Browsing by Subject "CD44"

Now showing 1 - 4 of 4
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    Crosstalk Between Adhesion Molecules Influences Cell Traction and Migration
    (2023-07) Kelly, Marcus
    Cell migration is the major driver of invasion and metastasis during cancer progression. For cells to migrate, they utilize the actin-myosin cytoskeleton and adhesion molecules, such as integrins and CD44, to generate traction forces in their environment. Whereas CD44 primarily binds to hyaluronic acid (HA), integrins primarily bind to extracellular matrix proteins (ECM) such as collagen. However, the role of CD44 under integrin-mediated conditions, and vice versa, is not well known. Here we used TFM to assess the functional mechanical relationship between integrins and CD44. Performing TFM on integrin-mediated adhesion conditions, i.e., collagen, we found that CD44KO U251 cells exerted more traction force than wild-type (WT) U251 cells. When using untreated WT and CD44-blocked WT, we observed comparable results with CD44KO cells again showing an increase in traction force on collagen gels. Conversely, in CD44-mediated adhesive conditions, integrin-blocked WT cells exerted higher traction force than untreated WT cells. Our data suggests that CD44 and integrins have a mutually antagonistic relationship where one receptor represses the other’s ability to generate traction force on its cognate substrate.
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    The Effects Of Different Wheat Types On Colon Cancer Risk
    (2020-08) Thyne, Vanessa
    Colon cancer is the third most common cancer and the second leading cause of cancer-related deaths in the United States (1). A variety of risk factors play a role in the etiology of this disease, including environmental risk factors (2, 3). Because of this, considerable research has gone into finding ways to increase consumption of foods that have an inverse association with colon cancer (4). While several epidemiological studies have shown an association between a diet high in whole grains and a lower risk of colon cancer, experimental studies have been inconsistent. This study looks at the effects of wheat class on colon carcinogenesis during the post-initiation stage of colon cancer development in rats. It also examined whether intermediate wheatgrass (IWG) commercially known as Kernza TM, a perennial grass being developed as an alternate to wheat, modifies colon cancer risk in a way similar to red wheat. A major endpoint of this study was enumeration of colonic phenotypic markers known as aberrant crypt foci (ACF), an early pre- cancerous lesion. Additionally, based on previous findings indicating that the type and amount of mucin production is a marker for dysplasia (5), changes in mucin production was examined as well. Finally, CD44, a putative marker of cancer stem cells, was determined immunohistochemically as an additional indicator of colon cancer risk. It was found that there was a significantly greater number of sialomucin-stained ACF (SIM_ACF), and mucin-depleted ACF (MDF) staining in white wheat and vs. red wheat, indicating a higher degree of dysplasia in white wheat. This shows a greater protective effect of red wheat vs. white wheat in the ACF of the colon. Moreover, staining for CD44 was found to be higher in ACFs of white wheat and IWG vs. red wheat. The correlation between the two, indicated by a dysplasia score, 0.7029 (p<0.0001) demonstrates a positive relationship between CD44 and dysplasia. The reduced number of dysplastic markers along with a higher dysplasia score in white wheat and IWG vs. red wheat supports a protective effect of red wheat.
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    Physical Determinants of Glioma Cell Migration and Disease Progression
    (2015-09) Klank, Rebecca
    Glioblastoma (GBM) is a highly aggressive brain cancer (generally, “glioma”) with poor patient prognosis, even with current standard treatments. In order to rationally develop novel treatments that can significantly extend patient survival, we must first understand at a basic scientific level how the disease progresses. GBM is thought to be fatal due to highly invasive cells that migrate beyond the visible bulk tumor and lead to tumor recurrence after therapeutic intervention. Therefore, we sought to investigate what makes GBM cells invasive at the single-cell level (Chapter 1). Using a genetically induced mouse glioma model and confocal imaging of intact tumor-containing brain slices, we found that, consistent with previous biophysical models, glioma cell migration is biphasic with respect to the concentration of the transmembrane cell adhesion molecule CD44. By contrast, cell proliferation is independent of CD44 level. Additionally, mouse model and human patient survival are also biphasic with respect to CD44 level, with poorest prognosis occurring at intermediate CD44 levels. Thus, migration and survival are both biphasic and are anti-correlated to each other, suggesting that CD44-dependent migration directly affects survival outcomes. We next investigated how these single-cell behaviors impact overall tumor growth and progression (Chapter 2). Noticing that previous models of GBM migration use parameter values for migration rate (defined by a diffusion coefficient, also known as a random motility coefficeint) that are much higher than our measurements of single-cell migration behavior in Chapter 1, a Brownian dynamics (BD) approach was used to simulate single-cell growth, proliferation, and migration, and compare model assumptions. These studies showed that employing the physically-based assumption that tumor cells occupy volume, an assumption not captured in current reaction-diffusion (RD) simulations, resulted in increased tumor spreading behavior with the same input parameters. Specifically, non-overlapping cells can enter a jammed regime where interior cells are subdiffusive, and peripheral cells become biased outward and superdiffusive in a quasi-ballistic expansion. Thus, we show that, when we account for volume conservation, the relatively low values of diffusion coefficient, such as what was measured in Chapter 1, can generate fast progressing tumors that are similar to RD simulations which use diffusion coefficients much greater than what is observed experimentally for single migrating cells. Therefore, we suggest that cellular jamming behavior contributes to the fast spreading of GBM tumors, and that subsequent simulations of GBM growth should incorporate this assumption so that models are physically grounded and achieve consistency between single-cell behavior and bulk tumor progression. Overall, these studies demonstrate the potential importance of fundamental physical effects in driving tumor progression generally, and glioblastoma specifically.
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    A spontaneous murine model for the study of CD44 In glioma progression.
    (2012-09) Decker, Stacy Ann
    Mouse models of malignant glioma that accurately recapitulate the genetic and phenotypic heterogeneity are essential for advancing brain tumor therapeutics. We have developed a novel model using the Sleeping Beauty transposable element to achieve chromosomal integration of human oncogenes into endogenous brain cells of any mouse strain. The phenotype of these genetically engineered brain tumors is influenced by the combination of oncogenes delivered, but many of the pathological features of malignant human glioma are present in the majority of cases. At least five different genes can be cotransfected simultaneously, including reporters that allow measurement of tumor progression. The flexibility of this model enabled studies on the role of the microenvironment in brain tumor development. The data presented here demonstrate that glioma cells make an abundance of CD44 and HA starting early in tumor development and continue to make both receptor and ligand as gliomas progress to highly invasive disease. We show that CD44-/- tumors progressed significantly slower than CD44+/+ tumors, but that expression of full length CD44 within tumors restores the CD44-/- tumor progression. In addition, we show that CD44 loss of function caused severe impairment in single cell motility. The data presented here suggest that HA-engaged CD44 mediates tumor progression by facilitating glioma cell invasion. These studies highlight the therapeutic potential for targeting the infiltrative glioma population through antagonists of the HA-CD44 complex.