Chemo‐mechanistic multi‐scale model of a three‐dimensional tumor microenvironment to quantify the chemotherapy response of cancer

Exploring efficient chemotherapy would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. As in vivo experimental methods are unable to isolate or control individual factors of the TME, and in vitro models often cannot include all the contributing factors, some questions are best addressed with mathematical models of systems biology. In this study, we establish a multi‐scale mathematical model of the TME to simulate three‐dimensional tumor growth and angiogenesis and then implement the model for an array of chemotherapy approaches to elucidate the effect of TME conditions and drug scheduling on controlling tumor progression. The hyperglycemic condition as the most common disorder for cancer patients is considered to evaluate its impact on cancer response to chemotherapy. We show that combining antiangiogenic and anticancer drugs improves the outcome of treatment and can decrease accumulation of the drug in normal tissue and enhance drug delivery to the tumor. Our results demonstrate that although both concurrent and neoadjuvant combination therapies can increase intratumoral drug exposure and therapeutic accuracy, neoadjuvant therapy surpasses this, especially against hyperglycemia. Our model provides mechanistic explanations for clinical observations of tumor progression and response to treatment and establishes a computational framework for exploring better treatment strategies. A novel strategy of systems biology combining tumor biology and promoter engineering for modeling solid tumor dynamics and progression in its microenvironment and quantification of cancer response to chemotherapy was developed in this study. This systems biology model provides potential applications in tumor biology and oncology through an engineered pathway to achieve high yield and productivity. By using this strategy, a comprehensive perspective of cancer behavior and anti‐cancer therapeutic response was obtained.