Trends in Cancer
Volume 3, Issue 9, September 2017, Pages 621-630
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Opinion
Targeting Inflammation to Improve Tumor Drug Delivery

https://doi.org/10.1016/j.trecan.2017.07.006Get rights and content

Trends

Drug delivery to the tumor is often compromised due to vascular hyperpermeability (leakiness) of tumor blood vessels or vessel compression, both of which can lead to inefficient delivery of the cytotoxic drug and therapeutic failure.

Methods of vascular normalization aim to fortify the tumor vessel wall and reduce vessel leakiness, and thus they may improve drug delivery to the tumor, thereby enhancing the efficacy of therapeutic agents.

Vascular normalization is usually achieved with the use of anti-angiogenic agents.

Vessel leakiness can be potentially reversed by NSAIDs and/or inflammation resolution mediators, inducing vessel normalization and improving tumor drug delivery.

Inefficient delivery of drugs is a main cause of chemotherapy failure in hypoperfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness, and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on anti-angiogenic drugs, whereas stress alleviation is based on stroma-depleting agents. We present here an alternative approach to normalize tumor vasculature, taking into account that malignant tumors tend to develop at sites of chronic inflammation. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyperpermeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or inflammation resolution mediators, as an alternative means to increase tumor drug delivery might prove promising.

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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