tribute considerably to observed differences in cell motility. In support, we did not observe any differences in the surface expression of CD44 between the mock-transfected and ADAM17-silenced MC38CEA cells as evaluated by flow cytometry. ADAM17 is also a sheddase for EpCAM, homophilic cell adhesion molecule, often highly expressed on carcinoma cells. It has been shown that the loss of EpCAM SCD-inhibitor supplier weakens cell-cell interactions contributing to increased migratory potential of the cells. We disregarded EpCAM as a molecule decisive for the differences in MC38CEA motility observed upon ADAM17silencing because the analysis of recorded cell movements indicated 
that impaired migration was characteristic even for single cells with diminished ADAM17 activity. To sum up, at this stage of research we are unable to indicate any ADAM17-dependent events, other than shedding of NRG-1, that may affect migratory potential of MC38CEA cells. How does ADAM17 influence anti-tumor immune response All IFNc and the majority of TNF in MC38CEA tumors are produced by infiltrating immune cells, thus the differences in their concentrations between mock-transfected and ADAM17-silenced tumors must reflect differences in the subpopulations of immune cells or their activity. It remains unclear which of ADAM17 substrates expressed by MC38CEA cancer cells could trigger changes in immune response. Tumor associated antigens could fulfill this role as ADAM17-mediated shedding of TAA might result in weaker recognition of tumor cells by the immune system. However, so far only one such antigen, namely MUC1, has been shown to be susceptible to ADAM17-mediated shedding and CEA, the model TAA expressed by MC38CEA, has not been released more efficiently from mock-transfected than from ADAM17- silenced cells. The potential importance of other immune system-related ADAM17 substrates as IL-6R or MIC-A/B, the ligands of NKG2D receptors, in murine tumor development is questionable because of species specificity. ADAM17 is a major sheddase for ADAM17 affects MC38CEA angiogenesis We have observed enhanced angiogenesis in the mocktransfected but not in ADAM17-silenced MC38CEA. This could ADAM17 in Tumor Development human- but not 11335724 for mouse IL-6R and MIC-A/B are not expressed in mice at all. The identification of the ADAM17 substrate present in MC38CEA that may influence anti-tumor immune response will be a priority for the future research. Conclusions Throughout the last decade ADAM17 has been recognized as a new, promising target for cancer therapy. A number of ADAM17 selective inhibitors in form of either small molecule compounds or the specific anti-ADAM17 antibody fragments are presently being 24074843 developed. Such therapeutic approaches are directed against tumors which drive their proliferation in an autocrine manner via EGF family members. Our results indicate that ADAM17-directed therapies could be applicable towards a much wider panoply of cancers. untreated or were stimulated for 10 min with rmHis-NRG1b1. Protein from cell lysates were subjected to Western blotting and probed with anti-ErbB2-P. Data are representative of two independent experiments. MCF-7 cells were plated in 96-well plate. Next day the medium was changed for DMEM without FCS and to some wells rmHis-NRG-1b1 was added at different concentrations. After 4 days MTT assay was performed. Data are presented as relative A545 absorbance measurements with the value obtained for control cells taken as 1. Data are from a single exper
