Medical Anatomy Commons^™

Proline-Rich Tyrosine Kinase 2 (Pyk2) Regulates Igf-I-Induced Cell Motility And Invasion Of Urothelial Carcinoma Cells, Marco Genua, Shi-Qiong Xu, Simone Buraschi, Stephen C. Peiper, Leonard G. Gomella, Antonio Belfiore, Renato V. Iozzo, Andrea Morrione

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in …

The Metastasis Suppressor Kiss1 Lacks Antimetastatic Activity In The C8161.9 Xenograft Model Of Melanoma., Jean-Marc Navenot, Barry Evans, Shinya Oishi, Shohei Setsuda, Nobutaka Fujii, Stephen C Peiper

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The objective of this study was to use the established xenograft model of human melanoma (C8161.9) to test a pharmacological approach to the effect of the metastasis suppressor KISS1. A KISS1 analog was used to inhibit the metastatic development of C8161.9 cells in nude mice. Further experiments were performed to test the validity of the C8161.9 model and test the connection between KISS1 expression and loss of metastatic potential. New clones of C8161.9 cells were obtained, with or without KISS1 expression, and were tested for metastasis formation. The absence of benefit in survival with the KISS1 analog compared with PBS …

Decorin-Mediated Inhibition Of Colorectal Cancer Growth And Migration Is Associated With E-Cadherin In Vitro And In Mice., Xiuli Bi, Nicole M Pohl, Zhibin Qian, George R Yang, Yuan Gou, Grace Guzman, Andre Kajdacsy-Balla, Renato V Iozzo, Wancai Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27(kip1) and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435-1440]. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn(-/-) mice) and manipulated expression of decorin …

Uterine Dysfunction In Biglycan And Decorin Deficient Mice Leads To Dystocia During Parturition., Zhiping Wu, Abraham W Aron, Elyse E Macksoud, Renato V Iozzo, Chi-Ming Hai, Beatrice E Lechner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, …

Decorin Protein Core Affects The Global Gene Expression Profile Of The Tumor Microenvironment In A Triple-Negative Orthotopic Breast Carcinoma Xenograft Model., Simone Buraschi, Thomas Neill, Rick T Owens, Leonardo A Iniguez, George Purkins, Rajanikanth Vadigepalli, Barry Evans, Liliana Schaefer, Stephen C Peiper, Zi-Xuan Wang, Renato V Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that …

Kaempferol Nanoparticles Achieve Strong And Selective Inhibition Of Ovarian Cancer Cell Viability., Haitao Luo, Bingbing Jiang, Bingyun Li, Zhaoliang Li, Bing-Hua Jiang, Yi Charlie Chen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Ovarian cancer is one of the leading causes of cancer death for women throughout the Western world. Kaempferol, a natural flavonoid, has shown promise in the chemoprevention of ovarian cancer. A common concern about using dietary supplements for chemoprevention is their bioavailability. Nanoparticles have shown promise in increasing the bioavailability of some chemicals. Here we developed five different types of nanoparticles incorporating kaempferol and tested their efficacy in the inhibition of viability of cancerous and normal ovarian cells. We found that positively charged nanoparticle formulations did not lead to a significant reduction in cancer cell viability, whereas nonionic polymeric nanoparticles …

Mir-145 Directly Targets P70s6k1 In Cancer Cells To Inhibit Tumor Growth And Angiogenesis., Qing Xu, Ling-Zhi Liu, Xu Qian, Qi Chen, Yue Jiang, Dan Li, Lihui Lai, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

MiR-145 can regulate cell apoptosis, proliferation, neural development and stem cell differentiation. Previous studies indicate that miR-145 is downregulated in human colon cancer cells. However, the molecular mechanisms of miR-145 used to regulate colon carcinogenesis and angiogenesis remain to be clarified. Here, we show that the expression of miR-145 is downregulated in colon and ovarian cancer tissues and cell lines. MiR-145 inhibits p70S6K1 post-transcriptional expression by binding to its 3'-UTR. The angiogenic factors hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF), which are downstream molecules of p70S6K1, are decreased by miR-145 overexpression. P70S6K1 rescues miR-145-suppressed HIF-1 and VEGF …

Integrative Gene Regulatory Network Analysis Reveals Light-Induced Regional Gene Expression Phase Shift Programs In The Mouse Suprachiasmatic Nucleus., Haisun Zhu, Rajanikanth Vadigepalli, Rachel Rafferty, Gregory E Gonye, David R Weaver, James S Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We use the multigenic pattern of gene expression across suprachiasmatic nuclei (SCN) regions and time to understand the dynamics within the SCN in response to a circadian phase-resetting light pulse. Global gene expression studies of the SCN indicate that circadian functions like phase resetting are complex multigenic processes. While the molecular dynamics of phase resetting are not well understood, it is clear they involve a "functional gene expression program", e.g., the coordinated behavior of functionally related genes in space and time. In the present study we selected a set of 89 of these functionally related genes in order to further …

Thomas Jefferson University, Department Of Pathology, Anatomy And Cell Biology, Oral Administration Of Apigenin Inhibits Metastasis Through Akt/P70s6k1/Mmp-9 Pathway In Orthotopic Ovarian Tumor Model., Jun He, Qing Xu, Min Wang, Chongyong Li, Xu Qian, Zhumei Shi, Ling-Zhi Liu, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Apigenin, a flavonoid commonly present in the daily diet, is known for its potential anti-tumor properties. However, the effect of apigenin via oral administration on tumor growth and metastasis remains unknown. In this study we developed an orthotopic ovarian tumor model in nude mice to test the effect of apigenin oral administration, and showed that apigenin inhibited the micrometastasis of cancer cells in the animal tumor model. To understand the mechanism of apigenin in inhibiting metastasis, we found that apigenin greatly inhibited MMP-9 expression and p-AKT and p-p70S6K1 levels in the tumor tissues compared to the control group. We further …

Lung Carcinoma In The Era Of Personalized Medicine: The Role Of Cytology., Maureen F Zakowski, Marluce Bibbo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

In 2004, three groups working independently [1–3] , almost simultaneously, reported remarkable findings: that activating mutations in the epidermal growth factor receptor (EGFR) were common in certain lung carcinomas and that these mutations correlated with the response of those lung tumors to therapy with gefitinib and erlotinib, both EGFR tyrosine kinase inhibitors (TKIs). This was the first time driver mutations in lung cancer that responded to targeted therapy had been identified, marking the beginning of a new era of personalized medicine in lung cancer. Prior to the discovery of these mutations, patients had been treated with EGFR TKIs but predicting …

Knockdown Of Ki-67 By Dicer-Substrate Small Interfering Rna Sensitizes Bladder Cancer Cells To Curcumin-Induced Tumor Inhibition., Sivakamasundari Pichu, Swapna Krishnamoorthy, Andrei Shishkov, Bi Zhang, Peter Mccue, Biddanda C Ponnappa

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Transitional cell carcinoma (TCC) of the urinary bladder is the most common cancer of the urinary tract. Most of the TCC cases are of the superficial type and are treated with transurethral resection (TUR). However, the recurrence rate is high and the current treatments have the drawback of inducing strong systemic toxicity or cause painful cystitis. Therefore, it would be of therapeutic value to develop novel concepts and identify novel drugs for the treatment of bladder cancer. Ki-67 is a large nucleolar phosphoprotein whose expression is tightly linked to cell proliferation, and curcumin, a phytochemical derived from the rhizome Curcuma …

Temporal Changes In Innate Immune Signals In A Rat Model Of Alcohol Withdrawal In Emotional And Cardiorespiratory Homeostatic Nuclei., Kate Freeman, Anthony Brureau, Rajanikanth Vadigepalli, Mary M Staehle, Melanie M Brureau, Gregory E Gonye, Jan B Hoek, D Craig Hooper, James S Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Chronic alcohol use changes the brain's inflammatory state. However, there is little work examining the progression of the cytokine response during alcohol withdrawal, a period of profound autonomic and emotional upset. This study examines the inflammatory response in the central nucleus of the amygdala (CeA) and dorsal vagal complex (DVC), brain regions neuroanatomically associated with affective and cardiorespiratory regulation in an in vivo rat model of withdrawal following a single chronic exposure.

METHODS: For qRT-PCR studies, we measured the expression of TNF-α, NOS-2, Ccl2 (MCP-1), MHC II invariant chain CD74, and the TNF receptor Tnfrsf1a in CeA and DVC …

Emergence Of Bimodal Cell Population Responses From The Interplay Between Analog Single-Cell Signaling And Protein Expression Noise., Marc R Birtwistle, Jens Rauch, Anatoly Kiyatkin, Edita Aksamitiene, Maciej Dobrzyński, Jan B. Hoek, Walter Kolch, Babatunde A Ogunnaike, Boris N Kholodenko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses.

RESULTS: We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally …