Research

The research profile of our laboratory include the biology  of TGF-beta, especially its role in the regulation of cell proliferation and extracellular proteolysis and the roles of netrins on glioblastoma growth and invasion. We analyze  the biology of latent forms of TGF-ß family growth factors, their association with the extracellular matrix structures by LTBPs (latent TGF-ß binding proteins) and proteolytic release and activation of the latent complexes. A link to the regulation of extracellular proteolysis is via plasminogen activators and metalloproteinases. We have analyzed plasmin mediated processing/activation of gelatinase A, and identified membrane type-1 MMP (MT1-MMP) as a major effector in the cell surface associated activation of gelatinase A.

Glioblastoma is a highly aggressive and lethal cancer type. It is characterized by extensive angiogenesis in tumor tissue, and lethality occurs by infiltration/invasion of tumor cells to brain tissue. The focus of our research is to reveal mechanisms affecting glioblastoma pathogenesis. Netrins are secreted extracellular matrix components, initially identified as axon guidance molecules.  In clinical samples of glioblastoma, netrin-1 expression is elevated. In vitro, netrin-1 promotes glioma cell survival, proliferation and invasion (Ylivinkka et al., 2013). To determine the proteins mediating the effects of netrin-1, we have carried out TAP-TAG pulldown assays in glioblastoma cells. We have identified numerous cell surface receptors associating with netrin-1. Among the interactions, we have identified Notch signaling pathway components. Netrin-1 induces Notch signaling, and the induced signaling is accompanied by increased glioma cell invasion.

Accordingly, we have carried out an analysis of netrin-4 expression, functions and binding receptors in glioblastoma cells. Netrin-4 expression is slightly decreased upon glioma progression. However, the expression of netrin-4 is needed for the glioma cell proliferation and migration. The positive effects of Netrin-4 on cell proliferation are mediated by beta4 integrin. High concentrations of netrin-4 lead to decreased cell proliferation, and this effect is mediated by classical netrin receptor unc5b. Our results have identified a mechanism where glioma cells reduce netrin-4 expression to decrease its inhibitory effects. In parallel, the expression of integrin beta-4 is upregulated to sensitize the cells to low concentrations of netrin-4.

References:

Vehviläinen, P., Koli, K., Myllärniemi M., Lindholm, P., Soini, Y., Salmenkivi, K., Kinnula V.L. and Keski-Oja, J.: Latent TGF-beta binding proteins (LTBPs) -1 and -3 differentially regulate TGF-beta activity in malignant mesothelioma. Hum. Pathol. 42: 269-78, 2011.

Chan, S.H., Yee Ko, J.M., Chan, K.W., Chan, Y.P., Tao, Q., Hyytiäinen, M., Keski-Oja, J., Law, S., Srivastava, G., Tang, J., Tsao, S.W., Chen, H., Stanbridge, E.J. and Lung, M.L.: The ECM protein LTBP-2 is a suppressor of esophageal squamous cell carcinoma tumor formation but higher tumor expression associates with poor patient outcome. Int. J. Cancer 129: 565-573, 2011.

Tamminen, J.A., Myllärniemi, M., Hyytiäinen M., Keski-Oja, J. and Koli, K.: Asbestos exposure induces alveolar epithelial cell plasticity. J. Cell. Biochem. 113: 2234–2247, 2012.

Hu, Y., Ylivinkka, I., Chen, P., Li., L., Hautaniemi, S., Keski-Oja, J. and Hyytiäinen, M.: Netrin-4 promotes glioblastoma cell proliferation via integrin β4 signaling. Neoplasia 14: 219–227, 2012.

Leppäranta, O., Sens, C., Salmenkivi, K., Kinnula, V.L., Keski-Oja, J., Myllärniemi, M., and Koli, K.: Regulation of TGF-β storage and activation in the human idiopathic pulmonary fibrosis lung. Cell Tissue Res. 348: 491-503, 2012.

Chen, H., Ko, J.M., Wong, V.C., Hyytiäinen, M., Keski-Oja, J., Chua, D., Nicholls, J.M., Cheung, F.M., Lee, A.W, Kwong, D.L., Chiu, P.M., Zabarovsky, E.R., Tsao, S.W., Tao, Q., Chan, S. H. Stanbridge, E.J., and Lung, M.L.: LTBP-2 confers pleiotropic suppression and promotes dormancy in a growth factor permissive microenvironment in nasopharyngeal carcinoma. Cancer Letters, 325: 89-98, 2012.


Ylivinkka, I., Hu, Y., Chen, P., Hautaniemi, S., Rantanen, V., Nyman, T.A., Keski-Oja, J. and Hyytiäinen, M.: Netrin-1 induced activation of Notch signaling mediates glioblastoma cell invasion. J. Cell Sci. 126, 2459-2469, 2013.

159. Makarov, A., Nyman, T.A, Ylivinkka, I., Hyytiäinen M, and Keski-Oja, J.: Ephrin-As, Eph receptors and integrin α3 interact and colocalize at membrane protrusions of U251MG glioblastoma cells. Cell Biol. Int. 37, 1080-1088, 2013.