BACR 19: Role of CCR7 in head and neck cancer.
1Institute of cancer therapeutics, University of Bradford, Bradford, UK
Metastasis is a leading cause of cancer related deaths. The chemokine system has emerged as a key player in the metastatic process, specifically in organ specific metastasis. In particular, the CCL19/CCL21/CCR7 chemotactic axis has been implicated in the lymph node metastasis of different tumour types. Since lymphatic invasion is a critical step in the metastatic process, these observations identify this chemotactic axis as an important therapeutic target in cancer.
Currently, many aspects on the role of CCR7 in cancer remain unclear. There is little known about the regulation of CCR7 expression in the literature and how it affects its expression and functionality. In addition, antagonism of CCR7 receptor could provide valuable information in its role of cancer progression that might lead to discovery of a novel therapeutic target that could have a strong impact on the survival rate of patients
We used immunofluorescence, flow cytometry and Immunohistochemistry to show expression of CCR7 on head and neck (OSC-19, Fadu, SCC-4, Detroit 562 and A-253) cell lines.We then invistigated the functionality of CCR7 on OSC-19 cell line by Ca2+ flux assay and the role of CCL21 and CCL19 on proliferation, invasion and migration. In addition, we also studied the effect of hypoxia and nutrient deprivation on CCR7 expression and its response to CCL21 and CCL19. In addition, we used ICT13069, a novel CCR7 small molecule antagonist, in a number of in vitro assays (wound healing, transwell and 3D spheroid invasion assay) to investigate the therapeutic potential of modulating this axis in head and neck cell lines.
We showed high expression of CCR7 in head and neck cell lines that was upregulated under hypoxia. We then confirmed that CCR7 activation by CCL21/ CCl19 cause an increase of Ca2+ flux, cell migration and invasion . However, there was no increase in proliferation in response to CCL21 or CCL19. Subsequently, we showed that CCR7 antagonism by ICT13069 decreased cell migration and invasion in response to CCL21 and CCL19.
Our results validate CCR7 as a promising therapeutic target in preventing metastasis and improving patient survival.