Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications☆
Introduction
Most tumors have unique growth characteristics, particularly rapid growth rate and metastatic potential to the distant sites. To sustain such growth, the solid tumor is equipped with various vascular mediators, which facilitate extravasation of plasma components or vascular permeability (Table 1). Enhanced vascular permeability in solid tumor is considered to supply continuously great nutritional demand as well as oxygen. These factors are also involved in dissemination across vascular vessel, as demonstrated in bacteria [1], [2]. Transfer of tumor cells across vascular wall also appears to be involved in similar factors [e.g., matrix metalloproteinase (MMP), as discussed later]. Among such various vascular permeability mediators, it is interesting that proteinaceous vascular permeability factor (VPF) in solid tumor discovered by Dvorak et al. [3] is later identified to be similar to vascular endothelial growth factor (VEGF) from a completely different line of research on angiogenesis [4], [5]. This indicates that vascular permeability enhancement is playing a role on the other side of the same coin—facilitation of tumor angiogenesis.
The enhanced vascular permeability of solid tumor is important not only in tumor biology, but more critical in targeted delivery of macromolecular anticancer drugs to tumor [6], [7], [8], [9]. Unlike small molecular anticancer drugs used today, which do not discriminate tumor tissue from normal tissue, macromolecular (or polymeric) drugs can target tumor with high selectivity by taking advantage of the enhanced permeability and retention effect (EPR effect) in solid tumors. Namely, almost all tumor tissues exhibit the extravasation of macromolecules. However, because of the suppression of lymphatic function in tumor, clearance of macromolecules from tumor is so impaired that they remain in the tumor for a long time [6], [7], [8], [9]. The EPR effect is now recognized as a general characteristic of solid tumor, thus, regarded as a “gold standard” in new antitumor drug designing [6], [7], [10]. In this article, we will review the various factors involved in vascular permeability of solid tumor, and discuss its importance in tumor biology and macromolecular antitumor drug targeting and delivery.
Section snippets
Tumor targeting with EPR effect and molecular size of drugs
Various vascular mediators and characteristics of vascular pathophysiology, as described in Table 1, make targeted delivery of macromolecular drugs to tumor, and furthermore, their prolonged retention in tumor [6], [7], [8], [9], [10]. To describe this phenomenon, related to the fate of macromolecular drugs and lipids in solid tumor, the term EPR effect was coined [6], [11]. According to the EPR concept, biocompatible macromolecules accumulate at much higher (>6-fold more) concentrations in
What is unique in cancer vessels: angiogenesis, hypervasculature, irregularity and high permeability
It become well known by the work of Folkman et al. that tumor generates angiogenesis-stimulating factor as the tumor size becomes above 2–3 mm. In the clinical setting, one can demonstrate hypervasculature of solid tumors usually as high-density area by angiographic technique with arterial infusion of a contrast agent with a few exceptions, such as pancreatic and prostate cancers. Although some tumor appears to be avascular area under angiography, Suzuki et al. [13] and Hori et al. [14], [15]
Bradykinin and receptor
We have previously reported that tumor cells in culture generate plasminogen activator [18], [19], which ultimately activate prekallikrein and kallikrein and generate bradykinin (BK). Bradykinin, as well as its hydroxylated form 3hydroxypropyl (Hyp) bradykinin, of which third amino acid in BK is replaced by Hyp, exists at high levels in blood plasma, peritoneal and pleural fluids of cancer patients [18], [19], [20]. When the inhibitor of kallikrein (soybean trypsin inhibitors, Kunitz type) or
Nitric oxide in vascular permeability in solid cancer tissues
NO is produced from l-arginine and oxygen by NO synthases (NOS). In case of inflammation and cancer tissues, the inducible form of NOS (iNOS) plays a major role, where large numbers of infiltrated leukocytes are in action. In addition, another isoform of NOS, endothelial from eNOS in tumor, also plays an important role. We have demonstrated that NO dissolved in biocompatible oil (medium chain triglycerides) exhibited extravasation of Evans blue-bound albumin, and NO scavenger
Peroxynitrite and pro-MMP activation
MMPs belong to a group of zinc neutral endopeptidases, and produced by a variety of cells, such as fibroblasts, macrophages at inflammatory tissues, and also in cancer tissues; some of which are released extracellularly as inactive precursors (pro-MMPs) [32], [33]. Activation of pro-MMPs is achieved either by limited proteolysis of the zymogens or by chemical modification on inhibitory domain of pro-MMPs, such as by bacterial proteases (e.g., streptococcal thiolpeptidase), organomercurial
Prostaglandins, PGE1 and PGI2
As known among various inflammatory mediators, BKs, for instance, cross-talk to upregulate prostaglandins (PGs) [22], [49], [50]. As discussed earlier, prostaglandins I2 and E1 behave very similarly to NO not only preventing platelet aggregation, leukocyte adhesion and thrombosis formation, but also facilitating extravasation and EPR effect. Namely, we found recently that stable analogue of PGI2, Beraprost (Dornar®) at 7 g/kg given either intravenously or intra-arterially, resulted in 2- to
VEGF in tumor or normal tissue and organs
As described above, vascular permeability factor was reported initially by Dvorak et al. [3] and Senger et al. [52] as early as 1980s, which was later confirmed to be identical to the VEGF [4], [5]. We have recently quantified VEGF in various tumors and normal tissues in mice as shown in Table 4. The amount of VEGF was far higher in tumor than in most of normal tissues with the exception of the lung (i.e., 2- to 30-fold). Also, we examined the extravasation of Evans blue in guinea-pig skin by
Augmentation of EPR effect and macromolecular tumor delivery under angiotensin II-induced hypertension
In addition to the tumor-preferred advantageous accumulation of macromolecular drugs based on EPR effect, one can enhance this effect by modulating blood pressure. Namely, one of the remarkable difference between normal and tumor tissues is in the vascular response to angiotensin II, which can affect only normal blood vessels, inducing systemic high blood pressure, while blood flow remains constant in normal tissue regardless of the blood pressure applied. The blood flow of tumor tissue will,
Concluding remarks
Cancer and inflammatory tissues have various common vascular mediators, such as NO, BK and PGs, and their most predominant physiological effect is vascular permeability enhancement. These effects are now referred as “enhanced permeability and retention (EPR) effect” in solid tumor, and this extravasation is observed only for macromolecular or polymeric substances as well as lipid formulation (liposomes, micelles). Recovery of these macromolecules extravasated into the interstitial tissues of
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This paper is part of the Proceedings of the 16th International Conference on the Kallikrein-Kinin System (Kinin 2002) which was held in Charleston, SC, May 26–31, 2002 (see International Immunopharmacology Volume 2/13–14).