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Meme Kanseri Hücreleri Tarafından Üretilen Fibronektinin Miyeloid Hücre Karakteri Üzerine Etkisi

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Gürcan Tunalı - Doktora Tezi (12.36Mb)
Tarih
2019
Yazar
Tunalı, Gürcan
Ambargo Süresi
6 ay
Üst veri
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Özet
Basal-like breast cancer (BLBC) possess high capacity to regulate inflammation and identified with high-level myeloid cell infiltration. Extracellular matrix components produced by tumor cells, e.g. fibronectin (FN), can support myeloid cells’ maturation. Macrophages in the tumor gain immunosuppressive characters with the contribution of the STAT3 transcription factor. Tumor-associated macrophages (TAM) contribute to the formation of inflammatory microenvironment. EDA fragment released by elastase-2-mediated cleavage of FN can stimulate TLR4 receptor. This study is based on the hypothesis that the factors produced by BLBC cells regulate STAT3 activity in myeloid cells and interleukin-1β (IL-1β) production, which plays an important role in the inflammatory character of the tumor microenvironment, and FN/FN-EDA, elastase and TLR4 axis provide the contribution of inflammation in breast cancer. Peripheral blood monocytes and myeloid leukemia cell lines, as immature myeloid cell model, were used. Phenotypic (CD11b, CD11c, CD14, CD40) and functional (production of reactive oxygen species, chemotaxis and phagocytosis capacity, stimulation of CD4+ T cell proliferation) differentiation parameters were evaluated. STAT3 activation, TLR4 levels, IL-1β and elastase-2 production were investigated in myeloid cells incubated with BLBC cells’ supernatants. IL-1β, TLR4, elastase-2 and NF-kappa B stimulation by myeloid cell were evaluated following STAT3 activation. In the presence of pro-inflammatory cytokines, total FN and FN-EDA levels were evaluated in breast cancer cells. The effect of FN-EDA on TLR4 and NF-kappa B activity was investigated. Factors produced by BLBC cells induced phenotypic and functional maturation in myeloid cells. In myeloid cells with increasing chemotaxis capacity, STAT3 activation was stimulated by factors produced by BLBC. IL-1β secretion increased in myeloid cells with high STAT3 activity. Total FN and FN-EDA isoform was highly produced by IL-1β-induced BLBC cells. BLBC cell supernatants and FN-EDA were synergistically promoted IL-1β production from monocytes and stimulated NF-kappa B activity. The effect on IL-1β production and NF-kappa B activity were associated with STAT3 activation. Either secreted by BLBC cells or recombinant FN-EDA, when treated with neutrophil supernatants containing high levels of elastase-2, did not stimulate TLR4 and NF-kappa B activity. In conclusion, a positive feedback mechanism between BLBC and monocytes through STAT3/IL-1β/FN molecules supports chronic inflammation in the tumor microenvironment. Targeting STAT3, IL-1β and FN in BLBC may modulate inflammatory microenvironment in favour of cancer therapy. The development of treatment strategies for BLBC should take into account the presence of this positive feedback mechanism.
Bağlantı
http://hdl.handle.net/11655/6961
Koleksiyonlar
  • Kanser Enstitüsü Tez Koleksiyonu [62]
Künye
Tunalı G. Meme kanseri hücreleri tarafından üretilen fibronektinin miyeloid hücre karakteri üzerine etkisi. Hacettepe Ünversitesi Sağlık Bilimleri Enstitüsü, Tümör Biyolojisi ve İmmünolojisi Programı Doktora Tezi, Ankara, 2019.
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