Examining the Impact of TGFβ-1, IL-6 and HGF on Metastatic Pathways and the Use of Oseltamivir Phosphate as a Novel Treatment Strategy
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Authors
Naeeni, Leili Baghaie
Date
2024-06-10
Type
thesis
Language
eng
Keyword
Cytokines , Cancer , Metastasis , Oseltamivir Phosphate
Alternative Title
Abstract
As cancer incidences continue to rise, it is becoming more necessary to understand the underlying mechanisms of metastasis. Management of metastatic cancer poses challenges in treatment, and in many who undergo surgical resection or neoadjuvant therapy, cancer recurrence occurs with a much stronger ability. As a result, the overwhelming burden of cancer-related deaths is associated with metastasized tumours. Of particle concern are colorectal, breast, and pancreatic cancers, which have high rates of metastasis associated with secondary lesions in the lungs, liver and brain.
Surgical resection remains the most used therapy; however, it is not a perfect system. Several studies have demonstrated that the primary tumour and distant micrometastases can communicate with each other through various signals. When the tumour is handled, an immediate rise in circulating tumour cells is noted alongside several postoperative changes that allow the cells to survive immune detection. One of these associated signals may be from the inflammatory cytokines released following surgical resection as part of the wound healing response. These signals may also be inducing metastasis through phenotypic changes linked to epithelial-mesenchymal transition (EMT).
Here, we demonstrate that the inflammatory cytokines TGFβ-1, IL-6, and HGF upregulated mesenchymal markers (N-cadherin, Vimentin, ALDH-1) while simultaneously decreased the epithelial marker E-cadherin in pancreatic, breast, and colorectal cancer cells. These cytokines also increased the wound-healing response in pancreatic cells and the formation of cellular communication networks in pancreatic and breast cancer cells. Furthermore, we elucidate that the receptors of these cytokines colocalized with Neu-1 and cytokine-receptor binding increased the neuraminidase activity believed to be associated with downstream cell signalling involved in cell migration, proliferation, and metastasis. Lastly, we investigated the impact of the inhibition of Neu-1 using oseltamivir phosphate and highlighted its role in decreasing the wound healing response and tunnelling nanotube formation. The findings presented here suggest that these inflammatory cytokines may facilitate metastasis and propose targeting them as a novel anti-metastatic treatment.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NonCommercial-NoDerivatives 4.0 International