Browsing by Subject "laminin"
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(2013)Laminins are a family of heterotrimeric glycoproteins found mainly in basement membranes. They interact with numerous other extracellular matrix components and cell surface receptors, including integrins and α-dystroglycan. Laminins play roles in myriad of functions including tissue morphogenesis, organogenesis, maintenance of tissue integrity and compartmentalization. In central nervous system laminins are involved in every major developmental stage from neural tube closure to synaptogenesis. Laminin expression in central nervous system decreases after maturation but has been found inducible by injury after trauma or disease. Since laminins are known to promote neurite outgrowth and neuronal survival, this has been proposed as a regenerative response to injury. Although the effects of endogenous laminin are clearly inadequate for repair, laminin based compounds could be powerful therapeutic agents. In previous in vivo studies KDI-tripeptide, a neurite outgrowth promoting fragment from γ1-laminin, has proved effective neuroprotective and regeneration promoting compound. Encouraged by these results I set out to test whether KDI would rescue midbrain dopaminergic neurons in unilateral 6-hydroxydopamine-induced rat model of Parkinson's disease. KDI (1-30µg) was injected to the striatum six hours prior to 6-hydroxydopamine. The severity of the lesion was then evaluated by measuring D-amphetamine induced rotation 2, 4 and 6 weeks postlesion and by assessing the number of neurons in substantia nigra pars compacta and optical density of striatum after tyrosine hydroxylase immunostaining at week seven. The only effective KDI dose studied was 3 µg. Compared to control it decreased Damphetamine induced rotational behaviour significantly at week four. KDI, however, failed to save tyrosine hydroxylase positive dopaminergic neurons in substantia nigra pars compacta or their axons in striatum. KDI might be usable in treating Parkinson's disease but it's mode of action doesn't appear to rely on protecting dopaminergic neurons or promoting the branching of their axons. KDI is known to inhibit ionotropic glutamate receptors and could therefore improve motor function by opposing striatal denervation induced overactivity of glutamatergic subthalamic nucleus neurons.
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(2023)Extracellular matrix components such as laminins have important roles in supporting the mammary gland epithelium and guiding its development and homeostasis. Adhesion to laminin alpha-5 subunit (Lama5), notably secreted by the hormone receptor positive luminal epithelial cells, promotes luminal epithelial differentiation and cellular identity, as well as controls mammary progenitor activity, contributing to physiological growth of the mammary epithelium. Lama5 loss in luminal mammary epithelial cells results in abnormal epithelial differentiation, aberrated ductal development, and diminished mammary epithelial growth in mice. Breast cancer is one of the most common forms of cancer, and the most common subtypes are hormone receptor positive luminal breast cancers. While expression of other epithelial laminin alpha subunits is often lost, Lama5 is commonly overexpressed in human breast cancer cells, notably in luminal cancer subtypes, as opposed to basal-like and other cancers subtypes. However, the role of Lama5 in mammary tumor growth and identity has not been experimentally studied in neither mice nor humans. In this thesis, the role of Lama5 in the growth and identity of mammary tumors was studied using both in vivo mouse and in vitro human approaches. Lama5 deletion in luminal epithelial cells of tumor-bearing mice was shown to result in five-fold decrease in the amount of tumorous growth in mouse mammary glands in vivo. In vitro LAMA5 downregulation of MCF-7 luminal human breast cancer cells was shown to lower the proliferation rate and increase the doubling time in 2D culture, decrease their mammosphere forming capacity, as well as decrease total growth in 3D culture, while no effects were observed in triple-negative basal-like MDA-MB-231 human breast cancer cells with LAMA5 downregulation. Additionally, downregulation of LAMA5 was shown to promote the expression of basal-like breast cancer and EMT markers vimentin and fibronectin in luminal MCF-7 cells, while the expression of luminal identity markers was not altered. No changes in the expression of luminal or basal cytokeratin markers CK8 and CK14 were seen in mammary tumors in vivo on mice with luminal laminin alpha-5 deletion. This thesis provides the first set of experimental evidence of the role of laminin alpha-5 as a factor promoting mammary tumor growth in both mice and human cells, especially in hormone receptor positive luminal cancer types. Lama5 contribution to tumor identity, and the exact mechanisms require further studies.
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