Investigating tumour micro environment dynamics based on cytokine-mediated innate-adaptive immunity

[摘要] ENGLISH ABSTRACT : Cancer is a leading cause of death worldwide, yet much is still unknown about its mechanismof establishment, recurrence cycle and destruction. It is known that the successivealterations that occur in a set of specific genes in the cell can trigger carcinogenesiswhich is the process of transforming a normal cell into a cancer cell. This process isusually done in the following three steps: initiation, proliferation and progression. Cancerstem cells are regulated by complex interactions with the components of the tumourmicro-environment (TME) through networks of cytokines and growth factors. Thus, understandingthe role of cytokines can be crucial in the fight against cancer in the contextof improving diagnostic, prognostic and therapeutic strategies. Several studies have investigatedtumour-immune cell dynamics. However, some of these studies are mostlylimited to cells that directly kill cancer cells, such as natural killer (NK) and cytotoxic Tlymphocytes (CTLs), and they do not explicitly integrate cytokines in the cell dynamics.Furthermore, none of these studies has combined cellular-level mathematical modelswith molecular-level/signalling pathway analysis, to predict biological processes andenriched pathways associated in cancer disease.In this study, a new non-linear mathematical model integrating cytokines in the activation of innate and adaptive immunity was developed to predict the role of cytokinesin tumour and immune cell dynamics. Our work complements the role Th2 and Th17cells play in inhibiting the proliferation of M1 macrophages, CTLs, NK and Th1 cells.Numerical analysis of the model suggested that, lack of TGF-β inhibition effect resultedin tumour clearance, however, the immune cells grew without bound and exceeded thecarrying capacity of immune cells. TGF-β is responsible for promoting tumour progression,tumour proliferation and limiting the effectiveness of type 1 immune response. Inaddition, we established the necessary conditions for tumour clearance by varying parametervalues. For an immune (effector) cell to be activated from a resting state, its geneexpression must be altered. We used datasets from The Cancer Genome Atlas (TCGA)and an expression level-based model to identify genes specific to cancer patients contributingto the regulation of cytokines in the context of the breast cancer disease. Wepredicted differentially expressed genes (DEGs) associated with breast cancer diseaseusing a permutation-based significance analysis of micro-array (SAM) approach. Usinga selected list of the DEGs, we determined significant pathways and enriched biologicalprocesses associated with breast cancer disease. Some of the identified significant biologicalpathways and processes, happened to be associated with cell differentiation orcell division and the predicted over-expressed genes in tumour samples may contributeto the proliferation of cancer. These genes, pathways and biological processes can befurther assessed to check for their suitability as targets for breast cancer disease.

[发布机构] Stellenbosch University