PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer.

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.

Utility of neutrophil-to-lymphocyte ratio as an indicator of tumor immune status in non-small cell lung cancer.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic biomarker in non-small cell lung cancer (NSCLC); however, the underlying biological rationale remains unclear. The present study aimed to explore the potential utility of NLR as a surrogate biomarker for immune response to cancer and to elucidate the underlying mechanism. METHODS: This retrospective study included the medical records of 120 patients with NSCLC who underwent surgery at the study institution in 2012. NLR in peripheral blood was determined from blood test within 30 days before surgery. Tumor immune status was evaluated using immunohistochemical staining to identify CD3+, CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs), and the relationship of NLR, with clinicopathologic characteristics including 5-year overall survival (OS), and the tumor immune status was investigated. The median values of NLR and TIL count were used as cutoff points. RESULTS: The 5-year OS was significantly better in patients with low NLR (<2.2) than in those with high NLR (≥2.2) (70.1% vs. 56.8%, P = 0.042) and in patients with high CD3+ TIL count (≥242) than in those with low CD3+ TIL count (<242) (70% vs. 56.8%, P = 0.019). Additionally, the CD3+ TIL count was negatively correlated with preoperative NLR (P = 0.005). CONCLUSION: NLR might potentially reflect the immune status of tumor microenvironment, explaining its impact on prognosis of patients with NSCLC.

Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer.

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

Prognostic Impact of Tumor-Infiltrating Lymphocytes, Tertiary Lymphoid Structures, and Neutrophil-to-Lymphocyte Ratio in Pulmonary Metastases from Uterine Leiomyosarcoma.

BACKGROUND: The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) in tumor tissue has been related to the prognosis in various malignancies. Meanwhile, neutrophil-to-lymphocyte ratio (NLR) as a systemic inflammation marker also has been associated with the prognosis in them. However, few reports have investigated the relationship between pulmonary metastases from sarcoma and these biomarkers. METHODS: We retrospectively recruited 102 patients undergoing metastasectomy for pulmonary metastases from uterine leiomyosarcoma at Okayama University Hospital from January 2006 to December 2019. TILs and TLSs were evaluated by immunohistochemical staining of surgically resected specimens of pulmonary metastases using anti-CD3/CD8/CD103/Foxp3/CD20 antibodies. NLR was calculated from the blood examination immediately before the most recent pulmonary metastasectomy. We elucidated the relationship between the prognosis and these factors. Because we considered that the status of tumor tissue and systemic inflammation were equally valuable, we also assessed the impact of the combination of TILs or TLSs and NLR on the prognosis. RESULTS: As for TILs, CD3-positive cells and CD8-positive cells were correlated with the prognosis. The prognosis was significantly better in patients with CD3-high group, CD8-high group, TLSs-high group, and NLR-low group, respectively. The prognosis of CD8-high/NLR-low group and TLSs-high/NLR-low group was significantly better than that of CD8-low/NLR-high group and TLSs-low/NLR-high group, respectively. CONCLUSIONS: CD3-positive TILs, CD8-positive TILs, TLSs, and NLR are correlated with the prognosis, respectively. The combination of CD8-positive TILs or TLSs and NLR may be the indicators to predict the prognosis of patients with pulmonary metastases from uterine leiomyosarcoma.

A case report of a collision tumor composed of pancreatic ductal adenocarcinoma and peri-pancreatic mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Collision tumors are composed of two distinct tumor components. Collision tumors composed of pancreatic ductal adenocarcinoma and malignant lymphoma occurring in the pancreas have not been previously described in the scientific literature. In this case report, we describe a unique patient with a collision tumor composed of pancreatic ductal adenocarcinoma and peri-pancreatic mucosa-associated lymphoid tissue (MALT) lymphoma occurring in the pancreas. CASE PRESENTATION: An 82-year-old woman presented to our hospital complaining of dizziness. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large lymphoid lesion spreading from the peri-pancreatic tissue heading to the hepatic hilar plate, involving the hepatoduodenal ligament and the entire duodenum, also showing a hard tumor in the pancreas head. We performed echo-guided needle biopsies for each tumor and diagnosed a collision tumor composed of pancreatic ductal adenocarcinoma and low-grade B cell lymphoma. The patient underwent pancreaticoduodenectomy. The resected specimen showed an elastic hard tumor, 90 × 75 mm in size, located in the pancreatic head, and a whitish-yellow hard tumor involving the lower bile duct, 31 mm in size, located in the center of the pancreatic head. Pathological and immunohistochemical examination proved that pancreatic ductal adenocarcinoma and MALT lymphoma originating from the peri-pancreatic head collided in the pancreatic head. CONCLUSIONS: To best of our knowledge, this is the first report of a surgically resected collision tumor of pancreatic ductal adenocarcinoma and MALT lymphoma originating from the peri-pancreatic head. A needle biopsy is useful when inconsistent findings are observed on diagnostic CT and MRI of tumor lesions since there is the possibility of a collision tumor.

A case series of histoplasmosis patients with elevated serum soluble interleukin-2 receptor levels.

Histoplasmosis is a common endemic mycosis that is usually asymptomatic but occasionally results in severe illness. Histoplasmosis and its causative agent, Histoplasma capsulatum, are found worldwide but rarely in Japan. In recent years, however, the number of histoplasmosis patients in Japan has increased. In addition, to our knowledge, there are no previous reports of increased serum soluble interleukin-2 receptor (sIL-2R) levels in patients with histoplasmosis. We report a case series of histoplasmosis in three Japanese temporary workers in Manzanillo, Mexico. All three patients developed a persistent high fever and general fatigue. Laboratory tests showed increased C-reactive protein levels and mild liver dysfunction. All patients also showed increased soluble interleukin-2 receptor (sIL-2R) levels. Chest computed tomography revealed multiple nodules in both lung fields. All patients were positive for serum anti-Histoplasma antibodies, and two patients were positive for Histoplasma on polymerase chain reaction tests. After treatment that included antifungals, their conditions gradually improved and laboratory data normalized. Although one patient developed respiratory failure, this patient recovered with antifungal therapy in combination with methylprednisolone. Serum sIL-2R levels in all patients gradually declined to normal levels, indicating their recovery from Histoplasma infection. From our experience with these patients, sIL-2R levels may be a useful biomarker for patients with histoplasmosis.