Do ultrastructural changes in aged peritoneum contribute to ovarian cancer metastasis? [abstract]

Epithelial ovarian cancer (EOC) will affect 1 in 69 women born in the United States today. Currently, 80% of women newly diagnosed with EOC already have metastatic disease, thus early intervention during the metastatic process will improve the long-term survival rates of women with EOC. Metastasis in EOC occurs through a unique process where cells are shed from a primary tumor and form multicellular aggregates (MCA) that disseminate intraperitoneally in the ascites fluid

Lysophoshatidic acid regulation of cell surface-associated proteases

Abstract only availableLysophosphatidic acid (LPA) is a potential biomarker of ovarian cancer and is thought to promote early stages of cancer progression through the stimulation of two cell surface associated proteases. The affects of LPA on the expression and cell surface association of two proteolytic enzymes associated with ovarian cancer progression, matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA), were analyzed. Both MMP-9 and uPA have been linked with cancer cell invasion due to their proteolytic activity. The cell surface association and activation of MMP-9 is a chief mechanism by which cells invade collagen rich barriers, whereas the increased binding of uPA to its cell surface receptor promotes the conversion of plasminogen to plasmin which also promotes cell invasion. LPA was shown to increase the expression of the MMP-9 protease in a concentration dependent manner in both OVCA 429 and OVCA 433 ovarian cancer cell cultures at concentrations well below those normally found in ascites fluids ( 1 M). LPA treatment (80 M) showed as much as a 3.5 fold increase in MMP-9 expression. Further, LPA treatment increased the expression of MMP-9 over MMP-2 in conditioned media of both OVCA 429 and OVCA 433 cells. Stimulation of uPA activity was also shown in culture medium but required the elevated concentrations ( 20 M) often found in the ascites of ovarian cancer patients. Inhibitor studies showed that inhibition of PI-3K signaling (most evidently in OVCA 433 cells) and p38 MAPK (namely in OVCA 429 cells) repressed LPA stimulation of MMP-9 expression in a dose-dependent fashion. Future studies involving matrigel invasion assays will evaluate the functional consequence of LPA-stimulated MMP-9 expression and enhanced cell surface proteolysis on ovarian cancer cell invasive activity.NIH grant to M.S Stac

Masticatory loading and soft-tissue plasticity in the mammalian circumorbital region

Abstract only availableMasticatory loading is the key to understanding the plasticity or epigenetic responses of many of the soft and hard tissues of the mammalian skull. Diet-induced variation in the magnitude and/or frequency of masticatory loads influences the organization, functional adaptation and postnatal development of craniofacial systems. While experimental work exists concerning masticatory stress as a determinant of maxillomandibular form, similar research concerning the mammalian circumorbital region of soft-tissue structures remains sparse. Indeed, controversy remains over the function of the circumorbital region, specifically whether the postorbital region in primates and other mammals is responsive to biomechanical loading. This hinders our understanding of evolutionary transformations during primate origins, where the earliest primates evolved a bony postorbital bar from an ancestor with a soft-tissue structure along the lateral orbital margin. To fill this gap, we examined the postorbital microanatomy of white rabbits (Oryctolagus cuniculus). Rabbits exhibit a masticatory complex and feeding behaviors like primates, yet retain a primitive circumorbital region similar to their common ancestor. To address the plasticity and function of soft tissues of the lateral orbital wall, three cohorts of 10 rabbits each were raised from weaning (1 month old) to adulthood (6 months old) on diets of different mechanical properties (under-use, control, over-use). Once sacrificed, tissues were collected from the left lateral orbital wall. Dissections revealed that, rather than the anticipated postorbital ligament, rabbits instead exhibit fibrocartilage. Samples were analyzed histologically and immunohistochemically for general anatomy, fibril architecture, collagen expression/organization, and protein abundance using Western Blot analysis. Preliminary data suggests that collagen fibers are aligned differently, with an overexpression of collagen in the over-use dietary cohort versus both the control and under-use groups. In sum, these experimental findings suggest that the postorbital fibrocartilage is mechanically responsive, which contrasts with the non-masticatory nature of bony elements in the circumorbital region.Life Sciences Undergraduate Research Opportunity Progra

Development and function of the mandibular symphysis in mammals [abstract]

The mandibular symphysis is the midsagittal articulation between left and right dentaries that is the third jaw joint of the mammalian feeding complex. There is remarkable evolutionary diversity in symphyseal anatomy that characterizes postnatal growth. It varies from the primitive mammalian condition of smooth joint surfaces loosely connected by a fibrocartilage pad and ligaments to a more tightly bound joint with greater sutural complexity and numerous variably calcified ligaments to an ossified joint. Unfortunately, load-induced responses of jaw-joint connective tissues are incompletely documented in growing mammals. To address this gap we investigated the proportions and composition of symphyseal tissues in growing rabbits subjected to diet-induced variation in masticatory stresses