Chemokines are a family of chemotactic cytokines that play a multifaceted role in
human biology. Chemokine receptor CCR7, activated by its ligands CCL19 &
CCL21, is known to play a significant role in cancer metastasis. In view of the wider
roles that chemokines play in the biology of the cell, we hypothesised that CCR7
could influence cancer progression through other mechanisms in particular
increased proliferation and/or increased chemo- and radioresistance, and whether
these effects may have a physiological/clinical relevance. Interestingly, CXCR4
involvement in cancer recurrence, metastasis and proliferation is already well
established. Thus, it was used as a point of reference to compare whether CCR7
axis effect on cancer proliferation and chemoresistance is similar to that observed
in CXCR4 axis.
It is proven that hypoxia is a driving factor in increased CCR7 expression. This
study shows that CCR7 expression is upregulated as a response to a number of
other stress factors, in particular that caused by different chemotherapeutic
treatments. In addition, we showed that CCL21, one of the two endogenous
ligands for CCR7 is similarly produced under these conditions
We used several techniques to establish the expression and functionality of CCR7 and CXCR4 in different cancer cell lines. We then showed that activation of the
CCR7 axis by physiologically relevant concentrations of CCL21 induces cancer
cell proliferation and chemo- and radio-resistance. Furthermore, these effects are
abrogated by small molecule antagonists (ICT13069), neutralizing monoclonal
antibody, or CCR7 knockdown.
Our findings support the hypothesis that antagonising CCR7 receptor will not only
inhibit cancer metastasis, as it is well-illustrated in the literature, but it would also
lead to alternative therapeutic approaches as well as potential clinical endpoints. / University of Tobruk, and the Ministry of Higher Education of Libya
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/19859 |
| Date | January 2021 |
| Creators | Salem, Anwar S.A.S. |
| Contributors | Afarinkia, Kamyar, Vinader, Victoria, Shnyder, Steven |
| Publisher | University of Bradford, Institute of Cancer Therapeutics. School of Pharmacy. Faculty of Life Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
Page generated in 0.0025 seconds