The overall hypothesis to be tested in Project 1 is that modification of the extracellular matrix (ECM) plays an important functional role in the progression of prostate carcinoma. Our group has discovered two specific alterations of the ECM. First, the loss of laminin 5 in the transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate carcinoma results in the failure of A6 B4 integrin heterodimer formation. The subsequent failure of hemidesmosome assembly results in a less stable adherence and the loss of A6 B4 transduction signaling through the MAP-kinase pathway, leading to altered gene expression. Without its ligand, B4 degrades, leaving A6 to form heterodimers with B1 and forming novel adhesion complexes attaching to the de novo -synthesized basal lamina (BL). Second, this new basal lamina expresses laminin 10 as one of its main components and interacts with the carcinoma cells through its receptors, alpha3 beta1 and A6 B1. We have more recently shown that laminin 10 is cleaved by the metalloproteinase, MT1-MMP, which is upregulated in PIN and prostate carcinoma.
In Aim 1 we wish to extend our investigations into the mechanism of the failure of laminin 5 expression in carcinoma.
In Aim 2 we intend to characterize the components of the new adhesion complexes, which form in prostate cancer in the absence of the A6 B4 complex.
In Aim 3 we will investigate the effect of cleavage of laminin 10 by MT1-MMP on cell proliferation, migration and invasion. Finally, in Aim 4 we will investigate the effect of laminin 5 and laminin 10 and cleaved laminin 5 and 10 on gene expression. In summary, we will investigate further the discovery that there is a conversion from laminin 5/A6 B4 integrin to a laminin 10/A6 B1, A3 B1 adhesion system in prostate carcinoma progression.
| Nagle, Raymond B; Algotar, Amit M; Cortez, Connie C et al. (2013) ERG overexpression and PTEN status predict capsular penetration in prostate carcinoma. Prostate 73:1233-40 |
| Sroka, Isis C; Sandoval, Cynthia P; Chopra, Harsharon et al. (2011) Macrophage-dependent cleavage of the laminin receptor ?6?1 in prostate cancer. Mol Cancer Res 9:1319-28 |
| Sroka, Isis C; Anderson, Todd A; McDaniel, Kathy M et al. (2010) The laminin binding integrin alpha6beta1 in prostate cancer perineural invasion. J Cell Physiol 224:283-8 |
| Sroka, Isis C; Pond, Gerald D; Nagle, Raymond B et al. (2009) Human Cell Surface Receptors as Molecular Imaging Candidates for Metastatic Prostate Cancer. Open Prost Cancer J 2:59-66 |
| Ports, Michael O; Nagle, Ray B; Pond, Gerald D et al. (2009) Extracellular engagement of alpha6 integrin inhibited urokinase-type plasminogen activator-mediated cleavage and delayed human prostate bone metastasis. Cancer Res 69:5007-14 |
| Demetriou, Manolis C; Kwei, Kevin A; Powell, Marianne B et al. (2008) Integrin A6 Cleavage in Mouse Skin Tumors. Open Cancer J 2:1-4 |
| Sroka, Isis C; Chen, Man Ling; Cress, Anne E (2008) Simplified purification procedure of laminin-332 and laminin-511 from human cell lines. Biochem Biophys Res Commun 375:410-3 |
| Moran, Carlos M; Garriock, Robert J; Miller, Melanie K et al. (2008) Expression of the fast twitch troponin complex, fTnT, fTnI and fTnC, in vascular smooth muscle. Cell Motil Cytoskeleton 65:652-61 |
| King, Tamara E; Pawar, Sangita C; Majuta, Lisa et al. (2008) The role of alpha 6 integrin in prostate cancer migration and bone pain in a novel xenograft model. PLoS One 3:e3535 |
| Demetriou, Manolis C; Stylianou, Panayiota; Andreou, Maria et al. (2008) Spatially and temporally regulated alpha6 integrin cleavage during Xenopus laevis development. Biochem Biophys Res Commun 366:779-85 |
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