Abstract
Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider–with the help of a theoretical model–the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various strategies to increase drug exposure time of tumor cells.
Highlights
Cancer is a complex disease which involves phenomena across different scales from the molecular genetic level to the tissue as a whole
We performed 15 simulation runs, producing 15 final states which differ in their initial blood vessel networks
At this point the system is in a state displaying the typical compartmentalization into high micro vascular density (MVD) rim, decreasing micro-vascular density (MVD) toward the tumor center, isolated vessels threading the tumor, necrotic regions associated with unvascularized regions and tumor proliferation confined to its rim
Summary
Cancer is a complex disease which involves phenomena across different scales from the molecular genetic level to the tissue as a whole. Cancerous cells of solid tumors have undergone mutations all of which combined lead to cancer [1] These involve a dysfunctional control of proliferation, the ability to survive under low nutrient conditions and the stimulation of increased vascularization through angiogenesis [2]. In response to inadequate supply cells produce signaling substances called growth factors which diffuse through the tissue and stimulate sprouting of new blood vessels from preexisting host vessels (angiogenesis). In tumors this angiogenic activity is located within a few hundred micrometers from the tumor rim. As a whole such a typical tumor vasculature is characterized by tortuous vessels, chaotic connectivity and heterogeneous distribution as well as a compartmentalization into a zone with high micro-vascular density (MVD) near the invasive edge and a rapid density drop towards the center
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