Cheryl L. Jorcyk Copyright (c) 2011 All rights reserved. http://works.bepress.com/cheryl_jorcyk Recent documents in Cheryl L. Jorcyk en-us Wed, 07 Dec 2011 01:38:57 PST 3600 Collagen a1(XI) in Normal and Malignant Breast Tissue http://works.bepress.com/cheryl_jorcyk/15 http://works.bepress.com/cheryl_jorcyk/15 Mon, 05 Dec 2011 11:59:21 PST Little is known about collagen XI expression in normal and malignant breast tissue. Tissue microarrays, constructed from 72 patients with breast carcinoma and matched normal tissue, were immunohistochemically stained with five antisera against isoform-specific regions of collagen a1(XI) N-terminal domain. Staining intensity was graded on a 0–3 scale in epithelial cytoplasm, stroma, and endothelial staining of the vasculature of each tissue core. The staining was compared to known pathologic parameters: age, tumor size, overall tumor grade, nuclear grade, tubule formation, mitotic counts, angiolymphatic invasion, node status, estrogen receptor status, progesterone receptor status, and HER-2/neu status. Estrogen and progesterone receptor status were used as a control for comparison. With antisera V1a and amino propeptide (Npp), stroma surrounding cancerous cells was found to have decreased collagen a1(XI) staining compared to stroma adjacent to normal epithelium (P¼0.0006, Po0.0001). Collagen a1(XI) staining with V1a antiserum in cytoplasm of cancer cells demonstrated decreased intensity in metastasized primary tumors when compared to nonmetastasized primary tumors (P¼0.009). Cytoplasmic staining with Npp antiserum in cancer demonstrated an inverse relationship to positive estrogen receptor status in cancer (P¼0.012) and to progesterone receptor status (P¼0.044). Stromal staining for Npp in cancerous tissue demonstrated an inverse relationship with tubule formation score (P¼0.015). This is the first study to localize collagen XI within normal and malignant breast tissue. Collagen a1(XI) appears to be downregulated in stroma surrounding breast cancer. Detection of collagen XI in breast tissue may help predict women who have lymph node metastases.

]]> Karen C. Halsted et al. Development and Characterization of a Progressive Series of Mammary Adenocarcinoma Cell Lines Derived from the C3(1)/SV40 Large T-antigen Transgenic Mouse Model http://works.bepress.com/cheryl_jorcyk/14 http://works.bepress.com/cheryl_jorcyk/14 Mon, 05 Dec 2011 11:59:17 PST We have developed four new mammary adenocarcinoma cell lines from the C3(1)/SV40 Large T-antigen (Tag) transgenic mouse model: M28N2 and M27H4 (weakly tumorigenic), M6 (carcinoma), and M6C (metastatic). The C3(1) promoter directs Tag expression to the mammary epithelium and 100% of female C3(1)/Tag transgenic mice develop mammary adenocarcinoma in a predictable and progressive manner. The cell lines we developed from this model are demonstrated to be of epithelial origin and display growth rates, both in vitro and following subcutaneous inoculation into nude mice, that are consistent with their representative stage of tumor progression. The more tumorigenic cell lines, M6 and M6C, both express the sodium/iodide symporter, a mammary carcinoma cell marker with potential therapeutic and diagnostic applications. All of the cell lines express estrogen receptor (ER) and ER mRNA, and Western blot analysis demonstrates that the ER protein is down-regulated in the M6 and M6C cell lines. M28N2 cells also express progesterone receptor (PgR), which is very unusual in a mouse mammary carcinoma cell line. In addition, all of the cell lines display growth inhibition when plated in media supplemented with charcoal-stripped fetal calf serum (CS FBS). When CS FBS is supplemented with estradiol or the progestin MPA, no significant difference in growth rates is observed relative to growth in CS FBS. The development and characterization of a progressive series of new mammary carcinoma cell lines will aid in the study of mammary carcinoma progression both in vitro and in vivo.

]]> Ryan G. Holzer et al. Clinical Significance of Interleukin (IL)-6 in Cancer Metastasis to Bone: Potential of Anti-IL-6 Therapies http://works.bepress.com/cheryl_jorcyk/13 http://works.bepress.com/cheryl_jorcyk/13 Mon, 05 Dec 2011 11:59:13 PST Metastatic events to the bone occur frequently in numerous cancer types such as breast, prostate, lung, and renal carcinomas, melanoma, neuroblastoma, and multiple myeloma. Accumulating evidence suggests that the inflammatory cytokine interleukin (IL)-6 is frequently upregulated and is implicated in the ability of cancer cells to metastasize to bone. IL-6 is able to activate various cell signaling cascades that include the STAT (signal transducer and activator of transcription) pathway, the PI3K (phosphatidylinositol-3 kinase) pathway, and the MAPK (mitogen-activated protein kinase) pathway. Activation of these pathways may explain the ability of IL-6 to mediate various aspects of normal and pathogenic bone remodeling, inflammation, cell survival, proliferation, and pro-tumorigenic effects. This review article will discuss the role of IL-6: 1) in bone metabolism, 2) in cancer metastasis to bone, 3) in cancer prognosis, and 4) as potential therapies for metastatic bone cancer.

]]> Ken Tawara et al. Involvement of HGF/SF–Met Signaling in Prostate Adenocarcinoma Cells: Evidence for Alternative Mechanisms Leading to a Metastatic Phenotype in Pr-14c http://works.bepress.com/cheryl_jorcyk/12 http://works.bepress.com/cheryl_jorcyk/12 Mon, 05 Dec 2011 11:59:08 PST

BACKGROUND

Hepatocyte growth factor/scatter factor (HGF/SF) facilitates intercellular communication between the epithelial carcinoma and its surrounding stromal tissue during metastatic invasion through interaction with its proto-oncogenic receptor, Met, found on carcinoma cells. This study utilizes the C3(1)/Tag transgenic mouse prostate cancer cell line model in an attempt to characterize the interaction between HGF/SF and Met on the metastatic potential of prostate cancer.

METHODS

Exogenous HGF was supplied to the prostate adenocarcinoma cell line (Pr-14) and metastatic cell line (Pr-14c) to evaluate mitogenicity by proliferation assays, morphological characteristics on an extracellular matrix substrate, and motogenic properties using the scatter assay, invasion chambers, and zymogram studies to analyze secretory enzymes produced by the cell lines.

RESULTS

RNA and protein analyses show that the cell lines express similar amounts of Met. Pr-14 cells have an increased growth rate following HGF/SF treatment, whereas the metastatic Pr-14c cells show little change. Morphological studies of Pr-14c cells on extracellular matrix demonstrate negligible changes when compared to the tubular formation of Pr-14 cells after HGF/SF stimulation. Motility studies of the metastatic cells following HGF/SF treatment reveal a potentially faulty signaling pathway downstream of Met activation in the metastatic prostate cells.

CONCLUSIONS

Our studies suggest that proliferation, invasion, and cell morphological characteristics may be induced independently from the HGF/SF-Met pathway in C3(1)/Tag metastatic prostate cancer cells.

]]> Christina MacDougall et al. Oncostatin M Induces Cell Detachment and Enhances the Metastatic Capacity of T-47D Human Breast Carcinoma Cells http://works.bepress.com/cheryl_jorcyk/11 http://works.bepress.com/cheryl_jorcyk/11 Mon, 05 Dec 2011 11:59:04 PST Oncostatin M (OSM), an IL-6 family cytokine, has previously been shown to increase migration of several breast cancer cell lines in vitro. Our studies report additional effects of OSM treatment on the human breast carcinoma cell line T-47D. OSM treatment alters T-47D cell morphology from a normal epithelial phenotype to a mesenchymal-like phenotype that is associated with cell detachment from substratum. These effects are also seen with H3922 human breast cancer cells. OSM treatment of T-47D cells for 5–8 days leads to a three-fold increase in cell detachment. OSM-induced detachment of T-47D cells is blocked by the protein kinase inhibitors UO126 and bisindolylmaleimide, indicating a role for MAP kinases and protein kinase C in OSM signaling events that regulate cell detachment. T-47D cells induced to detach by OSM have a reduced capacity to re-adhere to laminin in comparison to other extracellular matrix components. Detached multi-cell aggregates of T-47D cells are viable, whereas detached single cells appear apoptotic. In addition, OSM treatment induces the secretion of the lysosomal proteases cathepsins D and L from T-47D cells, which have been implicated in invasion and metastasis. Importantly, OSM-treated T-47D cells show a 250% increase in invasive capacity as measured by the Matrigel invasion chamber assay. Collectively, these data demonstrate that OSM induces a motile/invasive phenotype in T-47D cells in vitro, and suggest that OSM may enhance metastasis in vivo. Our results suggest that OSM itself may be a valid therapeutic target.

]]> Cheryl L. Jorcyk et al. Oncostatin M Stimulates the Detachment of a Reservoir of Invasive Mammary Carcinoma Cells: Role of Cyclooxygenase-2 http://works.bepress.com/cheryl_jorcyk/10 http://works.bepress.com/cheryl_jorcyk/10 Mon, 05 Dec 2011 11:58:59 PST Previously, oncostatin M (OSM) has been shown to inhibit the proliferation of breast cancer cells in vitro. Circumstantial evidence, however, suggests that OSM could be involved in the development of a metastatic phenotype in vivo. We examined the effects of OSM on the proliferation and metastatic potential of the murine mammary carcinoma cell lines M6 (adenocarcinoma) and M6c (metastatic adenocarcinoma). OSM inhibits the proliferation of both cell lines by 43%, but also causes a loss of cell-cell and cell-substratum adhesion that culminates in cell detachment from monolayer culture. OSM treatment results in a 258% and 550% increase in the detachment of M6 and M6c, respectively, in 32 hours. This effect was abrogated by the selective Cox-2 inhibitor NS-398, and by the anti-inflammatory glucocorticoid dexamethasone. Exogenous prostaglandin E2 (PGE2) partially reverses NS-398's inhibition of OSM-induced cell detachment, indicating Cox-2 involvement. In addition, OSM induces the expression of Cox-2 mRNA, and of the 74 kDa form of Cox-2 protein. M6 and M6c cells detached by OSM are viable and will re-adhere and proliferate in the absence of OSM. OSM-detached cells (M6DET and M6cDET) were collected and maintained in culture and their invasiveness was assessed in vitro. Importantly, M6DET and M6cDET are both significantly more invasive that their respective parental cells. These data suggest that OSM could contribute to the development of a metastatic phenotype in vivo, which would render OSM unsuitable as a cancer therapy and suggest that OSM itself is a potential therapeutic target.

]]> Ryan G. Holzer et al. Experimental Versus Numerical Data for Breast Cancer Progression http://works.bepress.com/cheryl_jorcyk/9 http://works.bepress.com/cheryl_jorcyk/9 Wed, 28 Sep 2011 09:54:29 PDT This paper deals with a mouse model of breast cancer based on two mammary adenocarcinoma cell lines derived from a spontaneous tumor of the mammary gland in a female BALB/c mouse. We investigate both animal and mathematical models of tumor progression, and demonstrate a correspondence between the experimental and predicted data. The mathematical model is solved numerically and the laboratory data are utilized in order to find unknown parameters for the model equations. The results of the numerical experiments illustrate that the mathematical model has a potential to describe the growth of cancer cells in vivo.

]]> Cheryl L. Jorcyk et al. Correlation Between Animal and Mathematical Models for Prostate Cancer Progression http://works.bepress.com/cheryl_jorcyk/8 http://works.bepress.com/cheryl_jorcyk/8 Wed, 09 Feb 2011 09:58:30 PST This work demonstrates that prostate tumour progression in vivo can be analysed by using solutions of a mathematical model supplemented by initial conditions chosen according to growth rates of cell lines in vitro. The mathematical model is investigated and solved numerically. Its numerical solutions are compared with experimental data from animal models. The numerical results confirm the experimental results with the growth rates in vivo.

]]> Z. Jackiewiczy et al. Biology of Cancer Class Metastasizes Knowledge http://works.bepress.com/cheryl_jorcyk/7 http://works.bepress.com/cheryl_jorcyk/7 Tue, 08 Feb 2011 13:39:49 PST Cancer, in all its forms, is a leading cause of death and serious disease. The pathology of cancer is very complicated. This combined with the fast pace of research and clinical innovation makes cancer biology a difficult topic, even for experts. As a consequence, patients who wish to gain a better understanding of cancer biology may find themselves stuck somewhere between the blog-a-sphere and technical journals. Cancer is a disease of miscommunication and confusion at the level of cellular signaling. In a sense, this theme of confusion extends to the experience of the patient. The body is in rebellion, perhaps refusing to cooperate with treatments. Not only the patient, but friends and family members may not understand what is happening and how to deal with it. Learning some basic cell and cancer biology may help to address these concerns. To meet this need, students from Boise State’s Molecular Biology of Cancer course translated their classroom experience into projects aimed at educating populations affected by cancer.

]]> Chris Barbey et al. Development of Bioluminescent Mammary Cancer Cells with Knocked Down Expression of OSM for Detection of Bone Metastasis in Vivo http://works.bepress.com/cheryl_jorcyk/6 http://works.bepress.com/cheryl_jorcyk/6 Tue, 08 Feb 2011 13:39:48 PST Oncostatin M (OSM) is a multifunctional cytokine belonging to the interleukin (IL)-6 subfamily. OSM was originally recognized by its ability to decrease breast and other tumor cell proliferation in vitro. Based on data from our lab, we hypothesize that OSM is a mediator of breast cancer metastasis to bone. For our model system, we are utilizing two cell lines, 4T1.2 and 66c14, which were derived from the mammary carcinoma of a Balb/c mouse. 4T1.2 cells express medium levels of OSM and are highly metastatic to bone, lymph nodes, and lungs when injected into the mammary fat pad of Balb/c mice. 66c14 cells express low levels of OSM and demonstrate low levels of metastasis that is restricted to the lymph nodes and lungs. A small hairpin RNA (shRNA) to OSM was designed and stably transfected into the cells in order to decrease or ‘knock down’ OSM expression. Enzyme-linked immunosorbent assay (ELISA) was used to quantify levels of secreted OSM protein in both cell lines and confirm knocked down OSM expression. Normal 4T1.2 and 66c14 cells, as well as knockdown 4T1.2 and 66c14 cells, will be injected into the mammary fat pad of female Balb/c mice. To visualize metastasis to bone in vivo, the cell lines are currently being transfected with pGL4, a vector containing a bioluminescence maker called luciferase. The luciferase gene was isolated from the firefly and encodes an enzyme, which along with its substrate luciferin, can be used to image the cells expressing luciferase in vivo. Our aim is to determine whether tumor cell-produced OSM is necessary for breast cancer metastasis to bone by measuring metastasis in cells that have knocked down expression of OSM. If our results confirm our hypothesis, inhibiting OSM and its signaling may be a new target for treating breast cancer metastasis to bone.

]]> Caleb Sutherland et al. Point-of-Contact, DNA-Based Amplifier for Detecting Cancer-Related Micro-RNA in Blood Serum http://works.bepress.com/cheryl_jorcyk/5 http://works.bepress.com/cheryl_jorcyk/5 Tue, 08 Feb 2011 13:39:47 PST Elton Graugnard et al. DNA Origami DNA Nanotechnology Kinetics of DNA and RNA Hybridization in Serum and Serum-SDS http://works.bepress.com/cheryl_jorcyk/4 http://works.bepress.com/cheryl_jorcyk/4 Tue, 08 Feb 2011 13:39:46 PST Cancer is recognized as a serious health challenge both in the United States and throughout the world. While early detection and diagnosis of cancer leads to decreased mortality rates, current screening methods require significant time and costly equipment. Recently, increased levels of certain micro-ribonucleic acids (miRNAs) in the blood have been linked to the presence of cancer. While blood-based biomarkers have been used for years in cancer detection, studies analyzing trace amounts of miRNAs in blood and serum samples are just the beginning. Recent developments in deoxyribonucleic acid (DNA) nanotechnology and DNA computing have shown that it is possible to construct nucleic-acid-based chemical networks that accept miRNAs as inputs, perform Boolean logic functions on those inputs, and generate as an output a large number of DNA strands that can be readily detected. Since miRNAs occur in blood in low abundance, these networks would allow for amplification without using polymerase chain reaction. In this study, we report initial progress in the development of a DNA-based cross-catalytic network engineered to amplify specific cancer-related miRNAs. Subcomponents of the DNA network were tested individually, and their operation in serum, as well as a mixture of serum with sodium dodecyl sulfate, is demonstrated. Preliminary simulations of the full cross-catalytic network indicate successful operation.

]]> Elton Graugnard et al. Operation of a DNA-Based Autocatalytic Network in Serum http://works.bepress.com/cheryl_jorcyk/3 http://works.bepress.com/cheryl_jorcyk/3 Tue, 08 Feb 2011 13:39:44 PST The potential for inferring the presence of cancer by the detection of miRNA in human blood has motivated research into the design and operation of DNA-based chemical amplifiers that can operate in bodily fluids. As a first step toward this goal, we have tested the operation of a DNA-based autocatalytic network in human serum and mouse serum. With the addition of sodium dodecyl sulfate to prevent degradation by nuclease activity, the network was found to operate successfully with both DNA and RNA catalysts.

]]> Elton Graugnard et al. DNA Nanotechnology Breast Cancer Cells Stimulate Neutrophils to Produce Oncostatin M: Potential Implications for Tumor Progression http://works.bepress.com/cheryl_jorcyk/2 http://works.bepress.com/cheryl_jorcyk/2 Thu, 22 Jan 2009 18:12:41 PST Tumor-associated and tumor-infiltrating neutrophils (TAN) and macrophages (TAM) can account for as much as 50% of the total tumor mass in invasive breast carcinomas. It is thought that tumors secrete factors that elicit a woundrepair response from TAMs and TANs and that this response inadvertently stimulates tumor progression. Oncostatin M is a pleiotropic cytokine belonging to the interleukin-6 family that is expressed by several cell types including activated human T lymphocytes, macrophages, and neutrophils. Whereas oncostatin M can inhibit the proliferation of breast cancer cells in vitro, recent studies suggest that oncostatin M may promote tumor progression by enhancing angiogenesis and metastasis. In addition, neutrophils can be stimulated to synthesize and rapidly release large quantities of oncostatin M. In this article, we show that human neutrophils secrete oncostatin M when cocultured with MDA-MB-231 and T47D human breast cancer cells. Neutrophils isolated from whole blood or breast cancer cells alone express little oncostatin M by immunocytochemistry and ELISA, but neutrophils express and release high levels of oncostatin M when they are cocultured with breast cancer cells. In addition, we show that granulocyte-macrophage colony-stimulating factor produced by breast cancer cells and cell-cell contact are both necessary for the release of oncostatin M from neutrophils. Importantly, neutrophilderived oncostatin M induces vascular endothelial growth factor from breast cancer cells in coculture and increases breast cancer cell detachment and invasive capacity, suggesting that neutrophils and oncostatin M may promote tumor progression in vivo.

]]> Marisa M. Queen et al.