Stress alleviation strategy in cancer treatment: Insights from a mathematical model

Abstract

Tumors generate mechanical forces during growth and progression, which are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. Tumor vessels—while nourishing the tumor—are usually leaky and tortuous, which further decreases perfusion. Consequently, vessel leakiness together with vessel compression causes a uniformly elevated interstitial fluid pressure that hinder drug delivery and compromise therapeutic outcomes. To enhance treatment efficacy, stress alleviation and vascular normalization strategies have been developed to improve tumor perfusion and drug delivery. Stress alleviation strategy aim to decrease solid stress levels and reopen compressed blood vessels leading to improve perfusion and drug delivery. On the other hand, vascular normalization strategy aims to restore the abnormalities in tumor vasculature by decreasing vessel leakiness and thus enhance drug efficacy. Here, we employed a mathematical model to study the stress alleviation strategy using published experimental data and performing new experiments in mice bearing breast tumors. Specifically, we accounted for variations in tumor hydraulic conductivity, elastic modulus and swelling related to changes in extracellular matrix components induced by the anti-fibrotic and stress alleviating drug, tranilast. We showed that alleviation of mechanical stresses in tumors reduces the tumor interstitial fluid pressure to normal levels and increases the functionality of the tumor vasculature resulted in improved drug delivery and treatment outcome. Finally, we used model predictions to show that vascular normalization can be combined with stress alleviation to further improve therapeutic outcomes.