Abstract
Tumor progression is affected by the tumor microenvironment. The tumor microenvironment (TME) is a complex population, including tumor cells and various immune cells. The tumor-associated components in TME are highly heterogeneous and could contribute to cancer development and poor prognosis.The pathogens within the tumor inflammatory microenvironment can colonize different solid tumour regions. The infecting bacteria, which can be classified as intratumoral bacteria (IB; within tumors) and extratumoral bacteria (EB; outside tumors), are linked to cancer development, especially in the digestive and urinary systems, and can cause chronic inflammation and lead to cancer-promoting effects. Although photodynamic therapy (PDT) is a promising modality to kill cancer cells and bacteria with high spatiotemporal precision, the low penetration of light limits its potential in deep tumor therapy. Furthermore, current 2D culture-based preclinical in vitro models failed to reflect the complexity of the tumor microenvironment.
Furthermore, components of the TME, such as tumor-associated macrophages (TAMs), influence tumor progression. The specific polarization and phenotypic transition of TAMs in the tumor microenvironment lead to two-pronged impacts that could promote or hinder cancer development and treatment. To mimic the TME within inflammatory and develop the in vitro tumor models based on a microfluidic chip, and to develop novel therapy strategies towards tumor inflammation, this thesis will be elaborated from three main aspects:
1) The in vitro tumor inflammatory models in studying the effects of distributions of bacteria on bladder cancer progression. We developed a microfluidic platform to analyze the influence of bacterial distribution on bladder cancer progression under defined conditions using uropathogenic Escherichia coli. This was achieved by establishing coating (CT) and colonizing (CL) models to simulate IB and EB's different invasion and colonization modes in tumor tissues. We demonstrated that both EB and IB induced closer cell-cell contacts within the tumor cluster, but cancer cell viability was reduced only in the presence of IB. Interestingly, cancer stem cell counts increased significantly in the presence of EB. These outcomes were due to the formation of extracellular DNA-based biofilms by EB. Triple therapy of DNase (anti-biofilm agent), ciprofloxacin (antibiotic), and doxorubicin (anti-cancer drug) could effectively eradicate biofilms and tumors simultaneously. The preclinical proof-of-concept in this study provides insights into how bacteria can influence tumor progression and facilitate future research on anti-biofilm cancer management therapies.
2) Developing bacterial targeted photosensitizers with aggregation-induced emission to promote chemotherapy for treating cancer inflammation based on a microfluidic platform. This part of the study developed an unprecedented synergistic combinatorial strategy of PDT and chemotherapy by co-delivering a bacterial-targeted photosensitizer with aggregation-induced emission (AIE) property and an anti-cancer drug, doxorubicin. The theragnostic system could selectively visualize and rapidly kill EB using a microfluidic-based 3D bladder cancer model. The effect of combinatorial therapy was synergistic, resulting in improved efficacy, as evidenced by at least a 2.5-fold reduction in the half-maximal inhibitory concentration of doxorubicin. Validation using a fish wound infection model further demonstrated the feasibility of AIE photosensitizers for efficient fluorescence imaging-guided PDT in vivo. We proposed a robust AIE PDT/chemotherapy strategy with great potential for rapid and concurrent treatment of bacterially infected cancer patients.
3) The 3D multi-faceted tumor inflammatory model incorporating tumor-associated macrophages. We further developed a novel microfluidic multi-faceted bladder tumor model (PIEBTAM) incorporating TAMs and cancer cells to evaluate the impact of bacterial distribution on immunomodulation within the tumor microenvironment in vivo. We demonstrated for the first time that biofilm-induced inflammatory conditions within tumors promoted the transition of macrophages from a pro-inflammatory M1-like to an anti-inflammatory/pro-tumor M2-like state. Consequently, multiple roles and mechanisms by which biofilms promote cancer by inducing pro-tumor phenotypic switch of TAMs were identified, including cancer hallmarks such as reducing susceptibility to apoptosis, enhancing cell viability, and promoting epithelial-mesenchymal transition and metastasis. Furthermore, biofilms formed by extratumoral bacteria could shield tumors from immune attack by TAMs, which could be visualized through various imaging assays in-situ. This part of the study sheds light on the underlying mechanism of biofilm-mediated inflammation on tumor progression. It provides new insights into combined anti-biofilm therapy and immunotherapy strategies in clinical trials.
| Date of Award | 17 Aug 2023 |
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| Original language | English |
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| Supervisor | Bee Luan KHOO (Supervisor) |