Distribution of histopathologic types of primary pulmonary neoplasia in dogs and outcome of affected dogs: 340 cases (2010–2019)

OBJECTIVE To provide updated information on the distribution of histopathologic types of primary pulmonary neoplasia in dogs and evaluate the effect of postoperative adjuvant chemotherapy in dogs with pulmonary carcinoma. ANIMALS 340 dogs. PROCEDURES Medical records of dogs that underwent lung lobectomy for removal of a primary pulmonary mass were reviewed, and histopathologic type of lesions was determined. The canine lung carcinoma stage classification system was used to determine clinical stage for dogs with pulmonary carcinoma. RESULTS Pulmonary carcinoma was the most frequently encountered tumor type (296/340 [87.1%]), followed by sarcoma (26 [7.6%]), adenoma (11 [3.2%]), and pulmonary neuroendocrine tumor (5 [1.5%]); there was also 1 plasmacytoma and 1 carcinosarcoma. Twenty (5.9%) sarcomas were classified as primary pulmonary histiocytic sarcoma. There was a significant difference in median survival time between dogs with pulmonary carcinomas (399 days), dogs with histiocytic sarcomas (300 days), and dogs with neuroendocrine tumors (498 days). When dogs with pulmonary carcinomas were grouped on the basis of clinical stage, there were no significant differences in median survival time between dogs that did and did not receive adjuvant chemotherapy. CLINICAL RELEVANCE Results indicated that pulmonary carcinoma is the most common cause of primary pulmonary neoplasia in dogs; however, nonepithelial tumors can occur. Survival times were significantly different between dogs with pulmonary carcinoma, histiocytic sarcoma, and neuroendocrine tumor, emphasizing the importance of recognizing the relative incidence of these various histologic diagnoses. The therapeutic effect of adjuvant chemotherapy in dogs with pulmonary carcinoma remains unclear and warrants further investigation.

Metformin promotes apoptosis of A549 cells via regulation of p-AMPK protein expression, bax/bcl-2 ratio and ROS levels

Purpose: To investigate the influence of metformin on apoptosis of pulmonary carcinoma cells (A549), and the associated mode of action.Methods: Pulmonary carcinoma cells in logarithmic growth phase were treated with graded concentrations of metformin, and the anti-proliferative and apoptotic effects of the drug were measured using MTT assay and flow cytometry, respectively. The levels of reactive oxygen species (ROS) in A549 cell suspension were determined with 2, 7- dihydrodichlorofluorescein diacetate (DCFH-DA) assay. The expression levels of phosphorylated AMP-activated protein kinase (p-AMPK), mammalian target of rapamycin (mTOR), and bax/bcl-2 ratio were measured using Western blotting and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR).Results: Metformin significantly promoted A549 cell apoptosis, but suppressed its proliferative potential in a dose- and time-based fashion. The levels of ROS, superoxide anion and MDA in A549 cells were significantly and dose-dependently increased by metformin (p < 0.05). Moreover, metformin markedly upregulated the mRNA and protein expressions of p-AMPK as well as bax/bcl-2 ratio, but had no impact on the expression level of mTOR (p < 0.05).Conclusion: Metformin promotes apoptosis in A549 cells via regulation of p-AMPK protein expression, bax/bcl-2 ratio, and ROS levels, and hence may play a role in lung cancer therapy.

Transcriptomic profiling in canines and humans reveals cancer specific gene modules and biological mechanisms common to both species

Understanding relationships between spontaneous cancer in companion (pet) canines and humans can facilitate biomarker and drug development in both species. Towards this end we developed an experimental-bioinformatic protocol that analyzes canine transcriptomics data in the context of existing human data to evaluate comparative relevance of canine to human cancer. We used this protocol to characterize five canine cancers: melanoma, osteosarcoma, pulmonary carcinoma, B- and T-cell lymphoma, in 60 dogs. We applied an unsupervised, iterative clustering method that yielded five co-expression modules and found that each cancer exhibited a unique module expression profile. We constructed cancer models based on the co-expression modules and used the models to successfully classify the canine data. These canine-derived models also successfully classified human tumors representing the same cancers, indicating shared cancer biology between canines and humans. Annotation of the module genes identified cancer specific pathways relevant to cells-of-origin and tumor biology. For example, annotations associated with melanin production (PMEL, GPNMB, and BACE2), synthesis of bone material (COL5A2, COL6A3, and COL12A1), synthesis of pulmonary surfactant (CTSH, LPCAT1, and NAPSA), ribosomal proteins (RPL8, RPS7, and RPLP0), and epigenetic regulation (EDEM1, PTK2B, and JAK1) were unique to melanoma, osteosarcoma, pulmonary carcinoma, B- and T-cell lymphoma, respectively. In total, 152 biomarker candidates were selected from highly expressing modules for each cancer type. Many of these biomarker candidates are under-explored as drug discovery targets and warrant further study. The demonstrated transferability of classification models from canines to humans enforces the idea that tumor biology, biomarker targets, and associated therapeutics, discovered in canines, may translate to human medicine.

The Short Non-Coding RNA 1251-5p Regulates Stemness Transformation and Inhibits Aggression of Lung Malignant Tumor Cells

Our study investigated the effect of short-chain non-coding RNA 1251-5p on the movement and permeation of pulmonary carcinoma stem cells. LCSC in pulmonary carcinoma cells was determined and isolated by flow cytometry. After cell transfection, qRT-PCR and immunoblotting measured the level of MiR-1251-5p, MiR-650, SLC34A2, Oct4 and CD133. Spherometric mensuration was used to assess sphericity formation situation. Transwell analyzed the movement and permeation of cells, detected the relationship among MiR-1251-5p, MiR-650 and SLC34A2 by fluorescein enzyme report gene, and the results were verified by RIP and RNA pull-down detection methods. Knock-down of MiR-1251-5p can enhance the stem cell-like characteristics of LCC, promote cell migration and invasion, upregulate the level of MiR-650, Oct4 and CD133, and downregulate the level of SLC34A2, while MiR-650 inhibitor can restore the effect of the knock-down on the hyperplasia, movement and permeation of LCSC cells. Si-Mir-1251-5p promoted stem cell like characteristics of pulmonary carcinoma cell lineage H1299 and downregulated the expression of Oct4 and CD133, and upregulated the level of SLC34A2. SLC34A2 expression was negatively correlated with MiR-650 expression and positively correlated with MiR-1251-5p in LCSC cellular tissues. MiR-1251-5p regulates LCC stem cell-like state, and inhibits the movement and permeation of pulmonary carcinoma cells via MiR-650/SLC34A2 axis.

Metastases of Urothelium Carcinoma: Differential Diagnosis, Resection, and Survival

Background Due to its very aggressive nature and low survival chances, the metastasized urothelium carcinoma poses a challenge in regard to therapy. The gold-standard chemotherapy is platinum based. The therapy options are considered controversial, including new systemic therapies. In this respect, surgical therapies, as already established for pulmonary metastases of other tumor entities play an increasingly important role. The consumption of nicotine is a risk factor not only for urothelium carcinoma but also for a pulmonary carcinoma. Thus, we examined the frequency of a second carcinoma in this cohort. Methods We retrospectively examined patients who had a differential diagnosis of pulmonary metastases, as well as those patients who underwent a surgery due to pulmonary metastases of a urothelium carcinoma between 1999 and 2015. Results A total of 139 patients came to our clinic with the differential diagnosis of pulmonary metastases of a urothelium carcinoma. The most common diagnosis was pulmonary carcinoma (53%). Thirty-one patients underwent surgeries due to pulmonary metastases of a urothelium carcinoma. The median survival was 53 months and the 5-year survival was 51%. With the univariate analysis, only the relapse-free interval of more than 10 months was statistically significant (p < 0.001). Conclusion There is a high coincidence of urothelial carcinoma and lung carcinoma. A histological confirmation should be endeavored. Selected patients undergoing a pulmonary metastasis resection have a survival advantage during the multimodal treatment of pulmonary metastasized urothelial carcinomas. For a definitive recommendation, randomized trials including a uniform multimodal therapy regimen and higher numbers of patients are necessary.