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

Amima, Innocenter Moraa (2018-03)

Thesis (MSc)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT : Cancer is a leading cause of death worldwide, yet much is still unknown about its mechanism of establishment, recurrence cycle and destruction. It is known that the successive alterations that occur in a set of specific genes in the cell can trigger carcinogenesis which is the process of transforming a normal cell into a cancer cell. This process is usually done in the following three steps: initiation, proliferation and progression. Cancer stem cells are regulated by complex interactions with the components of the tumour micro-environment (TME) through networks of cytokines and growth factors. Thus, understanding the role of cytokines can be crucial in the fight against cancer in the context of improving diagnostic, prognostic and therapeutic strategies. Several studies have investigated tumour-immune cell dynamics. However, some of these studies are mostly limited to cells that directly kill cancer cells, such as natural killer (NK) and cytotoxic T lymphocytes (CTLs), and they do not explicitly integrate cytokines in the cell dynamics. Furthermore, none of these studies has combined cellular-level mathematical models with molecular-level/signalling pathway analysis, to predict biological processes and enriched 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 cytokines in tumour and immune cell dynamics. Our work complements the role Th2 and Th17 cells 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 resulted in tumour clearance, however, the immune cells grew without bound and exceeded the carrying capacity of immune cells. TGF-β is responsible for promoting tumour progression, tumour proliferation and limiting the effectiveness of type 1 immune response. In addition, we established the necessary conditions for tumour clearance by varying parameter values. For an immune (effector) cell to be activated from a resting state, its gene expression 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 contributing to the regulation of cytokines in the context of the breast cancer disease. We predicted differentially expressed genes (DEGs) associated with breast cancer disease using a permutation-based significance analysis of micro-array (SAM) approach. Using a selected list of the DEGs, we determined significant pathways and enriched biological processes associated with breast cancer disease. Some of the identified significant biological pathways and processes, happened to be associated with cell differentiation or cell division and the predicted over-expressed genes in tumour samples may contribute to the proliferation of cancer. These genes, pathways and biological processes can be further assessed to check for their suitability as targets for breast cancer disease.

AFRIKAANSE OPSOMMING : Kanker is wereldwyd een van van die grootste oorsake van dood en steeds is daar nog baie onbekend oor die meganisme van onstaan, herverskynings siklus en vernietiging. Dit is bekend dat die opeenvolgende veranderinge wat in ’n stel spesifieke gene in die sel voorkom, kan karsinogenese veroorsaak, die proses waardeur ’n normale sel in ’n kankersel omskep word en gewoonlik in die volgende drie stappe gedoen word: inisiasie, proliferasie en progressie. Kankerstemselle word gereguleer deur komplekse interaksies met die komponente van die tumor mikro-omgewing deur netwerke van sitokiene en groeifaktore. Die tumor mikro-omgewing (TME) bestaan uit verskillende seltipes, insluitende aangebore en aanpasbare immuun selle, en sitokiene wat die aktivering of inhibisie van die immuun selle en proliferasie van tumorselle reguleer. Om die rol van sitokiene te verstaan, kan ’n belangrike rol speel in die stryd teen kanker. Verskeie navorsingsprojekte het die dinamika van hierdie sitokiene ge-ondersoek in die konteks van kanker om die evolusie van kanker te verstaan vir die verbetering van diagnostiese, prognostiese en terapeutiese strategieë. Hierdie studies is egter meestal beperk tot selle wat kankerselle direk doodmaak, soos natuurlike vernietigers (NV) en sitotoksiese T limfosiete (CTLs of CD8 + T) selle, en hulle eksplisiet nie sitokien-gemedieerde aangebore aanpassingsimmuniteit in ’n tumor dinamika. Verder het geen van hierdie studies selektiewe wiskundige modelle gekombineer met molekulêre-vlak / seinweganalise, biologiese prosesse en verrykde weë wat verband hou met kankersiekte, voorspel nie. In hierdie studie is ’n nuwe nie-lineêre wiskundige model wat sitokien-gemedieerde aangebore aanpassingsimmuniteit integreer ontwikkel om die sitokien-gemedieerde tumor en immuun seldinamika te voorspel. Numeriese analise van die model het voorgestel dat ’n gebrek aan TGF-β remmings-effek tot tumorruiming gelei het, maar die immuunselle het sonder gebind gegroei en die dravermoeë oorskry. Daarbenewens het ons die nodige toestande vir tumor verwydering deur verskillende parameterwaardes vasgestel. Vir ’n immuun (effektor) sel wat vanuit ’n rustende toestand geaktiveer moet word, moet sy geen uitdrukking verander word. Ons gebruik datastelle van The Cancer Genome Atlas (TCGA) en ’n uitdrukkingsvlakgebaseerde model om gene wat spesifiek vir kankerpasie¨nte is, te identifiseer wat bydra tot die regulering van sitokiene in die konteks van die borskanker siekte. Ons het differensieel uitgedrukte gene (DUG) voorspel wat verband hou met borskanker siekte deur gebruik te maak van ’n permutasiegebaseerde betekenisanalise van mikro-skikking benadering. Deur gebruik te maak van ’n geselekteerde lys van die DUG, het ons belangrike paaie en verrykde biologiese prosesse geassosieer met borskanker bepaal. Sommige van die geïdentifiseerde beduidende biologiese weë en prosesse, sowel as oor-uitgedruk gene, wat waargeneem word geassosieer met sel differensiasie of seldeling, kan bydra tot die proliferasie van kankerselle. Hierdie weë en oor-uitgedruk gene kan verder geassesseer word om na te gaan of hulle geskik is as teikens vir die borskanker siekte.

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