene is up-regulated in MPM but its role in MPM is unknown. Here, utilizing Drosophila genetics, I investigate the possible role FMR may be playing in MPM. I provide evidence which suggests that FMR may contribute to tumorigenesis by up-regulating a matrix metalloprotease (MMP) and by degrading the basement membrane (BM), both important for tumor metastasis. I also demonstrate a novel link between FMR and the JNK pathway and suggest that the effects of FMR in MPM could in part be mediated by up-regulation of the JNK pathway.

The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers.

Antitumor immune responses against solid malignancies correlate with improved patient survival. We conducted a comprehensive investigation of immune responses in tumor and tumor-associated stroma in epithelioid malignant pleural mesothelioma with the goal of characterizing the tumor immune microenvironment and identifying prognostic immune markers. We investigated 8 types of tumor-infiltrating immune cells within the tumor nest and tumor-associated stroma, as well as tumor expression of 5 cytokine/chemokine receptors in 230 patients. According to univariate analyses, high densities of tumoral CD4- and CD20-expressing lymphocytes were associated with better outcomes. High expression of tumor interleukin-7 (IL-7) receptor was associated with worse outcomes. According to multivariate analyses, stage and tumoral CD20 detection were independently associated with survival. Analysis of single immune cell infiltration for CD163+ tumor-associated macrophages did not correlate with survival. However, analysis of immunologically relevant cell combinations identified that: (1) high CD163+ tumor-associated macrophages and low CD8+ lymphocyte infiltration had worse prognosis than other groups and (2) low CD163+ tumor associated macrophages and high CD20+ lymphocyte infiltration had better prognosis than other groups. Multivariate analyses demonstrated that CD163/CD8 and CD163/CD20 were independent prognostic factors of survival. With a recent increase in immunotherapy investigations and clinical trials for malignant pleural mesothelioma patients, our observations that CD20+ B lymphocytes and tumor-associated macrophages are prognostic markers provide important information about the tumor microenvironment of malignant pleural mesothelioma.

An unusual cause of an anterior mediastinal mass.

Mesothelioma is a rare tumour and its radiological growth pattern varies. We report the case of a biopsy proven Malignant Pleural Mesothelioma (MPM) presenting as an anterior mediastinal mass in a platinum miner. The prognosis for this aggressive tumour remains poor, despite combination treatment modalities.