The role of VEGF-R3 pathway switch induced by M2-like tumour associated macrophages on the development of a pro-metastatic phenotype in papillary thyroid carcinoma
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2020
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Abstract
Cancer is the second leading cause of death globally. The major determinant of mortality in cancer patients is the presence of distant organ metastasis, and one of the most important clinical risk factors is the compromise of locoregional lymph nodes by cancer cells (lymph nodes metastasis or LNM). The pathogenesis of LNM includes many processes, and one of the main focuses of translational research in oncology has been the understanding of the biological mechanisms underlying those processes to develop novel diagnostic, prognostic and therapeutic clinical tools.
Among solid tumours, Papillary Thyroid Cancer (PTC) is an excellent model to study early events in LNM development, mainly due to three arguments: a significant number of samples can be potentially studied in a wide spectrum of the disease, from non-metastatic to widely invasive tumours; PTC is a well-differentiated tumour, so being possible to study early events in the cell transformation from a non-metastatic to a pro-metastatic phenotype; and PTC spreading occurs by lymphatic system in 95% of metastatic cases.
Previous background suggests that VEGF-R3/VEGF-C system could be an important signalling pathway by which epithelial tumours could develop a pro-metastatic architecture, not only by inducing the development of lymphatic vessels, but also by promoting the transformation of tumour epithelial cells to a pro-metastatic phenotype. Furthermore, M2-like tumour associated macrophages (M2-TAMs) seem to be key players in the pro-metastatic transformation as well. However, no previous studies have provided evidence suggesting that both, M2-TAMs and the VEGF-R3 pro-metastatic switch, could be associated. From prior results of our group, we postulate that, in PTC, M2-TAMs induce a VEGF-R3 pro-metastatic switch at the epithelial tumour cell, promoting the transformation toward a pro-metastatic phenotype. This work takes over two emerging questions aimed to confirm this hypothesis: which TAM subtype (M1-like or M2-like cells) induce a VEGF-R3 pro-metastatic switch in PTC?, and does the VEGF-R3 pro-metastatic switch activate biological mechanisms that lead to a pro-metastatic phenotype in epithelial tumour cells?
Our results showed that conditioned medium from M2-TAM induces the overexpression of VEGF-R3 in TPC-1 (a non-metastatic PTC cell model) but not in B-CPAP (a metastatic PTC cell model), which suggest that the switch is a pre-metastatic event. Furthermore, the receptor is functionally active when cells are treated with VEGF-C (the specific ligand of VEGF-R3), inducing pro-metastatic morphological changes, the overexpression of genomic regulator of epithelial-to-mesenchymal transition, and increasing the cell migration capability. Taken together, these results support our working hypothesis; however, further studies are required to better understand the real meaning of this signalling pathway in the LNM development, as well as to determine the mechanisms by which M2-TAMs could induce the switch.
We expect that this work can help, in the future, to a better understanding of the mechanisms underlying the LNM development process in PTC, with potential applications in other solid tumours. Ultimately, this could be useful to generate important advances in diagnostic, prognostic and therapeutic tools, with potential impact in thousands of patients with cancer.
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Tesis (Doctor of Philosophy in Medical Sciences)--Pontificia Universidad Católica de Chile, 2020