The journey that led to our recent successes began in earnest a few years after I completed my doctoral studies. Determined to find out why drugs do not penetrate tumors uniformly, my colleagues and I started by monitoring every step of the process in rodents. Using a variety of techniques, we observed the progress of drugs as they entered the tiny blood vessels of a tumor, crossed the vessel walls into the surrounding tissue, entered into cancer cells and eventually exited the mass. Together with my students and collaborators, we developed methods for tracking molecules, such as oxygen, within blood vessels and tissues. Eventually we could even watch as genes turned on and off inside cells.
Early on it was apparent that the vessels within tumors bear little resemblance to normal ones. Healthy tissues are fed by straight vessels that branch predictably into successively smaller capillaries and microvessels, creating a pervasive network for delivering oxygen and nutrients to cells. Tumors, which stimulate the growth of new vasculature of their own, tend to generate a tangle of vessels. These connect to one another randomly, with some oversize branches, many extraneous immature microvessels and areas of a tumor that will lack vessels altogether.
Over the course of many years we managed to delineate the processes that govern the movement of fluids, drugs and cells within this tortuous vasculature and gained insight into the consequences of the abnormalities. The picture that emerged was grim: the very first thing we realized was that tumor blood vessels are not just disorganized in their appearance but highly aberrant in every aspect of their structure and function. We found that blood flows quite briskly in some vessels within a tumor, whereas it is static in others. In a given vessel, blood may travel in one direction for a while and then reverse direction. These flow patterns alone create a major obstacle to uniform drug delivery. Moreover, some parts of the vessel walls are overly leaky and others are unusually which means that drugs and other molecules that managed to penetrate the vasculature would be distributed into the surrounding tumor tissue unevenly.
When we began investigating the causes of this nonuniform porousness, we discovered that in some tumors the pores in blood vessel walls could be as large as one or two microns in diameter, which is more than 100 times the size of pores in healthy vessels. As a result, these vessels are unable to maintain normal pressure gradients across their walls. Fluid pressure inside healthy blood vessels is typically much higher than in the surrounding tissue. Because tumor vessels are so porous, escaping fluid raises the outside—or interstitial—pressure until it nearly equals that inside the blood vessels.
This unnatural pressure gradient is not just an impediment to the ability of drugs to reach tumor cells; the accumulation of interstitial fluid produces swelling in and around tumor tissues. In patients with brain cancers, where tissue expansion is limited by the skull, that swelling becomes a severe, often life-threatening problem in itself. In those with other types of cancer, the exuded fluid can also accumulate in body cavities. Wherever it goes, the fluid oozing from a tumor carries with it tumor cells as well as various tumor-generated proteins that promote the growth of new blood and lymphatic vessels in the surrounding normal tissue and lymph nodes—which can then serve as conduits for the metastatic spread of the cancer cells to other parts of the body.