Browsing by Subject "Neoplasm metastasis"
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Item Author Correction: Inhibitory effects of dopamine receptor D1 agonist on mammary tumor and bone metastasis(Springer Nature, 2022-11-03) Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai‑Yan; Matsuura, Nariaki; Koizumi, Masahiko; Yin, Yukun; Gan, Liangying; Xu, Aihua; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyThis corrects the article "Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis" in volume 7, 45686. doi: 10.1038/srep45686Item Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis(American Association for Cancer Research, 2013) Gu, Dongsheng; Liu, Hailan; Su, Gloria H.; Zhang, Xiaoli; Chin-Sinex, Helen; Hanenberg, Helmut; Mendonca, Marc S.; Shannon, Harlan E.; Chiorean, E. Gabriela; Xie, Jingwu; Pediatrics, School of MedicinePancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here, we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of patients with pancreatic cancer.Item The effect of marrow secretome and culture environment on the rate of metastatic breast cancer cell migration in two and three dimensions(American Society for Cell Biology, 2021-05) Curtis, Kimberly J.; Mai, Christine; Martin, Hannah; Oberman, Alyssa G.; Alderfer, Laura; Romero-Moreno, Ricardo; Walsh, Mark; Mitros, Stephen F.; Thomas, Scott G.; Dynako, Joseph A.; Zimmer, David I.; McNamara, Laoise M.; Littlepage, Laurie E.; Niebur, Glen L.; Medicine, School of MedicineMetastasis is responsible for over 90% of cancer-related deaths, and bone is the most common site for breast cancer metastasis. Metastatic breast cancer cells home to trabecular bone, which contains hematopoietic and stromal lineage cells in the marrow. As such, it is crucial to understand whether bone or marrow cells enhance breast cancer cell migration toward the tissue. To this end, we quantified the migration of MDA-MB-231 cells toward human bone in two- and three-dimensional (3D) environments. First, we found that the cancer cells cultured on tissue culture plastic migrated toward intact trabecular bone explants at a higher rate than toward marrow-deficient bone or devitalized bone. Leptin was more abundant in conditioned media from the cocultures with intact explants, while higher levels of IL-1β, IL-6, and TNFα were detected in cultures with both intact bone and cancer cells. We further verified that the cancer cells migrated into bone marrow using a bioreactor culture system. Finally, we studied migration toward bone in 3D gelatin. Migration speed did not depend on stiffness of this homogeneous gel, but many more dendritic-shaped cancer cells oriented and migrated toward bone in stiffer gels than softer gels, suggesting a coupling between matrix mechanics and chemotactic signals.Item Improved Survival with Bevacizumab in Advanced Cervical Cancer(Massachusetts Medical Society, 2014) Tewari, Krishnansu S.; Sill, Michael W.; Long, Harry J., III; Penson, Richard T.; Huang, Helen; Ramondetta, Lois M.; Landrum, Lisa M.; Oaknin, Ana; Reid, Thomas J.; Leitao, Mario M.; Michael, Helen E.; Monk, Bradley J.; Pathology and Laboratory Medicine, School of MedicineBackground: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. Methods: Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. Results: Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). Conclusions: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.Item Predicting melanoma survival and metastasis with interpretable histopathological features and machine learning models(Frontiers Media, 2023-01-06) Couetil, Justin; Liu, Ziyu; Huang, Kun; Zhang, Jie; Alomari, Ahmed K.; Medical and Molecular Genetics, School of MedicineIntroduction: Melanoma is the fifth most common cancer in US, and the incidence is increasing 1.4% annually. The overall survival rate for early-stage disease is 99.4%. However, melanoma can recur years later (in the same region of the body or as distant metastasis), and results in a dramatically lower survival rate. Currently there is no reliable method to predict tumor recurrence and metastasis on early primary tumor histological images. Methods: To identify rapid, accurate, and cost-effective predictors of metastasis and survival, in this work, we applied various interpretable machine learning approaches to analyze melanoma histopathological H&E images. The result is a set of image features that can help clinicians identify high-risk-of-metastasis patients for increased clinical follow-up and precision treatment. We use simple models (i.e., logarithmic classification and KNN) and "human-interpretable" measures of cell morphology and tissue architecture (e.g., cell size, staining intensity, and cell density) to predict the melanoma survival on public and local Stage I-III cohorts as well as the metastasis risk on a local cohort. Results: We use penalized survival regression to limit features available to downstream classifiers and investigate the utility of convolutional neural networks in isolating tumor regions to focus morphology extraction on only the tumor region. This approach allows us to predict survival and metastasis with a maximum F1 score of 0.72 and 0.73, respectively, and to visualize several high-risk cell morphologies. Discussion: This lays the foundation for future work, which will focus on using our interpretable pipeline to predict metastasis in Stage I & II melanoma.Item Recurrent Parotid Adenocarcinoma Presenting as Diffuse Myocardial Metastatic Disease(Allen Press, 2022) El-Am, Edward A.; Jarori, Upasana; Grethlein, Sara J.; Mastouri, Ronald; Khemka, Abhishek; Medicine, School of MedicineA 64-year-old man who had undergone treatment for left parotid adenocarcinoma presented with progressive exertional shortness of breath. Evaluation revealed metastatic invasion of the myocardium as a rare presentation of recurrent parotid adenocarcinoma. This case highlights the importance of using multimodal imaging methods in diagnostic evaluation and a collaborative multidisciplinary approach in managing patient care.Item Small-Molecule Inhibition of the uPAR·uPA Interaction: Synthesis, Biochemical, Cellular, in vivo Pharmacokinetics and Efficacy Studies in Breast Cancer Metastasis(Elsevier, 2013) Mani, Timmy; Wang, Fang; Knabe, William Eric; Sinn, Anthony L.; Khanna, May; Jo, Inha; Sandusky, George E.; Sledge, George W., Jr.; Jones, David R.; Khanna, Rajesh; Pollok, Karen E.; Meroueh, Samy O.; Biochemistry and Molecular Biology, School of MedicineThe uPAR·uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR·uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to uPAR with sub-micromolar affinity of 0.2 μM. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration-dependent manner. Compound 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5h and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10h. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy.Item Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium(American Society of Clinical Oncology, 2021) Beyer, Jörg; Collette, Laurence; Sauvé, Nicolas; Daugaard, Gedske; Feldman, Darren R.; Tandstad, Torgrim; Tryakin, Alexey; Stahl, Olof; Gonzalez-Billalabeitia, Enrique; De Giorgi, Ugo; Culine, Stéphane; de Wit, Ronald; Hansen, Aaron R.; Bebek, Marko; Terbuch, Angelika; Albany, Costantine; Hentrich, Marcus; Gietema, Jourik A.; Negaard, Helene; Huddart, Robert A.; Lorch, Anja; Cafferty, Fay H.; Heng, Daniel Y. C.; Sweeney, Christopher J.; Winquist, Eric; Chovanec, Michal; Fankhauser, Christian; Stark, Daniel; Grimison, Peter; Necchi, Andrea; Tran, Ben; Heidenreich, Axel; Shamash, Jonathan; Sternberg, Cora N.; Vaughn, David J.; Duran, Ignacio; Bokemeyer, Carsten; Patrikidou, Anna; Cathomas, Richard; Assele, Samson; Gillessen, Silke; International Germ Cell Cancer Classification Update Consortium; Medicine, School of MedicinePurpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. Materials and methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.Item Transcriptional and Epigenetic Regulation of KIF14 Overexpression in Ovarian Cancer(Public Library of Science, 2014-03-13) Thériault, Brigitte L.; Basavarajappa, Halesha D.; Lim, Harvey; Pajovic, Sanja; Gallie, Brenda L.; Corson, Timothy W.; Ophthalmology, School of MedicineKIF14 (kinesin family member 14) is a mitotic kinesin and an important oncogene in several cancers. Tumor KIF14 expression levels are independently predictive of poor outcome, and in cancer cells KIF14 can modulate metastatic behavior by maintaining appropriate levels of cell adhesion and migration proteins at the cell membrane. Thus KIF14 is an exciting potential therapeutic target. Understanding KIF14's regulation in cancer cells is crucial to the development of effective and selective therapies to block its tumorigenic function(s). We previously determined that close to 30% of serous ovarian cancers (OvCa tumors) exhibit low-level genomic gain, indicating one mechanism of KIF14 overexpression in tumors. We now report on transcriptional and epigenetic regulation of KIF14. Through promoter deletion analyses, we identified one cis-regulatory region containing binding sites for Sp1, HSF1 and YY1. siRNA-mediated knockdown of these transcription factors demonstrated endogenous regulation of KIF14 overexpression by Sp1 and YY1, but not HSF1. ChIP experiments confirmed an enrichment of both Sp1 and YY1 binding to the endogenous KIF14 promoter in OvCa cell lines with high KIF14 expression. A strong correlation was seen in primary serous OvCa tumors between Sp1, YY1 and KIF14 expression, further evidence that these transcription factors are important players in KIF14 overexpression. Hypomethylation patterns were observed in primary serous OvCa tumors, suggesting a minor role for promoter methylation in the control of KIF14 gene expression. miRNA expression analysis determined that miR-93, miR-144 and miR-382 had significantly lower levels of expression in primary serous OvCa tumors than normal tissues; treatment of an OvCa cell line with miRNA mimics and inhibitors specifically modulated KIF14 mRNA levels, pointing to potential novel mechanisms of KIF14 overexpression in primary tumors. Our findings reveal multiple mechanisms of KIF14 upregulation in cancer cells, offering new targets for therapeutic interventions to reduce KIF14 in tumors, aiming at improved prognosis.