Trends in Cancer
OpinionTargeting Inflammation to Improve Tumor Drug Delivery
Section snippets
The Tumor Microenvironment and Drug Delivery
Tumors are complex tissues consisting of cancer cells and their microenvironment 1, 2, which includes structural and cellular components. Structural components of the tumor microenvironment comprise tumor blood and lymphatic vessels, and the extracellular matrix (ECM; see Glossary), while the stromal cell constituents [3] include angiogenic vascular cells (endothelial cells and pericytes), infiltrating immune cells, and cancer-associated fibroblasts (CAFs). Naturally, interactions between
Causes of Insufficient Drug Delivery to Tumors
Inefficient drug delivery may arise due to barriers posed by the abnormal structure and function of tumor stroma, known as desmoplasia. Desmoplastic tumors are characterized by a dense ECM that contains increased levels of total fibrillar collagen, hyaluronan, fibronectin, proteoglycans, and tenascin C [4], and which also provides the tumor with a reservoir of growth factors promoting its growth. The dense fiber composition of these tumors together with the abundance of stromal cells generate
Strategies to Improve Drug Delivery
Two approaches that have been proposed to bypass the causes of inefficient drug delivery are (i) stress-alleviation strategies targeting the ECM or CAFs, and (ii) vascular normalization strategies targeting the tumor vasculature (Figure 1, Key Figure). Stress alleviation strategies are based on the concept that desmoplasia hinders proper drug delivery by compressing intratumoral blood vessels, and thus agents that relieve the stress accumulated by ECM components will facilitate vessel
Cancer Development at Sites of Inflammation
It has been noted that malignant tumors often develop at sites of chronic injury, infection, or inflammation [29]. In fact, although the first connection between inflammation and cancer was made as early as 1983, the concept is still (but progressively) gaining ground [30]. It has become evident that many malignancies originate in areas of infection and inflammation as a result of a normal host response [31] which induces chronic inflammation. Immune cells generate reactive oxygen species (ROS)
Can Targeting Inflammation Improve Tumor Drug Delivery?
It has long been known that a hallmark of inflammation is increased vascular permeability, which leads not only to extravasation of inflammatory and immune cells by a so far unknown mechanism [38] but also to the escape of protein-rich fluid into the extravascular tissue. This in turn results in increased IFP which ultimately causes fluid accumulation in the tumor interstitial space. The increased accumulation of extravascular fluid is known as edema and is one of the main characteristics of
Concluding Remarks
In this article we discuss a different approach to improve drug delivery to solid tumors, taking into account the fact that malignant tumors tend to develop at sites of chronic injury, infection, or inflammation 29, 32. In fact, similarly to the vessel leakiness observed in tumors, inflammation is also characterized by vascular hyperpermeability which leads to edema. However, the key difference between the two conditions is that acute inflammation (and hence vessel leakiness) is self-limiting,
Acknowledgments
We thank Professor Rakesh K. Jain and Dr John D. Martin for insightful comments on the manuscript. This work has received funding from the European Research Council (ERC) under the European Commission 7th Framework Programme (FP7/2007–2013)/ERC Grant Agreement 336839 ReEngineeringCancer.
Glossary
- Cancer-associated fibroblast (CAF)
- a stromal cell population highly enriched in the tumor microenvironment that is implicated in cancer cell invasion and fibrosis.
- Cyclooxygenase (COX)
- an enzyme responsible for the formation of prostanoids such as prostaglandin, inhibition of which can provide relief from pain and inflammation. There are two types of COX enzymes, COX-1 and COX-2, both of which produce prostaglandins. However, COX-1 enzymes produce baseline levels of prostaglandins that activate
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