Transport Barriers and Oncophysics in Cancer Treatment

Abstract

Transport processes in cancer are the focus of transport oncophysics (TOP). In the TOP approach, the sequential negotiation of transport barriers is critical to both drug delivery and metastasis development. New and creative therapeutic opportunities are currently emerging, stimulated by the study of cancer hallmarks with the TOP approach.

Keywords: biophysical markers; drug partitioning; drug transport; transport barriers; transport oncophysics; transport phenotype.

Figure 1.. Transport Oncophysics Barriers to Drug Delivery and Metastasis.

This figure presents the effect of sequential transport barriers on drug concentration in tumors, and their relationship with cancer hallmarks such as drug resistance, angiogenesis, migration and metastasis, and proliferative signaling (yellow boxes). Transport barriers include the mononuclear phagocyte system (MPS), tumor vasculature, tumor endothelium, tumor extracellular matrix (ECM), and barriers within cancer cells. (A) When drugs enter the systemic circulation, they first encounter the MPS barrier, constituted by phagocytic cells such as macrophages. Because of sequestration by the MPS, drug concentration in circulation is significantly reduced. (B) Once drugs enter the characteristically disorganized tumor vasculature, created through accelerated tumor angiogenesis, diffusion and convection processes constitute an important local tumor transport barrier. (C) When drugs cross the tumor endothelium barrier, they then need to overcome the ECM barrier to reach cancer cells within the tumor microenvironment. There biophysical markers such as collagen Type IV and drug partitioning may severely affect drug micropharmacokinetics and distribution. In the tumor microenvironment, transport barriers not only affect drug distribution and delivery, but also transport of signaling molecules, whose propagation is affected by obstacles and different material properties. Overall, transport barriers severely hinder the capability of drugs to reach tumors in therapeutically significant concentrations, which contributes to drug resistance. From the tumor microenvironment toward systemic circulation, the same transport barriers modulate cancer cell migration and invasion (Box 1). The description of cancer hallmarks through transport barriers may lead to a new functional and mechanistic understanding of cancer development and treatment.