The quinoline-3-carboxamides (Q compounds) are a family of small molecules with immunomodulatory functions that have shown efficacy in various murine models of inflammatory diseases. One such compound has demonstrated antitumor effects in murine models. Q compounds bind to S100A9, thereby preventing its ligation to TLR4 and RAGE. S100A9 is a small molecule which has shown to have a role in the establishment of tumors.
In the first part of this thesis (paper I and II), effects of Q compounds during inflammation and cancer, with the focus on myeloid cells has been investigated. While, the focus of the second part (paper III and IV) was on the molecule S100A9. Given the important role of S100A9 during tumorigenesis, the aim was to evaluate the induction and expression of this molecule in vivo in the context of cancer.
In paper I, the effect of the Q compound tasquinimod was evaluated on myeloid cells in a mouse mammary carcinoma tumor. Short-term treatment reduced the accumulation of inflammatory monocytes in the tumors. Depletion of this cell population using an anti-Gr1 antibody resulted in the comparable anti-tumor effect as treatment with tasquinimod during the first few days of tumor growth. Furthermore, long-term tasquinimod treatment reduced myeloid cell expansion in the spleen and made the frequency of precursor cells in the spleen of tumor-bearing mice resemble the naïve state.
In paper II, the effect of the Q compound paquinimod was studied in the spontaneous mouse model of type 1 diabetes (NOD mouse). Paquinimod was given to the NOD mice in drinking water in two different protocols: short-term and longterm treatment and disease development were monitored weekly. Paquinimod induced a dose-dependent reduction in the incidence of diabetes and delayed the onset of disease in both treatment strategies. Interestingly, the treated mice showed less destructed islets in their pancreas. Moreover, the treatment reduced number of splenic inflammatory monocytes and macrophages.
In paper III, the formation of S100A9 homodimer under inflammatory conditions and cancer was investigated. The cellular source of S100A9 homodimer was shown to be CD11b+ Gr1+ cells. Given the fact that in order to act as a DAMP, S100A9 should reach extracellular space, the presence of S100A9 homodimer in the extracellular milieu was shown. The presence of cells expressing only S100A9, and not both S100A8 and S100A9 was shown in spleens of tumor-bearing animals.
In paper IV, the conditions that lead to de novo expression of S100A9 were studied. It was shown that in vivo environment induces S100A9 expression, and this induction is so dependent to this milieu that it was rapidly downregulated after removal of the cells from in vivo. Hypoxia in tumor microenvironment promotes tumor progression and survival and do so mainly by the activity of HIF-1 transcription factor which regulates the expression of many genes involved in the process of tumorigenesis. However, providing hypoxic condition was not sufficient for the induction of S100A9 expression in vitro. Combination of HIF-1α (one component of the transcription factor HIF-1) stabilizer and cytokines did not induce S100A9 expression either.
In summary, in the first part of this thesis, we showed that treatment with Q compounds can reduce recruitment of monocytes to the site of inflammation. Given the important role of these cells in promoting the development of inflammatory diseases and cancer, this observation may partially explain the ameliorating effects of the Q compounds in a broad range of disease models. Furthermore, the second part of the thesis shows the induction of formation of S100A9 homodimer in vivo under inflammatory conditions and cancer, which may create a positive feedback loop for the propagation of inflammatory cascades. Our results also suggest that there is a requirement for a complex interplay of different factors in vivo for induction of S100A9 expression.
- Institutionen för experimentell medicinsk vetenskap
- Ivars, Fredrik, handledare
- Leanderson, Tomas, Biträdande handledare
- Holmberg, Dan, Biträdande handledare
|Tilldelningsdatum||2018 dec. 13|
|ISBN (tryckt)|| 978-91-7619-723-3 |
|Status||Published - 2018|
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund
Name: Gullberg, Martin
Affiliation: Department of Molecular Biology, Umeå University
- Immunologi inom det medicinska området