Mechanisms involved in tumor progression
S100A4 in invasion and metastasis
The biological function and molecular mechanisms by which S100A4 exerts its putative metastasis-promoting effects is largely unknown, and the protein is most likely involved in several aspects of tumor progression [Boye and Mælandsmo, Am J Pathology, 2010]. One possible explanation for the multifunctionality is the fact that the protein is localized in different subcellular compartments and probably has different binding partners in the cytoplasm, the nucleus and in the extracellular space. In addition, the protein might also have different posttranslational modifications.
In the cytoplasm S100A4 co-localizes or co-sediments with different cytoskeletal proteins (actin, non-muscle myosin, and non-muscle tropomyosin), implying a possible role in cell motility and invasion. The protein has a wide variety of extracellular effects, including sensitization of osteosarcoma cells to IFN-g mediated apoptosis [Pedersen, BMC Cancer, 2004], stimulation of angiogenesis [Ambartsumian, Oncogene, 2001; Semov, JBC, 2005] and invasion through induction of matrix metalloproteinases [Schmidt-Hansen, Oncogene, 2004] and thereby promotion of metastasis [Schmidt-Hansen, JBC, 2004]. While strong data indicate that release of S100A4 into the tumor microenvironment is a crucial factor in the metastatic process. the signal transduction pathways responsible for S100A4-induced effects are only starting to become unraveled.
Extracellular effects of S100A4
In a previous study we demonstrated S100A4-induced activation of the transcription factor NFxB through the classical NFkB pathway in a subset of human cancer cell lines (Boye, Int. J. Cancer, 2008).. The intracellular signal transduction events leading to IKK phosphorylation and subsequent degradation of IkBa are poorly characterized. We seek to identify S100A4-induced signal transduction mechanisms upstream of the IKK complex. Such knowledge may provide important insight into S100A4 mediated signalling and thereby reveal possible targets for intervention. For more information contact Ida Grotterød or Kjetil Boye.
S100A4 and proteases
Central metastatic properties of cancer cells imply the aquirement of invasive properties to be able to degrade and invade into surrounding mesenchyme. Previous research by us and others, have demonstrated an association between the expression of S100A4, activity of matrix metalloproteinases (MMPs) and cellular metastatic capacity [Bjornland, K. et al. Cancer Res. 1999]. Furthermore, this regulation was suggested to involve NF-κB [Mathisen et al. Clin. & Exp. Metastasis, 2003]. The importance of the MMP-system have been shown to correlate with in vitro invasiveness and clinical outcome in several adult malignancies. Recently we found extracellular S100A4 to upregulate the metastatic associated protein osteopontin (OPN), followed by induced migration and invasion. Downstream of OPN, MMP-13, uPA and uPAR were identified as key proteases involved in this S100A4-induced invasion [Berge et al. Int. J. Cancer, 2011]. We propose S100A4 to enhance invasive ability by stimulating activation of proteolytic programs. We aim to identify inhibitors targeting key mechanisms involved in S100A4-stimulated invasion, and unravel their potential as anti-metastatic agents. For more information contact Gisle Berge.
S100A4 as a prognostic factor
A number of reports have demonstrated that S100A4 expression could be used as a prognostic factor in a variety of different cancer types. We have shown that S100A4 protein expression was correlated with disease-free survival in melanoma patients [Andersen, Mod Pathology, 2004]. In addition, we have demonstrated that S100A4 is also expressed in the nuclei of tumor cells from patients with colorectal cancer, and that the nuclear expression of S100A4 correlates with tumor stage [Flatmark, J Pathol, 2003]. Nuclear expression was further shown to be a robust prognostic factor in this patient cohort, and the prognostic significance was largely confined to stage II patients [Boye, Eur J cancer, 2010]. We are currently validating these results in a separate patient cohort. In the same tumor panel, we have shown that the extracellular matrix metalloproteinase inducer (EMMPRIN) was associated with expression of S100A4, and that EMMPRIN was a strong prognostic factor independent of S100A4 [Boye, Br J Cancer, 2012]. The expression of S100A4 has also been examined in primary tumors from a panel of non-small cell lung cancer patients, and in addition the S100A4-regulated proteins ephrin-A1 and osteopontin was investigated [ud, BMC Cancer, 2012]. The associations between expression of these proteins and patient outcome are currently under investigation. Previously, we have also developed an immunofluorometric assay for analysing S100A4 in serum, plasma or other body fluids [Flatmark, Tumor Biol, 2004]. Unfortunately, the high expression level of S100A4 in both red and white blood cells precluded the use of S100A4 as a tumor marker in serum or plasma.